Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:33]=[CH:32][S:31][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:34]>O1CCOCC1>[ClH:34].[NH2:23][CH:20]1[CH2:21][CH2:22][N:18]([C:16]2[N:17]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]3[N:33]=[CH:32][S:31][C:14]=3[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2nc(N3CCC(NC(=O)OC(C)(C)C)C3)nc3scnc23)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Yield: 100 %

Procedure:
A solution of tert-butyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate (191 mg, 0.40 mmol) in 50 mL of saturated HCl in dioxane was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure to give 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (165 mg, 100%) as a solid. This was used directly in the next step without further purification. LC-MS: 373.1 [M+H]+, tR=1.15 min.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(Cl)c(F)c3)c2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(Cl)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 40.9 %

Procedure:
An ice cold solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21 mg, 0.055 mmol) in N,N-Dimethylformamide (DMF) (500 μl) was treated with K2CO3 (37.9 mg, 0.275 mmol), DIEA (47.9 μl, 0.275 mmol), and 4-chloro-3-fluorobenzyl bromide (61.4 mg, 0.275 mmol), stirred at rt for 1 hr, and then heated to 70° C. for 18 hours. The reaction was diluted with water, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-chloro-3-fluorobenzyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (26.2 mg, 0.050 mmol, 91% yield) as clear oil. The ester intermediate was dissolved in Methanol (500 μl) and Tetrahydrofuran (THF) (500 μl), treated with 2M LiOH (150 μl, 0.3 mmol), and stirred at 60° C. for 2.5 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA, 12 min) to give title compound (11.6 mg, 0.022 mmol, 40.9% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.43 (s, 3H), 3.65 (s, 3H), 5.46 (s, 1H), 5.79 (d, J=2.3 Hz, 2H), 6.06 (d, J=2.8 Hz, 1H), 6.94-7.07 (m, 3H), 7.24-7.31 (m, 2H), 7.30-7.38 (m, 2H), 7.49-7.56 (m, 1H); LCMS (m/z) ES+=511 (M+1).
Reaction SMILES: C(O)(=O)C.[C:5]([C:9]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].[Br:17]Br>O>[C:5]([C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([Br:17])=[C:13]([CH3:15])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: BrBr
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(C)(C)C)cc(C)c1Br
Yield: 94.7 %

Procedure:
Under an inert atmosphere, 225 g of acetic acid was put into a 500 ml three-necked flask, and 24.3 g of 5-t-butyl-m-xylene was added. Then, after adding 31.2 g of bromine, it was reacted at 15-20° C. for 3 hours. The reaction liquid was added to 500 ml of water, and the deposited precipitate was filtrated. It was washed with 250 ml of water twice and 34.2 g of white solid was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[F:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][O:21]2)=[CH:16][CH:15]=1>O=P(Cl)(Cl)Cl.C(OCC)C.C(N(CC)CC)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]2[O:21][C@@H:22]([O:5][CH:4]([C:6]3[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=3)[CH2:3][CH2:2][Cl:1])[CH2:23][CH2:24][CH2:25]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(OCC2CCC=CO2)cc1
Reactant: OC(CCCl)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CCCl)c3ccc(F)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.2 %

Procedure:
One drop of phosphorus oxytrichloride was added to a solution of 222 mg of 3-chloro-1-(4-fluorophenyl)propanol and 233 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran in 5 ml of diethyl ether, and the mixture was stirred at room temperature for 2 days. At the end of this time, 2 drops of triethylamine were added, the solvent was evaporated off and the residue was purified by column chromatography through silica gel, to give 245 mg of the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH3:31])[C:5](=[O:30])[CH2:6][NH:7][C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:9]=2)[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>>[Cl:32][C:13]1[C:8]([NH:7][CH2:6][C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:31])=[O:30])=[N:9][C:10]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)=[N:11][C:12]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1)C1CC1
Reactant: O=C1CCC(=O)N1Cl
Product: CN(C(=O)CNc1nc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2)c1Cl)C1CC1

Procedure:
N-Cyclopropyl-N-methyl-2-[6-phenyl-2-(4-trifluoromethyl-phenyl)-4-pyrimidinylamino]acetamide and N-chlorosuccinimide are treated in the same manner as in Example 1, and the resultant is recrystallized from ethanol to give the desired compound.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[O:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=2)[CH2:47][CH2:46]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:55][C:54]4[CH:56]=[CH:57][C:51]([N:48]5[CH2:47][CH2:46][O:45][CH2:50][CH2:49]5)=[CH:52][CH:53]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-morpholinoaniline as the aniline component. (13%, MS=541.3 (M+H))
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[H][H]>O>[Cl:1][CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Solvent: CO
Solvent: O
Product: CCCC(O)C(Cl)C(=O)OCC
Temperature: 70 °C
Reaction time: 14 h
Yield: 72.3 %

Procedure:
Ethyl 2-chloro-3-oxohexanoate (2.5 g, 13 mmol), methanol (7.5 ml) and water (0.75 ml) were mixed, and nitrogen substitution was carried out after reducing the pressure. The above catalyst solution was added thereto, and hydrogen substitution (3 atmospheres) was carried out under reduced pressure. The mixture was stirred at 70° C. for 14 hours. After the mixture was cooled to room temperature, the solvent was evaporated away under reduced pressure. The concentrated matter was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.83 g, yield: 72%) ((2S,3R):(2S,3S):(2R,3S):(2R,3R)=6.2:58.5:33.2:2.2).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][SH:36]>>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][S:36][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1
Reactant: CN(C)CCS
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: Cl
Product: CN(C)CCSc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 2-dimethylaminoethanethiol hydrochloric acid salt.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[CH:25]([C:28]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:29]=1[CH:30]=O)([CH3:27])[CH3:26]>ClCCl>[CH:25]([C:28]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:29]=1[C:30]#[CH:1])([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(C)C)c(C=O)c(C(C)C)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Solvent: ClCCl
Product: C#Cc1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred, degassed solution of triphenylphosphine (21 g, 80 mmol) and carbon tetrabromide (13.3 g, 40 mmol) in dry dichloromethane at 0° C. was added 2,4,6-triisopropylbenzaldehyde (4.64 g, 20 mmol). The resulting mixture was stirred overnight as it was allowed to slowly warm to room temperature. Solids were filtered off, and the volatiles were evacuated under reduced pressure. Pentane was then added, and after extensive trituration the mixture was filtered on a SiO2 plug with pentane as the eluent to afford after evaporation of the solvents the crude intermediate dibromoalkene as a colorless oil that is directly taken to the next step without surther purification. The intermediate is dissolved in dry THF (50 mL), and to the stirred solution cooled to −78° C. is then added nBuLi (2.5M in hexanes, 10 mL) dropwise. The mixture is stirred for 1 hour at −78° C., and let to warm to room temperature for an additional hour. The reaction is quenched by the addition of saturated aqueous NH4Cl, extracted with pentane, and the organic fractions are dried over anhydrous MgSO4. After filtration and evaporation of the solvents, the crude alkyne is purified by filtration on a SiO2 plug with pentane as the eluent. A small crystal of hydroquinone is added to stabilize the product, and the volatiles are evaporated under reduced pressure to afford 9d as a pale pinkish oil (2.63 g, 58% over 2 steps). 1H-NMR (CDCl3, 300 MHz): δ=7.00 (s, 2H), 3.56 (sept, J=6.9 Hz), 3.43 (s, 1H), 2.91 (sept, J=6.9 Hz), 1.28 (d, J=6.9 Hz, 12H), 1.27 (d, J=6.9 Hz, 6H). 13C-NMR (CDCl3, 75 MHz): δ=151.6, 149.7, 122.3, 120.5, 84.5, 81.0, 34.7, 31.8, 24.1, 23.5. Characterization data for 9d are consistent with literature values. (See Knorr, R.; Ruhdorfer, J.; Böhrer, P.; Bronberger, H.; Räpple, E. Liebigs Ann. Chem. 1994, 433-438).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 4-tert-butylbenzaldehyde (3.24 g, 20.0 mmol) and 4-chlorobenzylamine (2.43 mL, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the reaction mixture was stirred at room temperature overnight. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (50 mL) and aqueous 1 M KOH (50 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 4.31 g (75%) of white solids.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[C@H:6]([OH:28])[C@@H:7]([NH:15][C:16]([C:18]1[NH:27][C:21]2=[CH:22][N:23]=[C:24]([Cl:26])[CH:25]=[C:20]2[CH:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[Cl:26][C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([C:16]([NH:15][C@@H:7]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:6]([OH:28])[C:5]([OH:29])=[O:4])=[O:17])[NH:27][C:21]2=[CH:22][N:23]=1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydroxide solution (0.24 mL, 2M, 0.48 mmol) was added to a solution of (S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-(R)-2-hydroxy-4-phenylbutyric acid methyl ester (EXAMPLE 43, 170 mg, 0.44 mmol) in methanol (5 mL) and the reaction stirred at rt for 24 h. The solvent was removed in vacuo and the residue partitioned between hydrochloric acid (1N, 30 mL) and ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid. δH DMSO): 2.71 (1H, dd), 2.91 (1H, dd), 3.56 (1H, d), 4.38-4.46 (1H, m), 4.77 (1H, s), 6.76 (1H, s), 7.11-7.16 (1H, m), 7.19-7.27 (4H, m), 7.45 (1H, s), 8.44-8.52 (2H, m); m/z (ES+)=374 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1ccnc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5nccn5C)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.035 g, 0.088 mmol, 1 eq), EtOH (2 mL) and DMF (0.3 mL), p-anisaldehyde (0.013 g, 0.097 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.26 mL, 0.26 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a dark yellow solid (0.009 g, 21%); 1H-NMR (500 Mz, DMSO-d6): δ 2.55-2.63 (m, 4H, piperazine N(CH2)2), 3.58-3.67 (m, 6H, piperazine N(CH2)2 and NCH2), 3.72 (s, 3H, imidazole Me), 3.84 (s, 3H, OMe), 6.77 (d, 1H, J=1.0 Hz, imidazole 4-H), 7.07-7.13 (m, 3H), 8.13 (d, J=8.5 Hz, 2H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.33 min—482/484 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 482.1297, calculated for C22H25BrN7O (M+H)+: 482.1304.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](#[N:12])[CH:10]=[CH2:11].C[O-].[Na+]>>[CH2:7]([S:8][CH2:11][CH2:10][C:9]#[N:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: N#CCCSCc1ccccc1

Procedure:
β-Benzylmercaptopropionitrile was prepared according to the procedure of Example 1 using α-toluenethiol (25.0 g; 0.20 moles), acrylonitrile (10.6 g; 0.20 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[NH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1)=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]([NH2:18])=[O:20])=[CH:22][CH:23]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: NC(=O)c1ccc(CC(=O)O)cc1
Product: NC(=O)c1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 11.5 %

Procedure:
Example 10 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and [4-(aminocarbonyl)phenyl]acetic acid (0.036 g) to give the title compound (0.01 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:27][OH:28]>O>[OH:28][N:27]=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: ON=C1CC(c2ccccc2)Oc2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one (50.0 g), methanol (535 ml), water (50 ml), potassium carbonate (59.3 g), and hydroxylamine HCl (59.8 g) was heated at reflux for 16 hours, then poured into ice-water; the oxime of 2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one was filtered off, washed with water, then dried in air. Yield: 52 g.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH3:24])=[CH:11][N:10]=[C:9]1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)C1C=CC=CC=1.[H][H]>CO>[CH3:24][C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:17][C:13]=1[C:12]1[NH:8][C:9]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[N:10][CH:11]=1
Reactant: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)n1Cc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)[nH]1
Reaction time: 70 h

Procedure:
The title compound is prepared from 5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole (Example 71) in a similar manner as described in Tetrahedron Letters, 2008, 64(26), 6060-6072. In this case, 5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole in methanol is debenzylated by hydrogenation under an atmospheric pressure of hydrogen using a balloon with vigorous stirring for 70 h under reflux. The reaction mixture is filtered through Celite, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=1)#[N:2].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:13]=[O:14])=[O:8])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: N#Cc1ccc(C(=O)N=C=O)cn1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 6-cyanonicotinamide (Synthesis (1983), 316) (1.2 g) in 1,2-dichloroethane (28 ml) was added oxalyl chloride (1.3 ml) and the mixture was heated at reflux with stirring for 2.5 hours. The reaction mixture was cooled and the solvents were removed in vacuo to yield 6-cyanonicotinoyl isocyanate as a yellow solid residue. Then in a similar manner to Example 1, starting material step (a), this residue, t-butyl 4-aminophenoxyacetate, acetate salt (1.59 g), triethylamine (3.8 ml) and acetonitrile (140 ml total) gave, after stirring at ambient temperature for 3 hours followed by evaporation of the solvents, a yellow solid, which was collected, washed with cold acetonitrile and with hexane and dried to give t-butyl 4-[3-(6-cyanopyrid-3-ylcarbonyl)ureido]phenoxyacetate (2.37 g): m.p. 220°-222° C. (decomposes); NMR Spectrum (DMSO-d6) 1.48 (9H, s), 4.67 (2H, s), 6.94 (2H, d), 7.52 (2H, d), 8.27 (1H, d), 8.58 (1H, dd), 9.25 (1H, d), 10.41 (1H, s), 11.40 (1H, s); Mass Spectrum m/Z 396 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluorophenol (1.06 g) in anhydrous DMF (10 mL) were added anhydrous potassium carbonate (2.07 g) and 4-fluorobenzaldehyde (1.2 g) at room temperature. The reaction was stirred at 100° C. for 16 h, then cooled to room temperature and diluted with ether. The organic layer was washed with 1N sodium hydroxide, and then with water, dried over sodium sulphate, and concentrated under reduced pressure. The crude aldehyde obtained was purified by flash-column chromatography on silica-gel using 20% EtOAc in hexanes to provide the pure aldehyde.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][N:16]2C(=O)C4C(=CC=CC=4)C2=O)[CH:3]3[CH2:2]1.O.NN.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][NH2:16])[CH:3]3[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCc2cccc3c2C1CC3
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCc2cccc3c2C1CC3
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of 2-[3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-isoindole1,3-dione (2 g, 5.78 mmol) and hydrazine hydrate (2.9 g, 57.8 mol) in ethanol (60 mL) was refluxed for 1 h. The reaction mixture was cooled down and treated with an additional amount of ethanol (30 mL) and concentrated HCl (7 mL). Then the reaction mixture was refluxed for 4 h and left overnight in a refrigerator. The precipitate was filtered off, and the solvent was evaporated. The residue was redissolved in water (15 ml) and made alkaline with 25% ammonia. Then, was extracted with CH2Cl2 (3×120 mL), the organic layer was dried over Na2SO4, and evaporated to dryness. The crude was dissolved in ethylacetate. A 2.8 M solution of hydrogen chloride in ethanol was then added. The precipitate formed was collected by filtration to give the desired product (0.80 g, 64% yield) as a beige solid.