Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][CH:3]([OH:9])[CH2:4]2
Reactant: O=C1CC2CCC(C1)O2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC1CC2CCC(C1)O2
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 71 mg of 8-oxabicyclo[3.2.1]octan-3-one (which was prepared by the method as described in Bull. Chem. Soc. Jpn., 1978, 51, 2745-2746) in tetrahydrofuran (2 ml), 32 mg of lithium aluminium hydride was added in nitrogen atmosphere at 0° C., and stirred for 30 minutes at the same temperature. To the solution 300 mg of sodium sulfate decahydrate was added, followed by 15 hours' stirring at room temperature. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 72 mg of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([CH3:35])[C@@H:22]([CH3:34])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:16][C:15]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[N:48]=[CH:49][NH:50][CH:51]=1)([O-:46])=[O:45]>>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH2:23][C@H:22]([CH3:34])[C@H:21]([CH3:35])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:50]3[CH:51]=[C:47]([N+:44]([O-:46])=[O:45])[N:48]=[CH:49]3)=[C:15]([O:36][CH3:37])[CH:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCOCCOCCOCCBr)c(OC)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCOCCOCCOCCn3cnc([N+](=O)[O-])c3)c(OC)c2)cc1OC
Yield: 57.3 %

Procedure:
The Standard Procedure 2 was followed by use of 9b (146.6 mg, 0.2512 mmol, 1.0 equiv), potassium carbonate (74.4 mg, 0.538 mmol, 2.1 equiv), and 4-nitroimidazole (6a, 56.3 mg, 0.498 mmol, 2.0 equiv). After workup and purification with column chromatography (100% EtOAc as eluant), 10c (88.4 mg, 0.144 mmol) was obtained in 57% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, J=6.4 Hz, 3H, CH3), 0.82 (d, J=6.4 Hz, 3H, CH3), 1.73 (m, 2H, 2×CH), 2.23-2.31 (m, 2H, 2×ArCH), 2.70-2.75 (m, 2H, 2×ArCH), 3.62-3.86 (m, 21H, 3×OCH3+6×OCH2), 4.09-4.14 (m, 4H, CH2N+CH2O), 6.62-6.68 (m, 4H, 4×ArH), 6.76-6.80 (m, 2H, 2×ArH), 7.47 (s, 1H, nitroimidazole C5-H), 7.88 (s, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 16.12, 16.18, 38.74, 38.84, 39.12, 39.21, 48.24, 55.76, 55.78, 55.85, 68.60, 69.49, 69.69, 70.54 70.57, 70.65, 110.97, 112.21, 112.81, 113.66, 120.17, 120.89, 121.04, 134.41, 135.24, 136.48, 146.18, 146.98, 147.95, 148.63, 149.22; IR (neat) 2924 (s), 2854 (s), 1634 (w), 1589 (w), 1515 (s), 1456 (m), 1417 (m), 1334 (s), 1260 (s), 1028 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3232.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:21](I)[CH3:22]>CN(C=O)C>[CH2:21]([N:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:3]=[O:4])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)[C:18](=[O:20])[CH3:19])[CH3:22]
Reactant: CCI
Reactant: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)C1CCN(c2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 63.8 %

Procedure:
A 60% suspension in oil of NaH (0.113 g, 2.8 mmol) was added to a 0° C. solution of N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.700 g, 2.8 mmol) in DMF (10 mL) and stirred for 35 minutes. To this mixture was added EtI (0.23 mL, 2.8 mmol) and the reaction was warmed to room temperature for 2 hours, quenched with H2O, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 5% MeOH/CH2Cl2, afforded N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.490 g, 64%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:21]I>CN(C=O)C>[I:21][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[O:14][C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[N:12][N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: CC(C)Nc1nnc(-c2ccc3[nH]ccc3c2)o1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(I)c3c2)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a solution of 5-(1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (150 mg, 0.6148 mmol) in DMF (1.5 mL) was added 1.2M aq. KOH (1.5 mL) and the reaction was stirred at 0° C. for 5 min. I2 (234 mg, 0.9297 mmol) was added and the mixture was stirred for additional 1 h. The reaction was quenched with H2O (10 mL) to get a pink precipitate. The precipitate was filtered, washed with H2O (6 mL) and dried. The crude product was purified with silica-gel column chromatography (eluent: 50% EtOAc in petroleum ether) to give 5-(3-iodo-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (140 mg, 61%) as a pink solid. MS (ESI, pos. ion) m/z: 369.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.85 (brs, 1H), 7.68 (m, 2H), 7.65 (m, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 3.70-3.75 (m, 1H), 1.20 (d, J=6.4 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[C@H:17]([CH3:18])[CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][C@@H:13]3[CH3:23])=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:23][C@@H:13]1[CH2:14][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:16][C@H:17]([CH3:18])[N:12]1[CH2:11][C:9]1[S:10][C:5]2[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)=[N:7][C:6]=2[C:8]=1[CH3:24]
Reactant: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 58.6 %

Procedure:
2-Chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (135 mg, 0.29 mmol) was reacted with 2-amino-pyrimidine-5-boronic acid pinacol ester (88 mg, 0.4 mmol) in General Procedure A. After extraction into 2M HCl, the mixture was washed with ethyl acetate then made basic and the precipitate collected by filtration. Purification using a thiourea SPE cartridge gave 420 as a cream solid (90 mg, 0.17 mmol) NMR (CDCl3, 400 MHz), 9.25 (s, 2H); 5.12 (s, 2H); 3.95 (t, 4H, J=4.6 Hz); 3.95 (s, 2H); 3.82 (t, 4H, J=4.8 Hz); 3.51 (d, 2H, J=11.3 Hz); 2.82 (m, 2H); 2.74 (s, 3H); 2.55 (t, 2H, J=10.8 Hz); 2.33 (s, 3H); 1.06 (d, 6H, J=6.3 Hz) MS: (ESI+): MH+=533.30
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)=[O:3].C(=O)([O-])O.[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>O.O1CCOCC1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=1)[CH:8]=2)=[O:3]
Reactant: NC(=O)Nc1[nH]c2cc(Br)ccc2c1C(N)=O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)Nc1[nH]c2cc(-c3ccc(F)cc3)ccc2c1C(N)=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
A solution mixture of 2-aminocarbonylamino-6-bromoindole-3-carboxamide (Compound 3-1, 80 mg, 0.27 mmol), sodium hydrogen carbonate (57 mg, 0.68 mmol), 4-fluorophenylboronic acid (57 mg, 0.41 mmol) and tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol) in water and 1,4-dioxane (water/1,4-dioxane=1/3, 15 mL) was stirred at 100° C. for 1.5 hours. Brine (5 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered throught Celite® pad. After the solvent was evaporated under reduced pressure, the resultant solid was washed with a solution mixture of methanol and diethyl ether (methanol/diethyl ether=1/10, 2 mL), and dried under reduced pressure to give the title compound (42 mg) as slightly brown solid (yield 51%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.[ClH:30].CCOCC.C(OCC)C>CO.Cl>[ClH:30].[F:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(F)ccc1F)c1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(F)c(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
The general procedure described in Example 4-A was followed using 2,5-difluoro-benzylamine as the amine in the preparation of the first intermediate and DMAP (1 equiv.) to give the BOC-protected compound. The protecting group was removed by dissolving (2,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester (99.6 mg, 0.24 mmol) in methanol (1 mL) and treating it with 1.0M HCl/Ether (3.68 mL, 3.68 mmol) and stirring the reaction mixture overnight at ambient temperature. Additional 1.0M HCl/ether (2 mL) was added to the reaction mixture and stirring continued overnight at room temperature. The reaction was still not complete, therefore conc. HCl (2 drops) was added and the resulting mixture stirred at ambient temperature overnight. Diethyl ether (20 mL) was added to the reaction mixture and stirring continued for 1 h. The solids were filtered from the reaction mixture, washed with Ether, and dried under high vacuum to give the title compound 4-P (64 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[C:8]([CH3:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[C:8]([CH3:22])[CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3C)nc2c1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3C)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (200 mg) and piperidine (2.0 mL) were heated at 100° C. for 2.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined, washed with brine, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (110 mg). 1H-NMR (CD3OD) δ 8.28 (d, J=7.0 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 4.04 (t, J=6.0 Hz, 2H), 2.50 (m, 12H), 1.99 (m, 2H), 1.64 (m, 4H), 1.51 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[N:15]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=O>C(O)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5](=[O:13])[C:6]2[CH:7]=[C:8]([N:12]=[N:15][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH:9]=[CH:10][C:11]1=2
Reactant: CCOC(=O)c1ccc(N=O)cc1
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 198.7 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-amino-1-(2H)-naphthalenone (Compound Z) in 5.0 ml glacial acetic acid was added 180.0 mg (1.00 mmol) of ethyl 4-nitrosobenzoate. The resulting solution was stirred overnight at room temperature, and then concentrated under reduced pressure. The product was isolated from the residual oil as a red solid, by column chromatography (15% EtOAc--hexanes). 1H NMR (CDCl3): δ 8.57 (1H, d, J=2.0 Hz), 8.19 (2H, d, J=8.4 Hz), 8.07 (1H, d, J=8.0 Hz), 7.94 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=8.6 Hz), 4.41 (2H, q, J=7.1 Hz), 2.79 (2H, t, J=6.6 Hz), 2.07 (2H, t, J=7.02 Hz), 1.44 (6H, s), 1.42 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:30]=[CH:29][C:16]2[CH2:17][CH2:18][N:19]([C:22](OC(C)(C)C)=O)[CH2:20][CH2:21][C:15]=2[CH:14]=1.[C:31]1(=O)[CH2:34]C[CH2:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:30]=[CH:29][C:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:34][CH2:31][CH2:32]3)[CH2:20][CH2:21][C:15]=2[CH:14]=1)[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(Cl)c1
Reactant: O=C1CCC1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(Cl)c1

Procedure:
The title compound was prepared from 3-chloro-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E267, Step 4) and cyclobutanone using the method outlined in Example 264 Step 7 (36 mg, 57%) MS (ES+), m/e 385 & 387 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:7]=[N:8][CH:9]=1)=[O:4].[Li+].[OH-]>C(O)C>[CH:10]1([N:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=[CH:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)c1cncn1C1CCCc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cncn1C1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester, which can be prepared as described in Example 2, (0.510 g, 1.990 mmol) in ethanol (20 mL) is added aqueous 4M LiOH (5 mL, 20 mmol) causing an immediate precipitate to form. After 3 hours, the mixture is evaporated to dryness, re-dissolved in a minimum amount of water, and the pH is adjusted to 6 with aqueous 2M HCl, causing a precipitate to form. The reaction is cooled to 0° C. and allowed to stand for 30 minutes. The precipitate is then filtered off and washed with cold phosphate buffer (pH 6). Upon standing, a solid precipitates out of the phosphate buffer which is filtered and combined with the initial precipitate to yield, upon drying under high vacuum, 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid; MS: (ESI) m/z 243.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.77-1.96 (m, 2 H), 2.21-2.36 (m, 2 H), 2.87-2.95 (m, 1 H), 3.05 (dt, J=16.9, 5.8 Hz, 1 H), 6.57 (t, J=5.6 Hz, 1 H), 7.01 (d, J=7.8 Hz, 1 H), 7.18-7.26 (m, 1 H), 7.26-7.36 (m, 2 H), 7.55 (s, 1 H), 7.79 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][CH:16]([C:19](OCC)=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[NH:3]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH:16]([CH:19]=[O:20])[CH2:17][CH2:18]3)[CH2:11][CH2:12]2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[NH:3]1
Reactant: CCOC(=O)C1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: -90 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a stirred solution of the cis and trans isomers of ethyl 1-[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]cyclohexane-4-carboxylate (2.16 g) in dry toluene (150 mL) at -90° C. under argon, was added diisobutylaluminum hydride (11.6 mL of a 1.5M solution in toluene). The reaction mixture was stirred at -90° C. for 1 h, then quenched with methanol (1 mL) followed by saturated sodium potassium tartrate (50 mL). The layers were separated, the aqueous layer was extracted with 2×100 mL of ethyl acetate, and the combined organic layers were dried over MgSO4 and concentrated to dryness under reduced pressure to give the cis and trans isomers of 1-[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]cyclohexane-4-carboxaldehyde as a colorless foam (1.82 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:14]([S:16](Cl)(=[O:18])=[O:17])[CH3:15].CC1C(C(N2CCNCC2)=O)=C(C)ON=1>>[CH2:14]([S:16]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:18])=[O:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCS(=O)(=O)Cl
Agent: Cc1noc(C)c1C(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCNCC1

Procedure:
Ethanesulfonyl-piperazine was prepared from 1-tert-butyloxycarbonyl-piperazine and ethylsulfonyl chloride in an analogous manner as described for the preparation of (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone in example 41.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1[CH:29]=[CH:28]C=CC=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:23][CH:29]1[CH2:28][O:23][CH2:12][CH2:13][O:14]1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccncc1
Reactant: CCOC(=O)C(O)(CCCNC(=O)OC(C)(C)C)C(=O)OCC
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)(OC1COCCO1)C(=O)OCC
Reaction time: 5 h

Procedure:
20 Mg of pTS acid are added to a solution of 1.6 g of ethyl 5-tert-butoxycarbonylamino-2-hydroxy-2-ethoxycarbonyl-pentanoate in 12 ml of 1,4-diox-2-ene. After 5 h. at r.t., 0.3 ml of pyridine are added, the excess reagent is distilled under vacuum and the residue is chromatographed on silica gel, to give 1.75 g of ethyl 5-tert-butoxycarbonylamino-2-(1,4-dioxan-2-yl-oxy)-2-ethoxycarbonyl-pentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:32])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[Ni].C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CCN(Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCN(Cc2ccc(CCC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
A reaction mixture of 80 mg (0.18 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-[4-(4-methylpiperidin-1-ylmethyl)phenyl]acrylamide and 20 mg of Raney nickel in 15 mL of ethyl acetate and 15 mL of methanol is hydrogenated for 1 hour at 50 psi and ambient temperature. The catalyst is filtered off, the filtrate is evaporated to dryness and stirred with diisopropylether. Yield: 40 mg (49.7% of theory); melting point: 150° C.-151° C.; C28H31ClN2O (M=447.02); calc.: molecular ion peak (M+H)+: 447/449; found: molecular ion peak (M+H)+: 447/449; Rf value: 0.5 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36]N)=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1>>[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to example 43 gave the desired product. MS: M=456.9 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:4][N:3]=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([Cl:16])=[O:15])[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2N)n1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: Cc1noc(-c2ccccc2NC(=O)Cl)n1
Reaction time: 4 h

Procedure:
A solution of 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzenamine (1.0 g) in dry dichloromethane (20 ml) was added dropwise to a 0° solution of phosgene (14.1 ml, 20% in toluene) in dry dichloromethane (50 ml) under a nitrogen atmosphere. After addition the reaction mixture was allowed to slowly attain room temperature and stirred for 4 h. Nitrogen, was bubbled through the resulting mixture for 16 h. Dichloromethane was added to the resultant precipitate and the solution was evaporated to give the title compound (1.322 g), max (Nujol) 2800-2500, 1782 (NCO-Cl), 1631 (C=N), 1501 (NH), 769 (aromatic) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])C2C=CC=CC=2Cl)[CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20].CC(C)([O-:24])C.[K+].O>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20])[C:8]([OH:16])=[O:24]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1cc(C(=O)O)cc(Br)c1OC
Reaction time: 6 h
Yield: 73.5 %

Procedure:
At ambient temperature, to a stirred mixture containing 2-bromo-4-(2-chlorobenzoyl)-6-ethylanisole (10.0 g, 28.2 mmol) and potassium t-butoxide (31.7 g, 0.283 mol) in ethylene glycol dimethyl ether (157 mL) was added H2O (1.52 mL). After 6 h, the reaction solids were collected by filtration and washed with ether (2×). The crude product was dissolved in H2O (200 mL), acidified with 2N HCl (pH <2) and stirred for 7 h. The precipitate was collected by filtration, washed with H2O (2×) and dried to give 5.37 g (73%) of the title compound. 1H NMR: consistent. mass spectrum (EI) m/z 258 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (300.0 mg, 0.8 mmol, 1.0 equiv) and 1-methylpiperazine (1.12 mL, 10.1 mmol, 12 equiv) in methylpyrrolidone (9.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (15.0 mL) and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide (95.6 mg, 0.20 mmol) as yellow solids in 27% yield: 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=5.1 Hz, 1 H), 7.12 (s, 1 H), 6.83-6.86 (m, 3 H), 6.78 (s, 1 H), 3.63-3.65 (m, 4 H), 2.35 (s, 3 H), 2.27 (s, 3 H), 2.04 (s, 6 H); ESI-MS: m/z 422.1 (M+H)+.