Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)=[O:4].[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[CH:6]4[CH2:7][CH:5]4[C:3](=[O:4])[N:2]([CH3:1])[C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[CH:14][CH:15]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)N(C)[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CC4C(=O)N(C)[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid methyl-((R)-1-phenyl-ethyl)-amide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[N:34]3[CH:35]=[N:36][CH:37]=[C:33]3[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)#[N:22].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[ClH:46]>O1CCCC1>[ClH:46].[CH2:38]([C:29]1([C:26]2[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][CH:27]=2)[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[CH2:32][CH2:31][CH2:30]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(C2CCCc3cncn32)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(Cc3ccccc3)CCCc3cncn32)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.80 mmoles of lithium diisopropylamide, prepared from 0.12 ml of diisopropylamine and 0.32 ml of 2.5M n-butyllithium in 6 ml of tetrahydrofuran at 0°, is slowly added to a solution of 0.17 g of 5-(4-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 2 ml of tetrahydrofuran at -78°. After 0.5 h, 0.1 ml of benzyl bromide is added dropwise. The reaction mixture is stirred for an additional 1 h, quenched with 5 ml of water, made acidic with 1N hydrochloric acid, diluted with 20 ml of ether and the layers are separated. The aqueous phase is adjusted to pH=7, extracted with ethyl acetate (3×15 ml) and the organic extracts are dried over sodium sulfate. Filtration and evaporation produces a foam which is treated with one molar equivalent of ethereal hydrogen chloride to yield 5-benzyl-5-(4-cyanophenyl)-5,6,7,8-tetrahydoimidazo[1,5-a]pyridine hydrochloride, m.p. 249°-251°.
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)(O)[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:10][CH:9]=1)=O)(C)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl>C(#N)C>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)=[CH:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:10][CH:9]=1)#[N:5]
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCc2c[nH]cn2)c2ccc(C(F)(F)F)cc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(C(=CCc2c[nH]cn2)c2ccc(C(F)(F)F)cc2)cc1
Yield: 97 %

Procedure:
4-[3-(4-tert-butylaminocarbonylphenyl)-3-(4-trifluoromethylphenyl)-3-hydroxypropyl]-1H-imidazole is refluxed with PCl5 (1,2 eqv) in dry acetonitrile to give the product. Yield 97%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH2:19]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (46 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.16 mmol) to afford the desired product (32 mg, 61%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.28 (s, 1H), 7.94 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.47-7.43 (m, 1H), 7.35 (dd, J=11.9, 2.4 Hz, 1H), 4.15-4.07 (m, 1H), 3.23-3.15 (m, 4H), 2.92 (d, J=6.8 Hz, 2H), 2.87-2.78 (m, 1H), 2.30 (d, J=12.7 Hz, 2H), 2.06-1.97 (m, 6H), 1.87-1.78 (m, 1H), 1.56 (q, J=12.4 Hz, 2H), 1.30-1.14 (m, 4H), 1.13-1.05 (m, 2H). ESI MS m/z 522 [C30H33ClFN3O2+H]+; HPLC>99% (AUC), tR=11.04 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>>[CH3:22][N:23]([CH3:25])/[CH:24]=[C:12]1\[C:11](=[O:16])[CH:10]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:15][CH2:14][CH2:13]\1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1cc(F)c(F)c(F)c1
Product: CN(C)/C=C1/CCCC(c2cc(F)c(F)c(F)c2)C1=O

Procedure:
2-(3,4,5-Trifluoro-phenyl)-cyclohexanone (100 mg, 0.44 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (123 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 284.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(OCC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ncc(CO)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (20.0 g, 86 mmol) in dichloromethane (400 mL) at −78° C. was added diisobutylaluminum hydride, 1.0 M in toluene (172 mL, 172 mmol). The reaction was allowed to warm to 0° C. over 2 h. To the reaction was added a 20% Rochelle's (1600 mL) and diethyl ether (750 mL). The emulsion was stirred for 30 min. The organics were sequestered and the aqueous was extracted further with diethyl ether (2×500 mL). The combined organics were washed with water (500 mL), brine (500 mL), dried over MgSO4, and concentrated in vacuo and filtered through a plug of silica eluting with 1:1; ethyl acetate:CH2Cl2 to obtain compound 223 (9.6 g, 59% yield). 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1 H) 4.75 (d, J=5.87 Hz, 2 H) 2.58 (s, 3 H) 2.06-2.25 (m, J=5.14 Hz, 1H) ppm.
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][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: CS(=O)(=O)OCc1ccccn1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccccn4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([C:27]5[N:28]([C:32]6[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=6[F:39])[N:29]=[CH:30][N:31]=5)[S:20][C:19]=4[C:18]=3[N:40]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(C)=O)C.[ClH:47]>CCOC(C)=O>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[N:28]1[C:27]([C:21]2[S:20][C:19]3[C:18]4[N:40]=[C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:15]=[CH:16][C:17]=4[O:26][CH2:25][CH2:24][C:23]=3[CH:22]=2)=[N:31][CH:30]=[N:29]1.[ClH:47]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CCNCC4)ccc2OCC3)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.61 g, 1.08 mmol) was dissolved in EtOAc, and EtOAc—HCl was added dropwise into the solution. And them the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered to gather the solid. The resulting solid was washed by DCM (10 mL) to give 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene as HCl salt (420 mg, yield: 77%). 1HNMR (D2O, 400 MHz): δ8.05 (s, 1H), 7.45-7.39 (m, 1H), 7.23 (t, J=8.8 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 7.01 (s, 1H), 6.99 (d, J=1.6 Hz, 1H), 6.99 (d, J=4.8 Hz, 1H), 3.97 (s, 1H), 3.39 (s, 4H), 3.19 (s, 4H), 2.83 (s, 2H) ESI-MS: m/z=503 [M+H+]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][Al](C)C.C1(C)C=CC=CC=1.Cl>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Commercially available 3-bromobenzaldehyde (5.0 g, 27 mmol) was dissolved in anhydrous dichloromethane (200 mL) under a dry nitrogen atmosphere and cooled in a dry ice/acetone bath to −78° C. Trimethyl aluminum 2M solution in toluene (16.2 mL, 32 mmol) was added dropwise. After 0.5 h the reaction mixture was allowed to warm to room temperature during which time the cloudiness of the reaction resolved to a clear yellow solution which then proceeded to a colorless solution. After stirring for 1 h at room temperature the reaction mixture was cooled in an ice bath and 1N HCl (100 mL) was added dropwise. The reaction mixture was transferred to a separatory funnel and the organic layer was isolated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 1:1 Ethyl acetate/hexane to provide 5.4 g (99%) of A4.1a as a colorless oil. LCMS (M+H−OH)+=183, 185
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]3)=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:37]=[N:36][C:35]([N:38]6[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(N3CC[C@@H](O)C3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CC[C@@H](O)C5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and (R)-1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-pyrrolidin-3-ol (stage 212.1.1) to give the title compound as a white solid. (HPLC: tR 2.03 min (Method A); M+H=456 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.25-8.22 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.57-7.53 (m, 1H), 7.43-7.41 (m, 1H), 6.55-6.51 (m, 1H), 4.95 (d, 1H), 4.42-4.36 (m, 1H), 3.92 (s, 3H), 3.56 (s, 3H), 3.54-3.43 (m, 3H), 3.37-3.31 (m, 1H), 2.08-1.86 (m, 2H), 1.96 (s, 3H))
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[Si:49]([O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50].N(C(N(C)C)=O)=NC(N(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:52]([Si:49]([CH3:51])([CH3:50])[O:56][C:57]1[CH:62]=[CH:61][C:60]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:59][CH:58]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of Compound 2 (2.8 g, 5.8 mmol) in toluene (10 ml), a solution of tributylphosphine (1.17 g, 5.8 mmol) in toluene (2 ml) was added at room temperature; this was followed by stirring for 1 hour. This was gradually added to a solution of Compound 18 (1.1 g, 4.9 mmol) and 1,1′-azobis(N,N-dimethylformamide) (1.0 g, 5.8 mmol) in toluene (10 ml), and this was followed by overnight stirring at room temperature. Ethyl acetate was added; the resulting insoluble matter was removed by Celite filtration, and washing was conducted with ethyl acetate. The combined organic phases were concentrated under reduced pressure; the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1)) to yield Compound 21 (colorless oil 2.03 g, 60%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)=[CH:27][CH:26]=2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:14]=1.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([NH:45][OH:46])=[O:35])=[CH:29][CH:30]=2)[CH:12]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH:14]=1
Reactant: CN1CCN(c2cc(Cl)cc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Reactant: On1nnc2ccccc21
Agent: NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Cl)cc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
(E)-3-(4-{(E)-3-[3-Chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid trifluoroacetate (40 mg, 0.076 mmol) was suspended in THF (5 ml). HOBT (16 mg, 0.116 mmol), EDC (22.3 mg, 0.116 mmol), TEA (0.04 ml, 0.291 mmol) and NH2OTHP (12 mg, 0.097 mmol) were added to the resulting mixture. The reaction was stirred at room temperature overnight and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4, evaporated in vacuo and the crude product was purified by column chromatography (eluent: AcOEt/MeOH 9:1). The collected fractions were evaporated and the resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered and purified by preparative LC-MS to give 20 mg of (E)-3-(4-{(E)-3-[3-Chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide as its trifluoroacetate salt.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:30]2=[O:32])[CH2:17][CH2:18]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(O)c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)OC(c3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol from Step 2 above (1.8 g, 4.7 mmol) was stirred in dry THF in an ice bath under nitrogen, and triphosgene (0.47 g, 1.57 mmol) was added followed by triethylamine (1.96 mL, 1.42 g, 14.1 mmol). The ice bath was removed and the mixture was stirred at ambient temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with 1N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 1-(1-Boc-4-piperidyl)-4-phenyl-3,1-benzoxazin-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]Br>C(OCC)C>[Br:11][C:5]1[O:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: COC(=O)c1occc1C
Reactant: BrBr
Solvent: CCOCC
Product: COC(=O)c1oc(Br)cc1C
Reaction time: 14 h
Yield: 85.3 %

Procedure:
To a solution of methyl 3-methylfuran-2-carboxylate (3.0 g, 21.41 mmol) in ethyl ether (100 mL) was added bromine (1.210 mL, 23.55 mmol) dropwise at RT and the mixture was allowed to stir for 14 h. Evaporation followed by purification by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) yielded the title compound (4.0 g, 85% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 6.31 (s, 1H), 3.88 (s, 3H), 2.33 (s, 3H); HPLC retention time: 2.776 min, LCMS (ES): m/z 219, 221 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:10]1([CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: BrCc1ccncc1
Reactant: c1c[nH]cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(Cn2ccnc2)ccn1

Procedure:
Synthesized from 4-(bromomethyl)pyridine hydrobromide (500 mg, 1.97 mmol), imidazole (538 mg, 7.90 mmol) and K2CO3 (1.36 g, 9.85 mmol) in DMF according to Method B. Yield: 212 mg, 1.35 mmol, 68%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.16 (s, 2H), 6.91 (s, 1H), 7.01 (d, J=6.3 Hz, 2H), 7.14 (s, 1H), 7.69 (s, 1H), 8.57 (d, J=6.3 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=49.4, 119.3, 121.4, 130.3, 147.6, 145.2, 150.4; MS (ESI): m/z=160.08 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[C:18]([O:29][CH3:30])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:32][CH2:33]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[C:18]([O:29][CH3:30])[CH:17]=4)[CH2:33][CH2:32][N:11]3[CH:12]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC(C)(C)O
Reactant: BrCCBr
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCCC(C)(C)O

Procedure:
Following the procedure described in Example 1 step D, the product of step B (120 mg) was alkylated with 1,2-dibromoethane to yield 15 mg of the title compound. MS (ESI) 455 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[N:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[N:9]=[CH:10][N:11]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]cnc2c1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1ncc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Reaction time: 3 h
Yield: 66.3 %

Procedure:
78.8 g of 5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one [CAS No. 76756-58-6] (Shih-Fong Chen and Raymond P. Panzica, Journal of Organic Chemistry 46, p 2467, 1981) was suspended in 2.5 L of dichloromethane at room temperature, and 78.8 of triethylamine was added thereto. 176 g of trityl chloride was added to the mixture, which was then stirred for three hours. 7.5 L of ethyl acetate was added to the mixture. After being washed successively with 3 L of water and 3 L of a saturated sodium chloride solution, the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 136.5 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (20:80 to 0:100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].[Na].Br[CH:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:23]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12](=[O:14])[CH3:13])([CH:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(Br)c1cccc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Acetylaminopropanedioic acid diethyl ester (20.8 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (2.2 g) and ethanol (100 ml). After the mixture was stirred for 10 minutes at ambient temperature, 1-(1-bromoethyl)naphthalene was added. The reaction mixture was stirred for 18 hours at room temperature. The precipitated solid was collected by filtration and dissolved in chloroform. The chloroform solution was dried over magnesium sulfate and evaporated to give 2-acetylamino-2-[1-(1-naphthyl)ethyl]propanedioic acid diethyl ester (21.59 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:19])=[O:20]
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a stirred solution of piperazine-2-one (353.3 mg, 3.5 mmol) and naphthalene-2-sulfonyl chloride (800 mg, 3.5 mmol) in anhydrous dichloromethane (15 mL) was added diisopropylethylamine (1.54 mL, 8.8 mmol). The mixture was stirred for 30 min. Reaction was complete as determined by TLC. The reaction mixture was filtered, washed with hexane to give a first batch. The mother liquor washed with saturated ammonium chloride, then washed with saturated brine, separated, dried over sodium sulphate. Then hexane was added, lots of precipitate formed. The was filtered, washed with hexane to give a second batch. The two batches were combined to yield 4-(naphthalene-2-sulfonyl)-piperazin-2-one in 92.5% yield (947 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.35-3.40 (m, 2H) 3.42-3.48 (m, 2H) 3.79 (s, 2H) 6.11 (s, 1H) 7.63-7.73 (m, 2H) 7.77 (dd, J=8.72, 1.89 Hz, 1 H) 7.94 (d, J=7.83 Hz, 1H) 7.98-8.05 (m, 2H) 8.38 (s, 1H).