Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][C:10]([CH2:18][CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[S:5][CH:6]=1.[CH2:20]([NH:22][C:23]([NH:25][C:26]1[S:27][C:28]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:33][C:32](B(O)O)=[CH:31][C:29]=2[N:30]=1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:18]([C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([C:32]3[CH:33]=[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[C:28]4[S:27][C:26]([NH:25][C:23](=[O:24])[NH:22][CH2:20][CH3:21])=[N:30][C:29]=4[CH:31]=3)[N:3]=2)[CH2:8][CH2:9]1)[CH3:19]
Reactant: CCOC(=O)C1(CC)CCN(c2nc(Br)cs2)CC1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3csc(N4CCC(CC)(C(=O)OCC)CC4)n3)cc(-c3ccccn3)c2s1
Temperature: 120 °C
Yield: 35.4 %

Procedure:
Ethyl 1-(4-bromothiazol-2-yl)-4-ethyl-piperidine-4-carboxylate (56 mg, 0.16 mmol), 2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl-boronic acid (50 mg, 0.15 mmol), and cesium carbonate (42 mg, 0.22 mmol) were suspended in DMF (1 mL) in a 5 mL microwave vessel. The resulting mixture was degassed with Ar for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (10 mg, 0.01 mmol), was added to the mixture, then the vessel sealed and heated at 120° C. for 60 min in a microwave. The mixture was cooled to rt then evaporated to dryness and the crude residue purified over a 12 g silica-gel column using a MeOH: DCM elution gradient (0-5%) to obtain the product as a viscous oil (30 mg, 36% yield). MS: 565.13 [M+H]+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12](=O)[CH2:13][O:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:12]1[CH2:11][C:10]2[C:15](=[CH:16][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[O:14][CH2:13]1
Reactant: CON
Reactant: COc1ccc2c(c1)OCC(=O)C2
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1COc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (459 mg, 5.49 mmol) was added to a solution of Example 3C (890 mg, 4.99 mmol) in pyridine (20 mL) and the mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure, taken up in ethyl acetate (100 mL) and 1N hydrochloric acid (100 mL). The separated organic layer was washed with brine, filtered, and dried over anhydrous sodium sulfate. Concentration and chromatography on silica gel eluting with 0-to-20% ethyl acetate in hexane afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.64 (s, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 4.49 (s, 2H), 6.47 (d, J=2.72 Hz, 1H), 6.57 (dd, J=8.48, 2.38 Hz, 1H), 7.10 (d, J=8.48 Hz, 1H). MS (DCI) m/z 208.05 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[N:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]([Br:16])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[N:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]([Br:16])[C:3]=1[CH2:4][OH:5]
Reactant: COc1nc(C(F)(F)F)c(Br)c(C=O)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1nc(C(F)(F)F)c(Br)c(CO)c1Br
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a solution of 3,5-dibromo-2-methoxy-6-(trifluoromethyl)isonicotinaldehyde (980 mg, 2.7 mmol) in ethanol (10 mL), was added sodium borohydride (102 mg, 2.7 mmol). The reaction mixture was stirred for 20 min, concentrated, and the residue was purified by flash column (silica gel, 50% EtOAc/hexane) to yield [3,5-dibromo-2-methoxy-6-(trifluoromethyl)pyridin4-yl]methanol (717 mg, 72.8%). 1H-NMR (400 MHz, CDCl3) δ 5.10 (s, 2H), 4.05 (s, 3H), 2.32 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([O:31][C:32](=[O:53])[NH:33][C:34]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1.CN1C(=O)CCC1>[C:8]1([C:7]2[N:6]=[C:5]3[N:14]4[C:20]([C:21]5[CH:26]=[N:25][CH:24]=[CH:23][N:22]=5)=[N:19][N:18]=[C:15]4[CH:16]=[CH:17][C:4]3=[N:3][C:2]=2[C:41]2[CH:42]=[CH:43][C:38]([C:34]3([NH:33][C:32](=[O:53])[O:31][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:37][CH2:36][CH2:35]3)=[CH:39][CH:40]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Clc1nc2ccc3nnc(-c4cnccn4)n3c2nc1-c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc5nnc(-c6cnccn6)n5c4nc3-c3ccccc3)cc2)CCC1
Temperature: 80 °C

Procedure:
To a microwave vial was added 3-chloro-2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (8-5, 0.151 g, 0.421 mmol), tert-butyl{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate (8-6, 0.236 g, 0.631 mmol), potassium carbonate (0.174 g, 1.262 mmol), bis(tri-t-butylphosphine)palladium(0) (21.51 mg, 0.042 mmol), water (0.2 mL), NMP (0.2 mL), and 1.4 Dioxane (0.8 mL). The reaction mixture was then heated to 80° C. under microwave irradiation for 10 minutes. The reaction mixture was then permitted to cool to room temperature, diluted with NMP/MeOH, and filtered through a syringe filter. The resulting residue was then purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 100% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then concentrated in vacuo to give 8-7 as a green solid. HRMS (M+H)+: observed=571.2591, calculated=571.2565.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[CH:34])=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58](I)=[CH:59][C:53]=2[N:52]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O.O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[C:34][C:57]4[CH:58]=[CH:59][C:53]5[NH:52][C:51]([C@@H:46]6[CH2:47][CH2:48][CH2:49][CH2:50][N:45]6[C:43]([O:42][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:44])=[N:55][C:54]=5[CH:56]=4)=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc2[nH]c([C@@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)nc2c1
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](c2nc3cc(C#Cc4ccc5[nH]c([C@@H]6CCCCN6C(=O)OCc6ccccc6)nc5c4)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7893.4 %

Procedure:
To a stirring solution of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (77 mg, 0.16 mmol), (S)-2-(5-iodo-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (70 mg, 0.15 mmol), CuI (3 mg, 0.015 mmol) and bis(triphenylphosphine)palladium(II)dichloride (10.6 mg, 0.015 mmol) in DMF (2 mL) is added TEA (0.1 mL, 0.76 mmol). The reaction mixture is stirred at room temperature for 2 hours, diluted with EtOAc and water. The mixture is filtered to remove insoluble material and the layers of the filtrate are separated. The organic layer is dried over sodium sulfate and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) and repurified by reverse phase HPLC using a gradient of CH3CN/water to give the title compound (9.4 g, 7%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH3:15]C(C)([O-])C.[K+].N#N>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[CH2:15]
Reactant: COc1cc(F)c2c(c1F)C(=O)CC2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCc2c(F)cc(OC)c(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A screw-cap vial was charged with H3.3 (0.962 g, 4.85 mmol), methyltriphenylphosphonium bromide (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (2.08 g, 5.83 mmol), and THF (20 mL). To the white slurry was added potassium tert-butoxide (1.0 M in THF) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (5.83 mL, 5.83 mmol) dropwise under N2. The resulting brown mixture was stirred for 30 minutes at room temperature, quenched with acetone (1 mL) and saturated aqueous NH4Cl, and diluted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated. The residue was suspended in hexanes, filtered, and concentrated, and the initially obtained product was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford H3.4 (0.835 g, 88% yield) as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[CH2:6][CH:7]([NH2:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>O.C(#N)C>[C:30]1(=[O:39])[N:16]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:17])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: CCOC(=O)CC(N)c1ccc(OC)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid ethyl ester hydrochloride (1.00 g, 3.85 mmol) and sodium carbonate (0.41 g, 3.85 mmol) in 40 mL of water was added N-carboethoxyphthalimide (0.84 g, 3.85 mmol) in 10 mL of acetonitrile. The reaction was complete in one hour by TLC. The reaction mixture was partially concentrated to remove the acetonitrile. To the resulting mixture was added 0.5 mL of ethyl ether and the mixture was stirred for 1 hour at room temperature. The resulting slurry was filtered and the solid was washed with copious amounts of water. The solid was air-dried overnight to afford 1.02 g (75%) of ethyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white gum: mp 32° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.86 (m, 4H), 6.90-7.37 (M, 4H), 5.66 (dd, 1H J1=7.5, J2=2.5), 4.00 (d, 2H, J=7.5), 3.3-3.6 (M, 2H), 1.04 (t, 3H, J=7.5 Hz); 13C (DMSO-d6) δ 170.1, 167.5, 158.7, 134.7, 131.0, 130.5, 128.3, 123.2, 113.88, 60.1, 55.0, 49.5, 35.7, 13.8. Anal. Calcd for C20H19NO5 : C, 67.98; H, 5.42; N, 3.90; Found C, 67.78; H, 5.30; N, 3.92.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@@H:4]1[OH:9].[CH3:12]C([O-])(C)C.[K+].S(OC)(OC)(=O)=O.O>C1COCC1.C(Cl)Cl>[CH3:12][O:9][C@@H:4]1[C:3]([O:10][CH3:11])([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: COC1(OC)CCOC[C@@H]1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1COCCC1(OC)OC
Reaction time: 0.75 h
Yield: 96 %

Procedure:
A 3-L 4-neck round bottom flask equipped with a overhead air stirrer, addition funnel with nitrogen inlet adapter, condenser, and thermocouple was charged with (S)-4,4-dimethoxytetrahydro-2H-pyran-3-ol (as prepared in the previous step, 80 g, 0.49 mol) in THF (1.1 L) and stirred in ice/acetone bath until <0° C. KOtBu (56 g, 0.49 mol) was added in one portion, and after stirring 45 min, dimethyl sulfate (47 mL, 0.49 mol) was added via addition funnel over 15 min. The reaction was allowed to stir at room temperature for 3 h. The reaction mixture was poured into a separatory flask containing H2O (1.25 L) and CH2Cl2 (1.25 L) and the layers were separated. The aqueous layer was back-extracted with CH2Cl2 (750 mL). The combined organic layers were washed with brine (1 L; Note: organic layer was on top), dried over MgSO4, filtered and evaporated to afford the title compound (83.5 g, 96%, chiral GC 94.6% ee) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]C(N)=O)=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=[N:28]CCC2)CC1.BrN1C(=O)CCC1=O.[OH-].[K+]>CO.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:28])=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COCOc1cc(OCc2ccccc2)ccc1CCC(N)=O
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COCOc1cc(OCc2ccccc2)ccc1CCN
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 28.42 g of 3-(4-benzyloxy-2-methoxymethoxyphenyl)propionamide and 40.4 mL of 1,8-diazabicyclo[5.4.0]-7-undecene in 895 mL of methanol was added 16.04 g of N-bromosuccinimide at 65° C. After the mixture was stirred at 65° C. for 15 minutes, to the reaction mixture was added additional 16.04 g of N-bromosuccinimide at 65° C. After being stirred at 65° C. for 15 minutes, the resulted mixture was concentrated under reduced pressure to remove the solvent. To the residue were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give oily product. To a solution of this residue in 242 mL of ethanol was added 67.6 mL of 8 mol/L aqueous potassium hydroxide solution, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue were added 500 mL of ethyl acetate, 50 mL of toluene, and 300 mL of water, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel (eluent: hexaneethyl acetate) to give 80.0 g of 2-(4-benzyloxy-2-methoxymethoxyphenyl)ethylamine as a colorless oil.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: Cc1ccnc(OCc2ccc(CC(Cl)=NO)cc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (4-(4-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (270 mg, 0.930 mmol) described in Manufacturing Example 43-1-5 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (189 μL, 1.36 mmol) at room temperature, which was stirred at room temperature for 4 hours. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (28.9 mg, 20.6%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[CH:20]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([C:22]2[N:21]=[CH:20][NH:19][CH:23]=2)=[O:25])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1c[nH]cn1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2c[nH]cn2)CC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), 1H-imidazole-4-carboxylic acid (191 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), 1-hydroxy-1H-benzotriazole monohydrate (260 mg), triethylamine (0.697 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give the title compound (322 mg, 75%.) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:25])=[CH:26][CH:27]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ncccc12
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example A142(5), ethyl 3-(methylamino)propanoate (155 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (329 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-100% ethyl acetate/hexane) to give the title object compound (333 mg, 85%) as a pale-yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].CS[C:13](=[N:16]C1C=CC(C(N2C=CN=C2)C(C)N(C)C)=CC=1)SC.CSC(SC)NC1C=CC(C(N2C=NC=N2)C(CC)CC)=CC=1>CS(C)=O>[S:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:13]1[NH2:16]
Reactant: CSC(=Nc1ccc(C(C(C)N(C)C)n2ccnc2)cc1)SC
Reactant: Nc1ccccc1S
Agent: CCC(CC)C(c1ccc(NC(SC)SC)cc1)n1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaOH (6.35 ml; 20 N) was added at RT to a solution of 2-aminobenzenethiol (0.0637 mol) in dimethylsulfoxide (115 ml). The mixture was stirred at RT for 30 minutes. (±)-β-[4[[bis(methylthio)methylene]amino]phenyl]-N,N,α-trimethyl-1H-imidazol-1-ethanamine (0.0637 mol), prepared according to intermediate (19a), was added. The mixture was stirred at 110° C. overnight, then poured out on ice, extracted with EtOAc and washed with HCl (3 N). The aqueous layer was basified with a concentrated NH4OH solution and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was separated by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1 and 90/10/0.1). Two pure fractions (F1 and F2) were collected and their solvents were evaporate F1 was crystallized from 2-propanone. The precipitate was filtered off and dried. The residue was taken up in K2CO3 (10%), filtered and the solvent was evaporated, yielding 1.12 g (5%) (±)-(A)-N-[4-[2-dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazolamine (comp. 1). F2 was crystallized from 2-propanone. The precipitate was filtered off and dried. The residue was recrystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (4%) of (±)-(B)-N-[4-[2-dimethylamino)-1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazolamine (comp. 2).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.[NH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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>[F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)COc1ccccc1Br
Reactant: Nc1cccc(B(O)O)c1
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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)COc1ccccc1Nc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide (Example 2, Step A) in 39 mL of toluene was added 0.136 g (0.118 mmol) of tetrakis(triphenylphosphine)palladium(0), 0.56 g (4.31 mol) of 3-aminophenylboronic acid, 47 mL (94.1 mmol) of a 2M solution of sodium carbonate and 8 mL of ethanol and the reaction mixture was heated at 90° C. for 22 hr. The reaction mixtur was colld to RT, and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc nd the combined organic fractions were washed with water and brine and dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4:1 hexanes:EtOAc) to give the title compound. Mass Spectrum (ESI) m/e M+1 268.1.