Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3c(Cl)cccc3Cl)c2c1

Procedure:
The titled compound (65 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,6-dichlorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([NH2:19])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1OCc1ccccc1
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccc(C(N)=O)cc1OCc1ccccc1
Yield: 94 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(O)C=Cc1cccs1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Yield: 45.3 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (966 mg, 3.89 mmol) was suspended in dry methylene chloride (5 ml). To the suspension, a solution of 3-(2-thienyl)acrylic acid (500 mg, 3.24 mmol), triethylamine (1.08 ml, 7.78 mmol), and ethyl 2-aminobenzoate (0.48 ml, 3.24 mmol) in dry methylene chloride (5 ml) was added dropwise. After the addition, the mixture was heated under reflux for 39 hours. Then, the reaction mixture was diluted with methylene chloride, washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a yellow solid, which was washed with n-hexane to give pale yellow solids of the title compound (442 mg, yield, 45%). m.p., 126°-127° C. (recrystallized from methanol)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8](I)=[N:9][N:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.Cl[C:14]1[CH:15]=CC2[C:18](=[C:20](I)[N:21]([CH3:23])N=2)[N:19]=1.CN1CCNCC1.N1CCC[C@H]1C(O)=O>[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([N:19]3[CH2:14][CH2:15][N:21]([CH3:23])[CH2:20][CH2:18]3)=[N:9][N:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1nc(I)c2nc(Cl)ccc21
Reactant: Cn1nc2ccc(Cl)nc2c1I
Agent: [Cu]I
Agent: CN1CCNCC1
Agent: O=C(O)[C@@H]1CCCN1
Product: CN1CCN(c2nn(C)c3ccc(Cl)nc23)CC1
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine (104 mg, 0.354 mmol, containing the isomer 5-chloro-3-iodo-2-methyl-2H-pyrazolo[4,3-b]pyridine (360 mg, 1.22 mmol) was added 1-methylpiperazine (184 mg, 1.84 mmol), CuI (70 mg, 0.368 mmol), L-proline (84 mg, 0.736 mmol). The reaction mixture was heated at 100° C. for 4 h. The reaction was cooled, washed by sat. NaHCO3, extracted with EtOAc, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C12H16ClN5: 266.1 (M+H+); Found: 266.2 (M+H+).
Reaction SMILES: NCCC[Si:5](OCC)(OCC)OCC.[CH:15]1[C:20]([N:21]=[C:22]=[S:23])=[CH:19][C:18]2[C:24]([O:26][C:27]3([C:37]4[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:36]=4[O:35][C:29]4[CH:30]=[C:31]([OH:34])[CH:32]=[CH:33][C:28]3=4)[C:17]=2[CH:16]=1)=[O:25]>C(O)C>[CH:15]1[C:20]([N:21]=[C:22]=[S:23])=[CH:19][C:18]2[C:24]([O:26][C:27]3([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=4[O:35][C:36]4[CH:41]=[C:40]([OH:42])[CH:39]=[CH:38][C:37]3=4)[C:17]=2[CH:16]=1)=[O:25].[SiH4:5]
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CCO
Product: [SiH4]

Procedure:
The adequate amount of 3-aminopropyltriethoxysilane (APTES) is dissolved in ethanol, and the adequate amount of fluorescein isothiocyanate (FITC) is added therein to mix well to form a ethanol solution of FITC-silane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:5]=2[N:6]=1.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:6]1[C:5]2[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:10]([CH3:11])[C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(C)c2[nH]c(C)nc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
A mixture containing 0.900 g of 2,4-dimethyl-6-methoxycarbonylbenzimidazole, 1.20 g of 2,4-dichlorobenzyl chloride, 0.200 g of sodium iodide, 0.610 g of potassium carbonate and 4 ml of N,N-dimethylformamide was stirred at 80° C. for 16 hours. After the organic solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate and with water. The organic layer was concentrated, and was crystallized with the addition of hexane. The crystals were separated through filtration, and were dried to give 1.08 g of 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole (353).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH2:32]([N:34]([CH2:49][CH3:50])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)[CH3:38])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:49]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:5])=[O:45])=[CH:47][CH:48]=1)[CH3:38])[CH3:50]
Reactant: CCN(CC)CCN(C)Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Into a 5-mL vial, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (5 mL), 4-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (74 mg, 0.28 mmol, 1.20 equiv), EDC.HCl (90 mg, 0.47 mmol, 2.00 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.50 equiv). The resulting solution was stirred overnight at 30° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 1×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 57.8 mg (31%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.684 (d, J=9 Hz, 1H), 8.392-8.400 (m, 1H), 8.179 (s, 1H), 8.047-8.075 (m, 3H), 7.991-7.999 (m, 1H), 7.589-7.727 (m, 5H), 7.078-7.087 (m, 1H), 4.007 (s, 2H), 3.556-3.615 (m, 4H), 3.393-3.436 (m, 2H), 3.171-3.263 (m, 4H), 3.052-3.095 (m, 2H), 2.538-2.560 (m, 3H), 1.998 (m, 4H), 1.788-1.804 (m, 2H), 1.286-1.334 (m, 6H). MS (ES, m/z): 676 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 1 h

Procedure:
A 2.0 g (6.15 mmol) portion of the product of Example 26 was stirred with 10 ml of acetic anhydride at 25° C. for 3 hours then 50 ml of distilled water were added and the stirring was continued for one hour. The yellow precipitate formed was filtered, washed with 3×10 ml of distilled water and dried at 80°-100° C. to obtain 2.6 g of raw product. After recrystallization from 10 ml of ethanol 1.94 g (85.8%) of the aimed product were obtained, m.p.: 140°-142° C.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH2:25](Br)[CH:26]=[CH2:27].C([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH:26]=[CH2:25]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: C=CCBr
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: C=CCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Yield: 81 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with allyl bromide according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1-allyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (81%). MS (ESI) m/z 369 ([M+H]+); HRMS: calcd for C21H21FN2O3, 368.1537; found (ESI+), 369.16115.
Reaction SMILES: [CH3:1][O:2][CH2:3]C(Cl)=O.[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCN(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated soldium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C. The product is tabulated in Table C as Compound No. C-2.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:8]=[C:7]([CH:9]([F:11])[F:10])[C:6]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])[C:4]=1[C:20]([N:22]1[CH:26]=CC=N1)=[O:21].CN>CCOCC>[F:11][CH:9]([F:10])[C:7]1[N:8]=[C:3]([C:2]([F:28])([F:1])[F:27])[C:4]([C:20]([NH:22][CH3:26])=[O:21])=[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)n2cccn2)c1NC(C)C
Agent: CN
Solvent: CCOCC
Product: CNC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Temperature: 30 °C
Reaction time: 4 h

Procedure:
To a mixture of 10 g (0.03 mol) of the acid chloride prepared in Example 200 in 500 mL of Et2O was added an excess of anhydrous methyl amine and the mixture was stirred at 30° C. for 4 hours. The reaction mixture was cooled to 25° C., and concentrated in vacuo to a white powder which was extracted with CHCl3 using a soxhlet apparatus. The CHCl3 was concentrated in vacuo to 8.8 g (88%) of product as a white solid: mp 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:15]([O:17]CC)=O)[N:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1.CC(C)([O-])C.[K+].[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:15](=[O:17])[CH2:27][C:26]([O:29][CH2:30][CH3:31])=[O:28])[N:5]([NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:6]=1
Reactant: CCOC(=O)c1nc(Br)cn1NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1nc(Br)cn1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
To a solution of ethyl 4-bromo-1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate (1.90 g, 5.69 mmol) in THF (4.4 ml) at 0° C., was added dropwise a cold (pre-cooled at 0° C.) 1M THF solution of potassium tert-butoxide (17.06 ml, 17.06 mmol). The reaction was stirred at 0° C. for 5 minutes. Dry ethyl acetate (1.410 ml, 14.40 mmol), which was pre-cooled at 0° C., was added dropwise. Stirring was continued at 0° C. for 15 minutes. The ice bath was removed. The reaction was stirred at room temperature for 2 hrs, becoming a darker yellow suspension. The reaction was cooled to 0° C., and treated with 1.0 N HCl via dropwise addition until complete dissolution of the suspension. The reaction was concentrated to half volume under reduced pressure, and diluted with ethyl acetate. The solution was adjusted to basic by addition of 1.0 N NaOH. The aq. layer was back extracted with ethyl acetate (3×). The ethyl acetate extracts were combined, dried with sodium sulfate, filtered, and concentrated to give ethyl 3-(4-bromo-1-((tert-butoxycarbonyl)amino)-1H-imidazol-2-yl)-3-oxopropanoate (1.502 g, 4.00 mmol, 70% yield) as a pale yellow solid. LCMS (Method B) m/z 376.1 [M+1], Br-pattern; HPLC (Method B): Rt 2.961 min. 1H NMR (400 MHz, MeOD, enoate form) δ 7.51 (s, 1H), 4.18 (q, J=7.3 Hz, 2H), 4.00 (s, 1H), 3.97 (s, 1H), 1.49 (br. s., 9H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1cnc2c(NC3CCCCC3)nc(Cl)nc21
Temperature: 50 °C
Yield: 81.8 %

Procedure:
2,6-Dichloro-9-methyl-9H-purine (1.40 g, 6.93 mmol) was dissolved in acetonitrile (25 mL). Triethylamine (4.81 mL, 34.5 mmol) and cyclohexylamine (0.79 mL, 6.90 mmol) were added and the reaction mixture was stirred at 50° C. over night. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water was added followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to give (2-chloro-9-methyl-9H-purin-6-yl)-cyclohexyl-amine (1.5 g, 82%) as a crystalline compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCn2ccnn2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (51 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[Br-].[CH:12]1([CH2:18][Zn+])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.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>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([CH2:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Reactant: [Zn+]CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(CC2CCCCC2)ncc(Br)c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
A solution of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.448 mmol; prepared according to the procedure of Example 46, Step B) and PdCl2(PPh3)2 (0.016 g, 0.022 mmol) in THF (2.5 mL) was sparged with N2, and then (cyclohexylmethyl)zinc(II)bromide (0.904 ml, 0.452 mmol; 0.5 M solution in THF) was added. The reaction mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc to afford 0.047 g (37%) of the product as a waxy yellow solid. LRMS (APCI pos) m/e 285, 287 (M+, Br pattern).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:21][C:22]1[C:23]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28](=O)[C:24]=2[CH:25]=[N:26][CH:27]=1.Cl>C1COCC1>[Br:21][C:22]1[C:23]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28](=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[C:24]=2[CH:25]=[N:26][CH:27]=1
Reactant: O=C1OC(c2ccccc2)c2c(Br)cncc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c(Br)cncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
A solution of 1,3-dihydro-indol-2-one (225 mg, 1.55 mmol) in THF (6 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (3.5 mL of a 1 M solution in THF, 3.5 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 7-bromo-1-phenyl-1H-furo[3,4-c]pyridin-3-one (305 mg, 1.0 mmol, AcOH salt) is added as a solid to the reaction mixture. The resulting solution is stirred for 3.5 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL) and stirred at room temperature for 48 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, 30% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (120 mg, 27%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][CH:25]=[C:2]([NH:1][C:27](=[O:28])[NH:26][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:3]=1)#[N:22]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (120 mg, 0.342 mmol) produced in Example 3(vi) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (63 mg, 0.445 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95). The obtained solution was concentrated under reduced pressure to give the title compound (173 mg, 94%) as a white powder.