Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1)[CH3:2].[CH2:34](C([Sn])=C(CCCC)CCCC)[CH2:35]CC.[Cl-].[Li+].[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH:34]=[CH2:35])[CH:4]=1)[CH3:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CCc1cc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1cc(CC)c(Cc2ccc(-c3ccn(C)n3)cc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A mixture of methyl 4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.32 g), tributylvinyltin (0.32 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g), lithium chloride (0.21 g) and DMF (6.00 mL) was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration. The filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.21 g). This compound was used in the next step without an additional purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:13](=[O:24])[C:14]([C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)([CH3:16])[CH3:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:11][C@@H:10]([N:12]2[C:22]3=[N:21][CH:20]=[CH:19][N:18]=[C:17]3[C:14]([CH3:16])([CH3:15])[C:13]2=[O:24])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](NC(=O)C(C)(C)c2nccnc2Cl)C1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2C(=O)C(C)(C)c3nccnc32)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a glass microwave reaction vessel was added tert-butyl(cis-3-(2-(3-chloropyrazin-2-yl)-2-methylpropanamido)cyclobutyl)carbamate (0.8210 g, 2.226 mmol), RuPhos Precatalyst (0.097 g, 0.134 mmol, Strem Chemicals), and sodium tert-butoxide (0.428 g, 4.45 mmol, Sigma-Aldrich Chemical Company, Inc.) in dry dioxane (2.226 ml) to stir at 80° C. for 24 h. The solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 40% to 100% EtOAc in hexane, to provide the title compound (0.1812 g, 0.545 mmol, 24.49% yield). LCMS showed product peak at 2.060 min (m+1=333.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 3 H) 1.39 (s, 5 H) 2.52-2.58 (m, 1 H) 2.80 (qd, J=9.16, 2.64 Hz, 1 H) 3.68-3.83 (m, 1 H) 4.34-4.47 (m, 1 H) 7.21 (d, J=6.85 Hz, 1 H) 8.13-8.18 (m, 1 H)
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[NH:12]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:13][C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([CH2:27]Br)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15]>>[NH:12]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH2:13][C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([CH2:27][O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])=[O:26])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Agent: [F-]
Agent: [K+]
Product: CC(C)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)COC(=O)c1ccccc1

Procedure:
Benzoic acid (1.19 g, 9.78 mmol), KF (0.568 g, 9.78 mmol), 16 (2.35 g, 4.89 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:15]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccccc1F
Yield: 10 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 16.0 g (0.1 mole) 2-fluorobenzoyl chloride in 250 ml xylene was heated at reflux for 20 hours. After filtration of the reaction mixture, the filtrate was concentrated to 30 ml whereupon a precipitation resulted. The precipitate was removed by filtration and recrystallized from benzene to give 3.4 g (10% yield) of pure product; m.p. 149° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.II.P(O)(O)O>C(O)(=O)C>[CH:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=2)=[CH:12][CH:11]=1
Reactant: OC(c1ccccc1)c1ccc(Br)cc1
Agent: II
Agent: OP(O)O
Solvent: CC(=O)O
Product: Brc1ccc(Cc2ccccc2)cc1
Temperature: 80 °C
Yield: 61 %

Procedure:
4-Bromodiphenylmethane was prepared as shown in Scheme 3. 4-Bromobenzhydrol in a 3-neck flask equipped with a reflux condenser and a thermometer was mixed with 500 ml of acetic acid, 113 g (445 mmol) of iodine and 226 ml, 50 wt. % of phosphorous acid (2.2 mol). The reaction mixture was heated at 80° C. for 24 hours and then cooled. 700 ml of ice-water was added to the reaction mixture and the reaction mixture was extracted with hexane (200 ml) 5 times. The combined organic layer was washed with 10 wt. % KOH solution and 200 ml of a saturated ammonium chloride solution and then further washed with a saturated Na2SO3 solution twice. The solvent was evaporated and the result product was dried under vacuum to provide a yield of 61% (276 mmol). BP: 103° C. (5*10−2 mbar)
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[C:20]([O-:22])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.C(N(C(C)C)CC)(C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[C:67]([C:73]([F:76])([F:75])[F:74])[CH:66]=2)[CH2:60][CH2:59]1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:23])[C:20]([N:58]3[CH2:63][CH2:62][CH:61]([NH:64][C:65]4[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[C:67]([C:73]([F:74])([F:75])[F:76])[CH:66]=4)[CH2:60][CH2:59]3)=[O:22])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(CN1CCN(c2ccc(C(C)(C)C)cc2)CC1)C(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(CN1CCN(c2ccc(C(C)(C)C)cc2)CC1)C(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reaction time: 2 h
Yield: 8 %

Procedure:
To a stirred suspension of 3-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-methyl-propionic acid lithium salt (16 mg; 0.05 mmol) in tetrahydrofuran (1.0 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformaide (0.5 mL). 15 minutes later, diisopropylethyl amine (25 μL; 0.15 mmol) and a solution of 4-(piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile hydrochloride (15 mg; 0.05 mmol, prepared in accordance with Example 155) in dimethylformamide (0.5 mL) are added. After 2 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (2 mg; 0.004 mmol). The structure was confirmed using Protocol I-D. Calculated mass=556; observed mass=556; HPLC retention time=1.60 min.
Reaction SMILES: [H-].[K+].COC1C=CC(CCN2CCC[C@H]2[CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=CC=1.ClC[CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][CH2:42][N:38]2[CH2:39][CH2:40][CH2:41][C@H:37]2[CH2:36][CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:49][CH:48]=1
Reactant: COc1ccc(CCN2CCC[C@H]2CCCl)cc1
Reactant: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(CCN2CCC[C@H]2CCN2c3ccccc3CSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Potassium hydride (35% dispersion in oil, 110 mg) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see Example 1) (570 mg) in DME (8 ml) and the mixture stirred at room temperature for 30 minutes, treated with a solution of (S)-2-(2-chloroethyl)-1-(4-methoxyphenethyl)pyrrolidine (480 mg) (prepared from the corresponding hydrochloride salt prepared in Preparation 4 by stirring a solution of the salt in dichloromethane with a slight excess of 10% aqueous sodium carbonate solution, separating the layers, drying the organic layer over sodium sulphate, and evaporating under reduced pressure to provide the desired free base) in DME (4 ml) and heated under reflux for two hours. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution using initially dichloromethane/hexane (3:1) as eluant, changing to dichloromethane/methanol (97:3). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (460 mg, 58%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].Cl[C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:13]2[N:12]=1>C1C=CC=CC=1>[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][O:8][C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:13]2[N:12]=1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCn1ncc2c1ncc1c(OCCCN(C)C)nc3cc(C)nn3c12

Procedure:
To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3-(dimethylamino)propanol are added and the mixture is refluxed for 6 hours. After this time, 28.6 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine are added in small portions with stirring. The solution is refluxed for 10 hours, and then the solvent is distilled off. The residue is treated with water, filtered off and recrystallized from ethyl acetate, yield 25 g (71%); m.p. 62°-64°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:16]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:16]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(C(=O)c2cccc(OCC(=O)O)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of 5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (1.0 g, 3.3 mmol) and trifluoroacetic acid (15 ml, 194 mmol) in methylene chloride (15 ml) was stirred overnight at room temperature. The organics were removed in vacuo and the residue was dissolved in toluene. The solution was concentrated and the residue was triturated between ethyl acetate and hexane to give 5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.8 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(Cl)cc(Cl)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
Cis-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.57 g, 8.87 mmol) was dissolved in MeOH (36.4 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (2.335 mL, 8.87 mmol) in water (3.64 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.544 mL, 8.87 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (45.9 mL, 275.11 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.000 g, 60.7%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.82-1.93 (m, 1H), 2.13-2.27 (m, 2H), 2.30-2.39 (m, 1H), 3.06-3.16 (m, 1H), 3.42-3.53 (m, 1H), 3.66 (s, 3H), 4.04-4.12 (m, 1H), 5.06 (dd, 1H), 5.64 (d, 1H), 7.14-7.18 (m, 2H), 7.27 (t, 1H). MS m/z 371 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[C:18]([O:29][CH3:30])[CH:17]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[C:18]([O:29][CH3:30])[CH:17]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: COc1cc(Nc2nc(Cl)c(C(C)(C)O)nc2C(N)=O)ccc1N1CCN(C)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc(Cl)c(C(C)C)nc2C(N)=O)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75.8 %

Procedure:
To a mixture of 5-chloro-6-(2-hydroxypropan-2-yl)-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 544) (300 mg) and trifluoroacetic acid (3 mL), triethylsilane (0.55 mL) was added under ice cooling and stirred under ice cooling for 10 minutes and at room temperature for 22 hours. After the reaction liquid was concentrated, the residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0.1) to give a crude product. The crude product was washed with diisopropyl ether to give 5-chloro-6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (219 mg) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH:8]([CH3:11])[O:7][C:6]=2[C:5]([C:12]([NH:14][CH2:15][CH2:16][C:17]23[CH2:24][CH2:23][CH2:22][N:21]2[CH2:20][CH2:19][CH2:18]3)=[O:13])=[CH:4][C:3]=1Cl>[Pd].C(O)C>[NH2:1][C:2]1[C:10]2[CH2:9][CH:8]([CH3:11])[O:7][C:6]=2[C:5]([C:12]([NH:14][CH2:15][CH2:16][C:17]23[CH2:24][CH2:23][CH2:22][N:21]2[CH2:20][CH2:19][CH2:18]3)=[O:13])=[CH:4][CH:3]=1
Reactant: CC1Cc2c(N)c(Cl)cc(C(=O)NCCC34CCCN3CCC4)c2O1
Agent: [Pd]
Solvent: CCO
Product: CC1Cc2c(N)ccc(C(=O)NCCC34CCCN3CCC4)c2O1
Reaction time: 20 h

Procedure:
A mixture of 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5yl)ethyl]-5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamide (100 mg) obtained by Example 2, 20% Pd-C (catalystic amount) and ethanol was stirred under hydrogen gas atmosphere for 20 hours. Then, the catalyst was removed by filtration and the solvent was distilled out in vacuo to afford the titled compound in quantitative amount.
Reaction SMILES: [O:1]=[C:2]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](COCC[Si](C)(C)C)[N:16]=[C:15]3[C:29](=[NH:31])[OH:30])=[O:10])[CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]([N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:45]=[CH:46][CH:47]=[CH:48][N:49]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:29](=[NH:31])[OH:30])=[O:10])[CH2:5]1
Reactant: C[Si](C)(C)CCOCn1nc(C(=N)O)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.4 %

Procedure:
To a solution of 33 from Step 1 (18 mg, 0.03 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 5 hrs. The crude was evaporated and quenched with sat. NaHCO3 at rt. The crude was evaporated and filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 18 mg of the product.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)cn1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.05 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(Cl)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](c3ccc(Cl)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
(2S,4R)-Methyl 2-(4-chlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.458 g, 1.36 mmol) (from example 27, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 10.72 mL, 61.20 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(4-chloro-phenyl)piperidin-4-yl)isoxazol-3(2H)-one (198 mg, 52%). 1H NMR (600 MHz, dmso) δ 1.32 (q, 1H), 1.44 (dq, 1H), 1.83-1.88 (m, 1H), 1.91-1.96 (m, 1H), 2.71 (dt, 1H), 2.84 (tt, 1H), 3.07-3.11 (m, 1H), 3.63 (dd, 1H), 5.70 (s, 1H), 7.31-7.40 (m, 4H). HRMS Calculated for [C14H15ClN2O2+H]+: 279.0900. Found: 279.0887
Reaction SMILES: O[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c(O)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Temperature: 0 °C

Procedure:
3.9 g of methyl 2-hydroxy-1H-benzimidazole-5-carboxylate and 50 ml of phosphorus oxychloride are stirred at 10° C. for 6 hours. The resulting thick slurry is, after cooling, stirred cautiously into 500 ml of ice-water, and the solid is filtered off with suction after one hour, washed with water and dried under reduced pressure.
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][O:14][C:15]1[CH:19]=[C:18]([CH2:20]O)[O:17][N:16]=1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH2:20][C:18]1[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[CH:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Yield: 89 %

Procedure:
To a solution of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (2.86 g) in toluene (50 ml) was slowly added thionyl chloride (0.80 ml) at room temperature and the mixture was stirred under reflux for 30 min. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (2.70 g, yield 89%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 105–106° C.