Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][C:25]=4[Cl:33])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>C(O)C>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:19]2[C:17]3=[N:18][C:13]([C:11](=[O:12])[NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])=[CH:14][CH:15]=[C:16]3[N:21]=[C:20]2[CH3:22])=[C:25]([Cl:33])[CH:26]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(N)cc1Cl
Yield: 32.6 %

Procedure:
5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (245 mg) was suspended in ethanol (3 ml) and reduced iron (141 mg) and acetic acid (0.289 ml) were added, and the mixture was refluxed under heating overnight. The reaction mixture was filtered through Celite, and the filtrate was washed with a mixed solvent of methanol/chloroform (1/4) and the filtrate was concentrated under reduced pressure. To the concentrated residue were added a saturated aqueous sodium hydrogen carbonate solution, water and a mixed solvent of methanol/chloroform (1/4) and the aqueous phase was made alkaline. The precipitated insoluble matter was filtered through Celite and the filtrate was washed with a mixed solvent of methanol/chloroform (1/9). The filtrate was partitioned and the organic layer was dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to give a crude product as a pale-brown powder. The crude product (100 mg) was recrystallized from N,N-dimethylformamide-water to give 3-(4-amino-2-chlorobenzyl)-5-(benzenesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine (75 mg) as brown crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][CH2:42][C@@H:43]1[CH2:48][CH2:47][C@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:40])([CH3:37])[CH3:36]>>[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][N:20]2[C:49]([C@@H:46]2[CH2:45][CH2:44][C@H:43]([CH2:42][NH:41][C:39](=[O:40])[O:38][C:35]([CH3:36])([CH3:34])[CH3:37])[CH2:48][CH2:47]2)=[O:50])[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:16][CH3:17])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)[C@H]3CC[C@@H](CNC(=O)OC(C)(C)C)CC3)nc2Cl)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 67 was treated with cis-4-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid to give the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N+:14]=[N-:15])=[CH:9][CH:8]=1)([O-:3])=[O:2].[N+:23]([C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32](=[O:43])[C:33](=[CH2:42])[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[C:38]([O:37][C:35]([NH:34][C:33]1([C:32]([O:31][CH2:30][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:45][CH:44]=2)=[O:43])[CH2:42][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:4]=3[N+:1]([O-:3])=[O:2])=[CH:8][CH:9]=2)[NH:14][NH:15]1)=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC(c2ccc(Oc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc2)NN1
Temperature: -15 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2,4-dinitrophenoxy)-phenyldiazomethane in CH2Cl2 (20 ml) is added to a solution of Boc-dehydroalanine-p-nitrobenzyl ester (2) in 20 ml CH2Cl2 at -15° C. After stirring 1 hr at -15° C. and 4 hr at 25°, the solution is evaporated to dryness and the residue is triturated with hexane. The solid product, p-nitrobenzyl 3-t-butoxycarbonylamino-5-(4-[2,4-dinitrophenoxyl]-phenyl)-pyrazoline-3-carboxylate (18), is recrystallized from ethyl acetate-hexane to constant melting point. NMR (CDCl3)δ: 4.8-5.4 (m, 1H, CH--N=N).
Reaction SMILES: C(CCCCCCCCCCN)C=C.C(N(CC)C(C)C)(C)C.ClC([O:27][CH2:28][CH:29]1C2C=CC=CC=2C2C1=CC=CC=2)=O.[C:42]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]CC=C)([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43]>ClCCl>[C:42]([N:59]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:29][CH:28]=[O:27])([O:44][CH2:45][CH:46]1[C:47]2[C:52](=[CH:53][CH:54]=[CH:55][CH:48]=2)[C:51]2[C:58]1=[CH:57][CH:56]=[CH:49][CH:50]=2)=[O:43]
Reactant: C=CCCCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: C=CCCCCCCCCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 5 °C

Procedure:
A three-necked, 500 mL round bottom flask equipped with a thermometer, mechanic stirrer and an addition funnel was purged with nitrogen and charged with N-allyldecylamine (˜0.11 mol) in dichloromethane from step a (210 mL) and N,N-diisopropylethylamine (20.0 mL, 14.8 g, 0.113 mol). The mixture was cooled in a 5° C. ice bath and a solution of 9-fluorenylmethyl chloroformate (25.6 g, 0.099 mol) dissolved in dichloromethane (50 mL) was added dropwise (total volume approximately 330 mL). The reaction was exothermic and the internal temperature was controlled below 10° C. throughout the 9-fluorenylmethyl chloroformate addition. The reaction mixture was warmed to 21° C. when the addition was finished, and monitored by the disappearance of 9-fluorenylmethyl chloroformate and the formation of N-FMOC-N-allyldecylamine using HPLC (retention time for FMOC-chloride=3.08 min; retention time for product=7.96 min). The reaction mixture was washed with 0.01 N HCl (100 mL). The organic layer was collected and used without further purification.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:4][F:5].[CH3:15][O:16][C:17]([C:19]1[S:28][C:22]2[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=2[C:20]=1[CH3:29])=[O:18]>>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:8]=1[NH:9][C:26]1[C:21]2[C:20]([CH3:29])=[C:19]([C:17]([O:16][CH3:15])=[O:18])[S:28][C:22]=2[N:23]=[CH:24][N:25]=1)[CH2:2][F:1]
Reactant: Nc1ccc(F)cc1OC(CF)CF
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(CF)CF)c2c1C

Procedure:
Prepared analogously to example 21.1 using 2-(1,3-difluoropropan-2-yloxy)-4-fluoroaniline and 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH:5][C:4](=[O:12])[CH:3]=1.[H-].[Na+].I[CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:16][CH:17]([CH3:19])[CH3:18])[N:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)CI
Reactant: CC(C)(C)c1cc(Br)cc(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(Br)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of compound 17b (1.0 g, 4.33 mmol) in dry DMF (10 mL) was added NaH (0.31 g, 13 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1-iodo-2-methylpropane (1.35 g, 7.3 mmol) was added and the resulting mixture was heated at 80° C. overnight. The mixture was quenched with water (5 mL) and extracted with EA twice. The combined organic layers were washed with brine (3×), concentrated and purified by CC (PE/EA=50/1) to give compound 17c (1.0 g, 91%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:34][CH2:33][C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:17]=[CH:18][C:13]=2[C:12]1=[O:35].C1COCC1>[Pd].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N:11]2[CH2:34][CH2:33][C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[N:17]=[CH:18][C:13]=3[C:12]2=[O:35])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
To a solution of 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (100 mg, 0.211 mmol) in the mixed solvent of THF (5 ml) and methanol (5 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [45] (Yield: 86.45 mg, 92.3%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(F)ccc1Br
Temperature: 25 °C
Yield: 111.4 %

Procedure:
In a 250 mL r.b. flask, a solution of 2-bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mmol, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3×120 mL); the extracts were washed with brine (1×80 mL), combined, dried (K2CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65° C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo-5-fluoroanisole: 1H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1H); 6.64 (dd, J=10.4, 2.8, 1H); 5.58 (dt, J=10.4, 2.4, 1H); 3.88 (s, 3H).
Reaction SMILES: O[CH:2]1[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl.O>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][C:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2[O:4][C:3]([CH3:22])([CH3:23])[CH:2]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:6]=2[C:7]=1[CH3:21])=[O:20]
Reactant: C1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(N1CCCCC1)C(C)(C)O2
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (450 mg, 1.41 mmol) obtained in Example 234 in dichloromethane (3 mL) was added triethylamine (0.79 mL, 5.64 mmol), and then added dropwise with ice-cooling methanesulfonyl chloride (0.22 mL, 2.82 mmol). The reaction solution was stirred for 30 minutes, and to the reaction solution was added piperidine (0.70 mL, 7.05 mmol), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=20:1) to obtain 270 mg (yield: 50%) of the title compound. Melting point: 229-230° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25]C=[CH:23][C:22]=2O)O1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:10]1[CH:9]=[CH:8][C:3]2[C:4](=[O:5])[O:6][C:7]3[C:25]([C:2]=2[CH:11]=1)=[CH:26][CH:21]=[CH:22][CH:23]=3
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: COC(=O)c1ccc(C)cc1Br
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: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(=O)oc3ccccc3c2c1
Temperature: 130 °C

Procedure:
A sealed tube containing methyl 2-bromo-4-methylbenzoate (650 mg, 2.84 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (781 mg, 3.55 mmol) and TETRAKIS(TRIPHENYLPHOSPHINE)PALLADIUM(0) (164 mg, 0.142 mmol) was evacuated and backfilled with nitrogen before Toluene (1.29E+04 μl) and Ethanol (1290 μl) were added, followed by K2CO3 (2838 μl, 5.68 mmol). The tube was heated in the microwave for 25 minutes at 130° C. The mixture was cooled, diluted with chloroform (15 mL), washed with aqueous ammonium chloride (saturated, 10 mL), dried (Na2 SO4), filtered and the solvent was evaporated under reduced pressure. The crude product was then purified by column chromatography on silica gel Isolute Flash Si; eluting with 5-10% EtOAc/isohexane to give 9-methyl-6H-benzo[c]chromen-6-one. 1H NMR (500 MHz; CDCl3): 8.32 (d, J=8.3 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.51 (m, 1H), 7.37 (m, 3H), 2.59 (s, 3H); LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:8][C:5]2=[N:6][CH:7]=1.[O:36]1[CH2:38][C@H:37]1[CH2:39][OH:40]>CO>[Cl:1][C:2]1[C:3]([NH:25][CH:26]2[CH:31]3[CH2:32][CH:28]([CH:29]=[CH:30]3)[CH:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:20][CH2:21][N:22]([CH2:38][C@H:37]([OH:36])[CH2:39][OH:40])[CH2:23][CH2:24]3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC[C@@H]1CO1
Reactant: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(C2CCNCC2)c1
Solvent: CO
Product: COc1ccc(-c2nc3c(NC4C5C=CC(C5)C4C(N)=O)c(Cl)cnc3[nH]2)c(C2CCN(C[C@H](O)CO)CC2)c1

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-methoxy-2-piperidin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XXX) (60 mg, 0.1 mmol) was stirred with (R)-1-oxiranyl-methanol (14.0 mg, 1.5 mmol) in methanol (5 mL) in a sealed tube overnight. The reaction was concentrated and the product purified by reverse phase chromatography (Gilson). Desired fractions were collected, combined, and lyophilized to afford the title compound as a white lyophilate (46 mg, 70%). 1H NMR (d-chloroform): 9.16 (br s, 1H), 8.03 (s, 1H), 7.65 (m, 2H), 7.30 (m, 1H), 7.02 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.32 (s, 1H), 6.17 (s, 1H), 5.52 (br m, 1H), 5.15 (m, 1H), 3.87 (m, 1H), 3.85 (s, 3H), 3.65-3.26 (m, 8H), 3.22-2.70 (m, 5H), 2.24 (d, J=9 Hz, 1H), 2.12 (m, 4H), 1.94 (m, 1H), 1.28 (s, 1H), 1.18 (d, J=5 Hz, 3H). MS: 567.17 (M+H). HPLC retention time: 1.91 minutes (G Method).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:20])[N:15]=[CH:16]N(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:29][C:30](=[O:33])[CH2:31][CH3:32]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:20][C:29]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCC(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 90 °C
Yield: 72 %

Procedure:
To a solution of 0.83 mmol 4-(dimethylaminomethylene-thiocarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml ethanol were added 2.50 mmol triethylamine and 1.00 mmol 1-bromo-2-butanone. The mixture was heated at 90° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 72%). MS (m/e): 326.1 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.Cl.[CH3:24][O:25][NH2:26]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[N:26][O:25][CH3:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: CON
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1cccc(C(C)c2nc(N)no2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 105.2 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.60 g, 2.0 mmol) in pyridine (10 ml) was added methoxyamine hydrochloride (0.224 g, 2.7 mol). After reflux with stirring for 18 h, the mixture was poured upon ice water, extracted with ethylacetate. The extracts were washed with water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(α-methoxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.678 g, quantitive yield) as oily substance: NMR(CDCl3)δ 1.70 (d, 3H), 3.97(s, 3H), 4.24(q, 1H), 4.48(broad singlet, 2H), 7.21-7.58(m, 9H) ppm; IR(neat) 3310, 1625, 1585, 1410, 1050 cm-1.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:23])[C@H:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:7][C:8]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH:11]=1)=[O:9].O.[CH]Cl>C1COCC1.O>[S:14]1[C:10]([C:8]([NH:7][C@H:6]([C:5]([OH:23])=[O:4])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:9])=[CH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]1=2
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1cc2ccccc2s1
Agent: [CH]Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2s1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
Lithium hydroxide (1.41 g, 59 mmol) was added in one portion to a stirred solution of N-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester (8.99 g, 29.4 mmol) in THF/H2O (1/1, 300 ml). After stirring for 12 hours at room temperature, the mixture was poured into water and acidifed to pH 1 with cHCl and extracted with Et2O (×2). Evaporation under reduced pressure afforded the title compound as a yellow solid, 6.1 g, 71% yield.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[Br:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1C.Cl>ClC(Cl)C>[Br:16][C:17]1[S:18][C:19]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:20][CH:21]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccsc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)c1ccc(Br)s1
Reaction time: 4 h

Procedure:
1.90 g of phthalic anhydride and 3.58 g of aluminum chloride were dissolved in 40 ml of dichloroethane, and 2-bromo-3-methylthiophene was added dropwise to the solution at room temperature. After stirring the solution for 4 hours, the reaction solution was poured into a 1-N hydrochloric acid under cooling with ice, and extracted with chloroform. By purifying the extract by silica gel chromatography (eluent: chloroform, ethyl acetate), 1.70 g of o-(5-bromo-2-thenoyl)benzoic acid was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[O:21][C:22]([F:25])([F:24])[F:23]>N1C=CC=CC=1>[C:19]([C:16]1[N:17]([CH3:18])[C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:8]([O:21][C:22]([F:24])([F:25])[F:23])[CH:9]=2)=[CH:14][CH:15]=1)#[N:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(OC(F)(F)F)c1
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)c(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 49.7 %

Procedure:
Methanesulfonyl chloride (0.05 mL, 0.65 mmol) was added dropwise to a solution of 5-[4-amino-3-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (0.16 g, 0.56 mmol) in dry pyridine (2.0 mL). The solution was heated to 50° C. overnight. The solution was cooled to room temperature and pre-adsorbed onto the Celite™ reagent. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.1 g (50%) of N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)phenyl]methanesulfonamide.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>ClCCl.O>[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Dimethyl sulfoxide (3.5 mL, 48.7 mmol) was dissolved in dichloromethane (100 mL) and was cooled to −78° C. Oxalyl chloride (3.65 mL, 41.8 mmol) was added. The mixture stirred for 30 min. To this solution was added a solution of 1-Boc-piperidine-4-methanol (7.5 g, 34.8 mmol) in dichloromethane (15 mL), and the mixture stirred for 1 h. Triethylamine (9.7 mL, 69.6 mmol) was added slowly and the mixture stirred at −78° C. for 30 min and warmed to room temperature over the course of 1 h. The mixture was diluted with water and the layers separated. The water layer was extracted with dichloromethane and the organic layers combined, dried (Na2SO4), filtered and concentrated to provide 1-Boc-piperidine-4-carboxaldehyde (6.75 g, 91%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:14]([N:6]1[CH:7]=[C:3]([CH2:2][OH:1])[N:4]=[CH:5]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 14 h
Yield: 99.8 %

Procedure:
4-hydroxymethylimidazole (4.53 g, 34 mmol) and triphenylmethylchloride (10.54 g, 38 mmol) were dissolved in DMF (50 mL). To this was added with stirring DIEA (13.46 g, 104 mmol) and the reaction mixture was stirred for 14 hrs. The reaction mixture was poured into water (750 mL) and stirred for about 30 min. The resulting solid was collected, washed with water (3×25 mL) and diisopropyl ether (3×25 mL), and dried in vacuo to yield 11.55 g (99%) of (1-trityl-1H-imidazol-4-yl)methanol. Purity (HPLC): 93%; retention time, 6.37 min.; column: Phenomenex Luna C18(2) (5 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. ES-MS: (M+H)+=341.1.