Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](OCC)(OCC)[CH:10]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][C:28]([C:32]4[CH:37]=[C:36]([F:38])[C:35]([O:39]COCC[Si](C)(C)C)=[CH:34][C:33]=4[CH2:48][CH3:49])=[CH:29][CH:30]=3)[N:25](C3CCCCO3)[N:24]=2)=[NH:22])[CH2:9]1)=O)(C)(C)C.[ClH:56]>C(O)C>[ClH:56].[ClH:56].[CH2:48]([C:33]1[C:32]([C:28]2[CH:27]=[C:26]3[C:31]([C:23]([C:21]4[NH:22][C:11]5[CH2:12][CH2:13][NH:8][CH2:9][C:10]=5[N:20]=4)=[N:24][NH:25]3)=[CH:30][CH:29]=2)=[CH:37][C:36]([F:38])=[C:35]([OH:39])[CH:34]=1)[CH3:49]
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Agent: Cl
Solvent: CCO
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 4,4-diethoxy-3-{[6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (Preparation 10, 46.65 g, 55.27 mmol) in ethanol (200 mL) was added concentrated hydrochloric acid (12M, 100 mL, 1.2 mol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (100 mL) and DCM (2×100 mL). The resulting gum was dried under vacuum for 3 hours. The crude material was triturated in MeCN (300 mL) and the resulting solid was collected by filtration. The solid was dissolved in ethanol (250 mL) and treated with concentrated hydrochloric acid (12M, 77.2 mL, 927 mmol). The resulting solution was heated at 40° C. for 18 hours, then at 50° C. for 2 hours. The solvents were removed in vacuo and the resulting gum was triturated in MeCN (200 mL). The solid which formed was collected by filtration, washed with further MeCN (200 mL) and dried under vacuum to give the title compound as a beige solid (23.5 g, 88% yield, dihydrochloride salt).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].OCC1N=CN(C)N=1.N1C=CC=CC=1CO[C:27]1[C:36]2[C:31](=[C:32](OCC3C=CC=CN=3)[CH:33]=[CH:34][CH:35]=2)[C:30]2=NN=C(C3C=C(C)ON=3)[N:29]2[N:28]=1.O>CN(C)C=O>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29][N:28]=1
Reactant: Cc1cc(-c2nnc3c4c(OCc5ccccn5)cccc4c(OCc4ccccn4)nn23)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cn1cnc(CO)n1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2cnncc2c1
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
Lithium hexamethyldisilazide (1.0M solution in hexane) (0.22 ml, 1.10 mmol) was added to stirred solution of 3-hydroxymethyl-1-methyl-1,2,4-triazole (90 mg, 0.79 mmol) prepared using the conditions of Itoh and Okongi, EP-A-421210) in N,N-dimethylformamide (10 ml) at −10° C. under nitrogen, and the mixture stirred for 0.25 h. After this time, Intermediate 6 (100 mg, 0.53 mmol) was added and the mixture stirred at −10° C. for 0.5 h and then room temperature overnight. Water was added to the reaction mixture and the resulting precipitate filtered off and recrystallised from dichloromethane/ethyl acetate to give the title-phthalazine (55 mg, 27%), mp 221-223° C.; 1H NMR (360 MHz, CDCl3) δ 1.54 (3H, t, J=10.2 Hz; CH3), 3.96 (3H, s, CH3), 4.47 (2H, q, J=10.2 Hz, CH2), 5.71 (2H, s, CH2), 6.26 (1H, s, Ar—H), 7.79 (1H, m, Ar—H), 7.94 (1H, m, Ar—H), 8.08 (1H, s, Ar—H), 8.25 (1H, d, J=11.0 Hz, Ar—H), 8.70 (1H, d, J=8.1 Hz, Ar—H); MS (ES+) m/e 393 [MH]+; Anal. Found. C, 54.87; H, 3.91; N, 28.27; C18H16N8O3 requires C, 55.09; H, 4.11; N, 28.55%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH3:15][NH:16][CH2:17][CH2:18][OH:19].C(OCC)(=O)C>C(O)C>[OH:19][CH2:18][CH2:17][N:16]([CH3:15])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reactant: CNCCO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCO)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a suspension of 2.946 g (13.73 mmol) of 2-chloro-N-(4-nitrophenyl)acetamide in 30 mL of ethanol was added 3.31 mL (41.18 mmol) of 2-(methylamino)ethanol and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature and condensed, then, the residue was treated with ethyl acetate. The organic layer was washed with water and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to give 2.05 g (59%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:9](=[O:24])[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2cccc(F)c2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2cccc(F)c2)cc1

Procedure:
The title compound was prepared as described in Example 62, substituting 4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 135 mg, 34%). mp 199-201° C. 1H NMR (300 MHz, DMSO-d6) δ 3.24 (s, 3H), 6.98 (d, J=9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.39 (t, 1H), 7.54 (d, J=9 Hz, 2H), 7.71 (m, 2H), 7.91 (d, J=9 Hz, 2H), 8.27 (s, 1H). MS (DCI/NH3) m/z 439 (M+H)+, 456 (M+NH4)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1>CCO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 64 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Excess NaOH (11 ml, 11.00 mmol, 1M aq) was added to a stirring solution of ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (1.9 g, 5.50 mmol) in EtOH (55 ml) and THF (55 ml) and was allowed to stir at 64° C. overnight. The mixture was concentrated and diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (1.7 g, quant.). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.31-7.48 (m, 2H) 7.71 (s, 1H) 8.00-8.14 (m, 2H) 8.29 (s, 1H) 10.80 (s, 1H) 13.35 (s, 1H). LC-MS retention time: 0.99 min; m/z (MH−): 416. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH3:15])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:14])[O:9]1)=O)CCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:15][C:8]1([CH2:6][OH:5])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:14])[O:9]1
Reactant: CCCCOC(=O)C1(C)CCC=C(C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=CCCC(C)(CO)O1
Reaction time: 3.5 h
Yield: 77.5 %

Procedure:
A mixture of 3,4-dihydro-2,6-dimethyl-2H-pyran-2-carboxylic acid butyl ester (23.7 g) and lithium aluminum hydride (4.2 g) in 160 ml tetrahydrofuran was heated briefly to reflux and then allowed to cool. After 3.5 hours, excess hydride was destroyed by addition of ethyl acetate (70 ml). Volatile solvents were then stripped, and the residue was treated with 100 ml 15% aqueous sodium hydroxide and extracted with ether. The organic phase was dried over potassium carbonate and distilled to afford 12.3 g colorless product with bp 48°-49° C. (0.03 torr).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl (R)-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro-benzene by method C. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10].C(Cl)(=O)C(Cl)=O.Cl.CO.OS(O)(=O)=O.N>C(Cl)Cl.O>[I:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)C(=O)NCCc1ccccc1I
Agent: Cl
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)C1=NCCc2c(I)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
A solution of methyl 3-((2-iodophenethyl)amino)-2-methyl-3-oxopropanoate (9.9 g, 27.4 mmol) in DCM (120 mL) was treated with oxalyl chloride (2.59 mL, 30.2 mmol) and the mixture was stirred at RT for 30 min. FeCl3 (5.34 g, 32.9 mmol) was then added portionwise at 0° C. and the resulting brown mixture was stirred at RT for 4 h. A 2N aqueous solution of HCl (35 mL) was then added and the mixture was stirred at RT for another 2 h. The mixture was then diluted with H2O and extracted with DCM. The combined org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in a 19:1 mixture of MeOH/H2SO4 (120 mL) and stirred at reflux for 3 h. The mixture was then concentrated in vacuo and the brown reside obtained was taken up in H2O. The mixture was rendered basic with ammonia and then extracted with AcOEt. The combined org. phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 70:30) gave the title compound (1.15 g) as yellow oil. UPLC-MS: MS 344.1 (M+H+); UPLC rt 0.96 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]1([O:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>>[O:18]([CH2:19][CH2:20][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1CCCN(CCOc2ccccc2)C1

Procedure:
A mixture of ethyl 3-piperidinecarboxylate (20.58 g), 2-bromoethyl phenyl ether (26.31 g), sodium bicarbonate (10.99 g) and IMS (100 ml) was boiled under reflux for 16 hours. The mixture was evaporated to dryness then diluted with water (100 ml) and 2M sodium hydroxide solution (20 ml). This mixture was extracted with dichloromethane and the combined dichloromethane extracts were extracted with 2M hydrochloric acid. The acidic extracts were washed with dichloromethane and then basified with 2M sodium hydroxide solution. This mixture was extracted with dichloromethane to give ethyl N-(2-phenoxyethyl)piperidine-3-carboxylate as an oil. A sample of the oil was dissolved in ether and ethereal oxalic acid was added. The precipitate was filtered off and recrystallised from aqueous propan-2-ol to give ethyl N-(2-phenoxyethyl)piperidine-3-carboxylate oxalate hemihydrate, m.p. 131°-132° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:49][C:50]1[S:51][C:52]([Cl:55])=[CH:53][N:54]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:55][C:52]1[S:51][C:50]([NH:49][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:54][CH:53]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(Cl)s2)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 40.2 %

Procedure:
A solution of triphenylphosphine (4.60 g, 17.55 mmol) in methylene chloride (50 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (3.12 g, 17.55 mmol). The reaction mixture was stirred at 0° C. for 25 min and then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared as in Example 128, 4.00 g, 13.50 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with a solution of 2-amino-5-chlorothiazole hydrochloride (5.77 g, 33.75 mmol) and pyridine (4.37 mL, 54.03 mmol) in methylene chloride. The resulting reaction mixture was allowed to stir at 25° C. overnight. The reaction mixture was then diluted with water (150 mL), a 1N aqueous hydrochloric acid solution (50 mL), and ethyl acetate (100 mL). The layers were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (2.24 g, 40%) as a yellow foam: mp 83–88° C. (foam to gel); [α]23589=−73.3° (c=1, chloroform); EI-HRMS m/e calcd for C18H21ClN2O3S2 (M+) 412.0682, found 412.0692.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][NH:4][N:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[CH2:10]([NH:12][C:7]([C:6]1[C:2]([CH3:1])=[N:3][NH:4][CH:5]=1)=[O:9])[CH3:11]
Reactant: CCN
Reactant: Cc1n[nH]cc1C(=O)O
Product: CCNC(=O)c1c[nH]nc1C
Yield: 99.9 %

Procedure:
Following the same procedure in Example 29 (Steps B and C in Method B), using 3-methyl-1H-pyrazole-4-carboxylic acid (252 mg, 2.0 mmol) and ethylamine (225 mg, 5.0 mmol), provided the desired crude compound (306 mg, 100%), which was used in Step A directly.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][C:12](=O)[CH2:13][Cl:14])[CH:7]=[C:6]([CH3:16])[N:5]=2>C1COCC1>[CH3:1][C:2]1[N:3]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13][Cl:14])[CH:7]=[C:6]([CH3:16])[N:5]=2
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(-n2c(C)nc3c(NCCCl)cc(C)nc32)c(C)c1

Procedure:
Treat a solution of N-[2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide (0.91 g, 2.55 mmol) in THF (5 mL) with borane-methyl sulfide complex (0.8 mL, 7.65 mmol). Heat the mixture to reflux for 18 h and quench at ambient temperature with a large excess of MeOH, followed by 6N HCl (5 mL). Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure to obtain the title compound as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][N:33]=[CH:32]1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][CH:32]=[N:33][CH:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1cncs1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cncs2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (263 mg, 0.903 mmol) was suspended in dichloromethane (DCM) (2 mL) before treating with triethyloxonium tetrafluoroborate (189 mg, 0.994 mmol) and stirring for 45 mins at RT under argon before adding 1,3-thiazole-5-carbohydrazide (I109)(155 mg, 1.084 mmol) and stirring for 18 hours (overnight). The DCM was removed and the residue was suspended in 1-butanol (2.0 mL) and heated at 110° C. for 3 hours. The reaction was cooled to RT, diluted with DCM (30 ml) and washed with saturated sodium bicarbonate solution (20 ml). The aqueous layers were extracted with DCM (2×20 ml), combined, washed with brine (20 ml), dried (MgSO4), filtered and evaporated to afford a yellow gum of crude product which was purified by MDAP. Desired fractions were isolated and solvent evaporated to afford a colourless gum which solidified when triturated with Et2O to afford a pale yellow solid of desired product in 100 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[CH:37]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[CH:37]=3)[CH:3]=[C:4]([N:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5]2=[N:10][CH:9]=1)#[N:12]
Reactant: CC(=O)Nc1cc(N)ccc1C
Reactant: COc1ccc(CN(c2ccc(OC)cn2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN(c2ccc(OC)cn2)c2cc(Nc3ccc(C)c(NC(C)=O)c3)nn3c(C#N)cnc23)cc1
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
A mixture of 5B (60 mg, 0.14 mmol), N-(5-amino-2-methylphenyl)acetamide (46.8 mg, 0.29 mmol), Pd2(dba)3 (13.1 mg, 0.014 mmol), Xantphos (18.2 mg, 0.031 mmol), copper(I) iodide (13.6 mg, 0.071 mmol) and Cs2CO3 (186 mg, 0.57 mmol) in DMA (1 mL) was purged with nitrogen and heated at 125° C. After 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed with 15% NH4OH, dried over Na2SO4, and concentrated to dryness under reduced pressure. The resulting oil was purified by silica column chromatography (gradient=0%-100% hexanes to ethyl acetate in 12 min.) to isolate 5C (47.5 mg, 60.7% yield). HPLC: Rt=3.805 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=549.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH3:33].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[CH:40][C:35]([CH2:34][N:32]([CH3:33])[CH3:31])=[CH:36][CH:37]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CN(C)Cc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN(C)C)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 53.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.2 g, 0.42 mmol) and (4-((dimethylamino)methyl)phenyl)boronic acid (0.15 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and the solution purged with argon for 15 min. Pd(PPh3)4 (0.048 g, 0.042 mmol) was the added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography over silica gel to afford the title compound (0.120 g, 53.8%). LCMS: 531.30 (M+1)+; HPLC: 94.88% (@254 nm) (Rt; 3.949; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.19 (t, 1H, J=4.4 Hz), 7.61 (d, 2H, J=8 Hz), 7.39-7.41 (m, 3H), 7.23 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.62-3.84 (m, 4H), 3.22-3.38 (m, 2H), 3.02-3.06 (m, 3H), 2.30 (bs, 6H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C[CH2:11][O:12]CC.[Na].C([Li])CCC>CN(C)C=O>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([CH:11]=[O:12])[S:3][C:4]=1[CH3:9]
Reactant: Cc1sc(Br)c(C)c1Br
Reactant: CCOCC
Agent: [Li]CCCC
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1sc(C=O)c(C)c1Br
Temperature: -35 °C

Procedure:
15.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 250 ml. of anhydrous ether and cooled to -70° C. with stirring under argon. 24 Ml. of a 2.4 M sodium of n-butyl lithium was slowly added to the solution and the mixture was warmed to -35° C. for 10 minutes, and then cooled again to -70° C. 7.3 G. of dimethylformamide was added slowly to the mixture and the reaction mixture was warmed to room temperature for 14 hours. The resulting solution was poured into ice water, stirred for 20 minutes and extracted with ethyl ether. The ether extracts were combined, washed with an aqueous solution of 5% sodium carbonate, saturated sodium chloride solution, dried with sodium sulfate, filtered and evaporated to yield 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde, m.p. 44°-45° C.