Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)#[N:2]
Reactant: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with thionyl chloride in N,N-dimethylformamide to obtain 3-cyano-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The properties (melting point and IR) of this compound were identical with those of the compound obtained in Example 4.
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:26]([N:17]1[CH2:18][CH2:19][N:14]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][NH:11][C:10](=[O:13])[CH:9]=2)[CH2:15][CH2:16]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1cc(N2CCNCC2)c(-c2ccccc2)n[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCN(c2cc(=O)[nH]nc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A 100 ml three necked round bottom flask was charged with 6-phenyl-5-(piperazin-1-yl)pyridazin-3(2H)-one (2.0 g), dry potassium carbonate (2.1 g) and dry DMF (150 ml) under nitrogen atmosphere. The reaction mixture was stirred at room temperature and benzoylchloride (1.5 g) was added into the reaction mixture very slowly. The reaction mixture was heated 120° C. for 4 hrs. The progress of reaction was monitored by TLC. After consumption of starting material reaction mixture was cooled to 0° C., ice-cold water (20.0 ml) was added to reaction mixture and the organic compound was extracted into ethylacetate (4×20 ml). Combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography using MeOH/CHCl3 (1:9) as eluent to afford 5-(4-benzoylpiperazin-1-yl)-6-phenylpyridazin-3 (2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cccc(Cl)c1
Product: O=Cc1ccc(Oc2cccc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-chlorophenol.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[CH3:7][C:8]([CH3:10])=O.N1CCCC1.C(O)(=O)C>CCOCC.O.CO>[CH3:1][C:2]1[CH:6]=[CH:5][C:4](=[C:8]([CH3:10])[CH3:7])[CH:3]=1
Reactant: CC(C)=O
Reactant: CC1=CC=CC1
Solvent: O
Solvent: C1CCNC1
Solvent: CCOCC
Product: CC1=CC(=C(C)C)C=C1
Yield: 92.5 %

Procedure:
To 130 ml of dehydrated methanol, 22.6 g (283 mmol) of methylcyclopentadiene and 8.50 ml (116 mmol) of acetone were added, then 14.5 ml (174 mmol) of pyrrolidine was dropwise added at 0° C., and the mixture was reacted at room temperature for one night. Then, 10 ml (180 mmol) of acetic acid was added at 0° C. The mixture was diluted with ether and water and then subjected to extraction. Then, the organic phase was separated, washed with water and dried over anhydrous magnesium sulfate to obtain 12.9 g of a brown liquid. The analyzed values are given below.
Reaction SMILES: C(C1C=CC(C[O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:14][CH:13]=2)=CC=1)CCCC>C1COCC1>[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:17][CH:16]=1)=[CH:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCCC=Cc1ccc(OCc2ccc(CCCCC)cc2)cc1
Solvent: C1CCOC1
Product: C=CCCC=Cc1ccc(O)cc1

Procedure:
Preparation of 4-(4-pentylbenzyloxy)-1-(1,5-hexadienyl) benzene ##STR1144## (Compound No. 279 expressed by general formula (1) wherein R1 represents pentyl group, X3 represents --CH2O--, C and D represent 1,4-phenylene ring, l, m, and n are 0, o is 1, p is 2, and R2 and R2 ' are hydrogen atom.) Solution of the 4-(1,5-hexadienyl)phenol (500 mmol) obtained by the same method as in Example 4 in 120 ml of THF was added dropwise to a mixture of sodium hydride (120 mmol), 20 ml of THF, and 50 ml of DMF, and stirred for about 2 hours until generation of hydrogen gas ceased. To this solution was added dropwise a solution of 4-pentylbenzylbromide (45 mmol) in 50 ml of THF at a temperature lower than 0° C. and stirred for further 5 hours. Water in an amount of 100 ml and 100 ml of toluene were added to this solution, and the organic layer was washed with 100 ml of 2M hydrochloric acid and 100 ml of saturated aqueous solution of sodium bicarbonate, washed with water until it became neutral, and then dried with anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was recrystallized from ethanol 5 times as much as the residue to obtain 21 mmol of white oily subject compound. NMR spectrum, mass spectrum, IR spectrum, and the values of elementary analysis of this compound well supported its structure.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>CO>[C:1]([N:9]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([O:13][CH3:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A 5-liter flask was installed in an oil bath on a magnetic stirrer, provided with a reflux condenser and charged with 3.0 liters of methanol and 750 g (3.2 moles) of (trans)-1-benzoyl-4-hydroxy-L-proline. 19 grams of p-toluenesulfonic acid monohydrate (0.1 moles) were added. The mixture was heated to reflux and the esterification followed by TLC. Refluxing was continued until starting material was no longer detectable. 8 grams (0.1 moles) of sodium acetate was added to neutralize the catalyst acid. The condenser was set for distillation and the mixture concentrated at atmospheric pressure until the pot temperature reached 80° C. The distillate was then discarded. The clear residue was rapidly diluted with 2 liters of warm water. The flask was swirled for quick mixing and to permit the ester to crystallize. The slurry was cooled to room temperature with occasional swirling and maintained at room temperature for at least another hour. The crystals were collected on a filter and the filtrate recycled to aid in the transfer. The cake was pressed down and washed with one liter of cold water. The cake was sucked dry as possible and the product dried via a laboratory fluid bed dryer to constant weight. The combined filtrate was vacuum concentrated from the first crop to a small volume and the resulting slurry cooled to room temperature. A second crop of crystals was collected on a filter and washed with a minimum of cold water. The cake was pressed down and suction applied until no more liquid emerged. The second crop was dried to constant weight.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[CH3:16][NH:17][CH3:18]>CO>[CH3:16][N:17]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)[CH3:18]
Reactant: CNC
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Solvent: CO
Product: CN(C)Cc1ccc2oc(S(N)(=O)=O)cc2c1
Temperature: 0 °C

Procedure:
An ice cold, stirred solution of 5-bromomethyl-2-sulfamoylbenzo[b]furan in methanol is treated with an excess of anhydrous dimethylamine to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[CH3:11][CH:12]([CH:14]([OH:20])[C:15]([CH2:18][OH:19])([CH3:17])[CH3:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:7][C:4]([CH3:8])([C:5](=[O:6])[CH:2]([CH3:10])[CH3:1])[C:3]([O:19][CH2:18][C:15]([CH3:17])([CH3:16])[CH:14]([OH:20])[CH:12]([CH3:13])[CH3:11])=[O:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Reactant: CC(C)C(O)C(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)C(C)(C)C(=O)OCC(C)(C)C(O)C(C)C
Temperature: 120 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a 1-liter round bottom flask was charged 2,2,4,4-tetramethyl-1,3-cyclobutanedione (140.2 g, 1.0 moles), TMPD glycol (146.2 g, 1.0 moles) and potassium carbonate (73 g, 0.53 moles). The mixture was heated to 120° C. and held for 4 hours. Reaction was cooled and 200 mL of toluene added. Organic layer was washed 4 times at 70° C. Toluene removed to provide 275 g of product. GC assay of the product was 95.9% (4.6:1 mixture of two major isomers).
Reaction SMILES: N1CCCCC1.[C:7]1([CH3:15])[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].C(=O)=O>N1C=CC=CC=1>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:15]=[CH:17][C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1)=[O:14]
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=Cc1ccc(C=CC(=O)O)cc1
Yield: 78 %

Procedure:
A drop of piperidine was added to a mixture of 13.4 g of p-tolualdehyde, 5 g of malonic acid and 50 ml of pyridine. The mixture was heated to reflux until evolution of carbon dioxide was discontinued. The reaction mixture was concentrated under reduced pressure and, 200 ml of water and 12 g of hydrogen sodium carbonate were added thereto. The mixture was washed with ethyl acetate and made acidic with conc. hydrochloric acid. The precipitated crystals were taken out by filtration, thoroughly washed with water and dried to give 6.6 g of p-formylcinnamic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:7]=1.[C:25]([OH:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:12]([CH3:14])[CH3:13])[CH:15]([CH3:16])[CH3:17])[CH:7]=1.[C:25]([O-:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CC(C)=O
Product: O=C([O-])c1ccccc1
Reaction time: 0.17 h

Procedure:
3.25 g of tolterodine dissolved in 50 mL of acetone was mixed at room temperature (25° C.) with 1.22 g of benzoic acid, which was suspended in 50 mL of acetone, and then stirred. In 10 minutes, there started to appear a solid precipitate. 50 mL of acetone was added thereto and the mixture was stirred at room temperature (25° C.) for 1 hour. The resulting solid precipitate temperature (25° C.) for 24 hours and 3.27 g (theoretical yield: 73.1%) of the final product in white solid was obtained.
Reaction SMILES: N[C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([C:10]#[N:11])=[CH:4][C:3]=1[O:12][C:13]1[C:14]([F:30])=[C:15]([CH2:20][NH:21][C:22]([C:24]2[NH:28][CH:27]=[N:26][C:25]=2[Cl:29])=[O:23])[CH:16]=[CH:17][C:18]=1[Cl:19].N(OC(C)(C)C)=O>C(#N)C>[Cl:29][C:25]1[N:26]=[CH:27][NH:28][C:24]=1[C:22]([NH:21][CH2:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([O:12][C:3]2[CH:4]=[C:5]([C:10]#[N:11])[C:6]([F:9])=[C:7]([Cl:8])[CH:2]=2)[C:14]=1[F:30])=[O:23]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c(N)c(Cl)c1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a solution of N-({3-[(2-amino-3-chloro-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (38 mg, 0.080 mmol) in Acetonitrile (10 ml) was added tert-butyl nitrite (0.021 ml, 0.161 mmol) and the reaction mixture was stirred at RT for 2 hours. The reaction was quenched with methanol, the solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (17 mg, 0.037 mmol, 46% yield). 1H NMR (DMSO-d6) δ ppm 8.25 (br. s., 1H) 7.74 (s, 1H) 7.69 (dd, 1H) 7.60 (t, 1H) 7.45 (d, 1H) 7.32 (t, 1H) 4.48 (d, 2H). LC-MS (ES+) m/z 457.05, [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:8]=2)[NH:3]1.[NH:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>C(O)C.N1CCCCC1>[O:1]=[C:2]1[C:10](=[CH:25][C:21]2[NH:20][CH:24]=[CH:23][CH:22]=2)[C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccc(NC(=O)c3ccccc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(NC(=O)c3ccccc3)ccc2C1=Cc1ccc[nH]1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 6-amino-1,3-dihydro-indol-2-one (0.15 g, 1.0 mmol) in 2:1 CH2Cl2-1,4-dioxane mixture (30 ml) is added triethylamine (0.30 g, 3.0 mmol) and benzoyl chloride (0.14 g, 1.0 mmol). The reaction is stirred for 2 hours at room temperature, and then a saturated aqueous solution of NH4Cl is added. The precipitate is collected and washed with water to give crude N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide. To a solution of this benzamide (20 mg, 0.079 mmol) and 1H-pyrrole-2-carbaldehyde (7.6 mg, 0.079 mmol) in ethanol (2 ml) is added 2 drops of piperidine. It is stirred at 80° C. for 4 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol and purified by HPLC(C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give the desired compound as an orange solid: 1H NMR (DMSO-d6) δ 6.34 (s, 1H), 6.80 (s, 1H), 7.33 (s, 1H), 7.39 (d, 1H, J=8.4 Hz), 7.53 (t, 2H, J=7.8 Hz), 7.57 (s, 1H), 7.59 (s, 1H), 7.61 (s, 1H), 7.64 (s, 1H), 7.96 (d, 2H, J=7.8 Hz), 10.29 (s, 1H), 10.94 (s, 1H), 13.23 (s, 1H); LC-MS: 330.1 (MH+).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:3]2[N:4]=[C:5]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:6]3[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1
Product: O=c1[nH]ccc2nc(N3CCC(O)CC3)nc(Nc3cccc(C(F)(F)F)c3)c12

Procedure:
The title compound was prepared as described in Example 1g by starting from 2-(methylthio)-4-(3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (100 mg, 0.26 mmol) and 4-hydroxypiperidine to yield the title compound (73 mg) as white solids. MS m/z: 406 (M+H)+, 1H NMR (300 MHz), δ ppm 1.21-1.35 (m, 4H), 3.76-3.78 (m, 1H), 4.26-4.28 (m, 4H), 6.17 (d, J=7.2 Hz, 1H), 7.38-7.68 (m, 4H), 7.90 (s, 1H), 8.61 (s, 1H), 11.42 (s, 1H), 12.10 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]([OH:11])=O)[O:6][N:5]=1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:42][C@@H:43]([CH3:60])[CH2:44][N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:57]=[C:56]([F:58])[C:53]([C:54]#[N:55])=[C:52]([Cl:59])[CH:51]=2)=[N:46]1>CN(C=O)C.O.CCOC(C)=O>[Cl:59][C:52]1[CH:51]=[C:50]([C:47]2[CH:48]=[CH:49][N:45]([CH2:44][C@@H:43]([NH:42][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:8]=3)=[O:11])[CH3:60])[N:46]=2)[CH:57]=[C:56]([F:58])[C:53]=1[C:54]#[N:55]
Reactant: CC(C)c1noc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
3-Isopropyl-1,2,4-oxadiazole-5-carboxylic acid (1.281 mmol, 0.2 g) was dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (1.601 mmol, 0.307 g), DIPEA (3.20 mmol, 0.414 g) and HOBt (1.601 mmol, 0.216 g) were added and the resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.067 mmol, 0.298 g) dissolved in DMF (5 ml) was added and the resulting mixture was stirred at RT for 2 days. The mixture was diluted with water and EtOAc, washed with 2 M Na2CO3, water and brine. The combined organics were dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.0056 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, 3H), 1.38 (d, 6H), 3.11-3.26 (m, 1H), 4.26-4.35 (m, 1H), 4.41-4.50 (m, 1H), 4.55-4.67 (m, 1H), 6.65-6.69 (m, 1H), 7.54-7.57 (m, 1H), 7.64-7.69 (m, 1H), 7.74-7.77 (m, 1H), 8.39 (d, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[CH3:41][N:42]1[CH2:48][CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.[OH-].[Na+]>C(O)C.CCN(CC)CC.O>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][CH2:48][N:42]([CH3:41])[CH2:43][CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CN1CCCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc2nc(-c3ccnc(N4CCCN(C)CC4)n3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 90 °C

Procedure:
A vial was charged with a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (10 mg), dioxane (500 μL), H2O (200 μL), Et3N (50 μL), and 1-methyl-1,4-diazepane (40 mg). The reaction was heated to 90° C. for 1 h. Ethanol (absolute, 500 μL) and 5 M aq NaOH (500 μL) were added. The reaction was heated to 90° C. for 30 min. The reaction was cooled to 23° C. and directly purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) giving the title compound. 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J=5.1 Hz, 1H), 7.92 (s, 1H), 7.74-7.47 (m, 5H), 5.24 (s, 1H), 4.67-3.39 (m, 6H), 3.39-3.20 (m, 2H), 2.92 (s, 3H), 2.63 (s, 3H), 2.29-2.10 (m, 2H), 0.97 (s, 9H). LCMS-ESI+: calc'd for C30H35ClN5O3S [M+H±]: 580.2, 582.2; Found: 580.4, 582.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.C(=[NH:27])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(Cl)(Cl)Cl>[NH2:27][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)cnc1OC
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(N)cnc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
In a nitrogen atmosphere, 11.38 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate is dissolved in 227 mL of toluene. To the solution are successively added 10.32 g of benzophenone-imine, 0.42 g of tris(dibenzylideneacetone) dipalladium, 0.86 g of (s)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 6.20 g of sodium t-butoxide. The resulting mixture is stirred at 80° C. for one hour. The reaction mixture is cooled and filtered. The filtrate is purified by column chromatography (eluent: toluene:ethyl acetate=20:1). The oily product thus obtained is dissolved in 140 mL of tetrahydrofuran, 7 mL of 2 mol/mL hydrochloric acid is added thereto and the resulting solution is stirred at ambient temperature for 15 minutes. A mixture of 200 mL of chloroform and 50 mL of water is added to the resulting reaction mixture, and alkalified with 1 mol/mL of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: toluene:ethyl acetate 1:1) to obtain 3.64 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([CH2:9][C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)[C:12](=[O:15])[NH:13][N:14]=2)[CH2:5]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].ClCCl>[C:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([CH2:9][C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:31]4[CH:40]=[C:39]5[C:34]([CH:35]=[CH:36][CH:37]=[N:38]5)=[CH:33][CH:32]=4)=[CH:18][CH:17]=3)[C:12](=[O:15])[NH:13][N:14]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 5-{[(3S)-1-acetyl-3-pyrrolidinyl]methyl}-4-(4-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.211 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.216 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (20 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized to purify the title compound (29 mg, 33%). MS(ES)+ m/e 413.8 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)[CH3:2].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH:7]=1)[CH3:2]
Reactant: CCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cn(Cc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
A mixture of 4-ethyl-1H-imidazole (2.46 g), 4-nitrobenzyl bromide (6.08 g), potassium carbonate (7.08 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1.95 g) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, v/v). A mixture of 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1.95 g), 10% palladium carbon (200 mg) and ethanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-(4-aminobenzyl)-5-methyl-1H-imidazole (1.44 g) as colorless prism crystals. melting point: 137-138° C.