Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1)=[O:13])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:22]=[CH:23][CH:24]=[C:9]([OH:8])[C:10]=2[N+:25]([O-:27])=[O:26])=[N:16][CH:17]=1
Reactant: O=C(Nc1ccc(Br)cn1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Br)cn1)c1cccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 93 %

Procedure:
To 10.7 g of 3-benzyloxy-N-(5-bromo-2-pyridyl)-2-nitrobenzamide were added 50 ml of trifluoroacetic acid and 4.88 g of pentamethylbenzene and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated in vacuo, to the residue was added a saturated aqueous solution of sodium hydrogen carbonate to such an extent that the residue did not become alkaline and the mixture was extracted with chloroform. The organic layer was extracted with 1N aqueous solution of sodium hydroxide and concentrated hydrochloric acid was added to an aqueous layer. The resulting precipitate was collected by filtration and dried in vacuo to give 7.86 g of N-(5-bromo-2-pyridyl)-3-hydroxy-2-nitrobenzamide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:29][C:28]#[CH:27])[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc2nc(N)c3nc4n(c3c2c1)[C@@H](C)COC4
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (100 mg, 0.370 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (241 mg, 0.740 mmol) and propargyl bromide (49 mg, 0.410 mmol) and stirred overnight at ambient temperature. The dark brown mixture was then poured into 150 mL of H2O and stirred for 30 minutes. The mixture was filtered to give a dark brown solid. Chromatography (SiO2, 0-30% CMA/CHCl3) followed by crystallization from ethyl acetate gave 51 mg of the title compound as an off-white solid, mp 184-186° C.
Reaction SMILES: [N:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].[Cl:18][CH2:19][C@H:20]([OH:22])[CH3:21].B(F)(F)F.CCOCC>ClCCl>[CH2:11]([O:10][C:8]([NH:1][C@H:2]([CH2:3][O:22][CH:20]([CH3:21])[CH2:19][Cl:18])[C:4]([O:6][CH3:7])=[O:5])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Reactant: C[C@@H](O)CCl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H](COC(C)CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
To a 100 mL flask was added 1-benzyl 2-methyl aziridine-1,2-dicarboxylate (1 g, 4.25 mmol), dichloromethane (12 mL), (R)-1-Chloro-2-propanol (0.76 mL, 8.50 mmol), and boron trifluoride diethyl etherate (0.05 mL, 0.398 mmol). The mixture was stirred at room temperature for 15 minutes Solvent was removed in vacuo and the residue purified on silica gel eluting with Hexanes-EtOAc (0-50%) to give (R)-methyl 2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg, 41%). MS [M+H] found 330.2.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: COc1nc(Cl)ccc1Br
Reactant: OC1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1nc(Cl)ccc1N1CCC(O)C1
Temperature: 100 °C
Yield: 5.9 %

Procedure:
A vial was charged 3-bromo-6-chloro-2-methoxypyridine (0.50 g, 2.2 mmol), pyrrolidin-3-ol (0.39 g, 4.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.10 g, 0.10 mmol), Xantphos (0.13 g, 0.20 mmol), sodium tertbutoxide (0.32 g, 3.4 mmol) and toluene (5 mL). The mixture was purged with nitrogen then sealed. The mixture was heated to 100° C. overnight. The mixture was cooled to room temperature, filtered and diluted with 15 mL of water. The solution was extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography to give the title compound (29.5 mg, 5.7%) as light brown solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[O:4].[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][SH:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>O1CCCC1>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][S:17][CH2:5][C:3](=[O:4])[CH2:2][Cl:1])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NCCS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCSCC(=O)CCl
Yield: 93.6 %

Procedure:
To a stirred solution of 1,3-dichloroacetone (5.00 g, 39.37 mmol) in tetrahydrofuran (50 mL) were added 2-t-butyloxycarbonylaminoethanethiol (6.98 g, 37.50 mmol) and triethylamine (3.77 g, 37.50 mmol) at 0° C. After 3 hours the reaction mixture was partitioned between ethyl acetate and water. Organic layer was washed with 1 M hydrochloric acid, water, sodium bicatbonate solution and brine. Organic extract was dried over sodium sulfate and concentrated under reduced pressure to afford oily residue of title product (9.40 g). 1H NMR (CDCl3) δ 1.58 (s, 9H), 2.76 (t, J=6, 2H), 3.40 (m, 2H), 3.58 (s, 2H), 4.42 (s, 2H), 5.00 (br s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:21])=[C:14]([C:17](=[O:19])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>CCCCCCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]([C:17](=[O:19])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CCCCCCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C

Procedure:
To a cooled (5° C.) stirred slurry of 0.100 g. of benzhydryl 7-(2-thienylacetamido)-3-acetyl-3-cephem-4-carboxylate in 1 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. The ester immediately dissolved. The resulting colorless solution was stirred with cooling for 20 minutes after which time approximately 40 ml. of n-heptane was added. The resulting solution was evaporated in vacuo to a low volume causing the precipitation of a white solid. The solid was filtered from the mixture and subsequently dissolved in acetone. The acetone solution was filtered and then evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate, and the resulting solution was extracted three times with cold sodium bicarbonate solution. The aqueous extracts were combined, layered with ethyl acetate and acidified with 1N.HCl. The ethyl acetate layer was separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave 0.067 g. of the title product as a pale yellow solid which failed to crystallize from methylene chloride-hexane:
Reaction SMILES: C([NH:9][CH:10]([CH:16]([Cl:34])[CH2:17][CH2:18][CH:19]([NH:25]C(=O)C1C=CC=CC=1)[C:20]([O:22]CC)=[O:21])[C:11]([O:13]CC)=[O:12])(=O)C1C=CC=CC=1>Cl>[ClH:34].[ClH:34].[Cl:34][CH:16]([CH:10]([C:11]([OH:13])=[O:12])[NH2:9])[CH2:17][CH2:18][C@@H:19]([C:20]([OH:22])=[O:21])[NH2:25]
Reactant: CCOC(=O)C(CCC(Cl)C(NC(=O)c1ccccc1)C(=O)OCC)NC(=O)c1ccccc1
Agent: Cl
Product: NC(C(=O)O)C(Cl)CC[C@H](N)C(=O)O
Yield: 89 %

Procedure:
Tetraprotected amino acid (11) (118 mg, 0.24 mM) is refluxed in 6N HCl (20 ml) for 8 hours. After cooling the aqueous solution was washed with Et2O (3×25 ml) and evaporated to dryness in vacuo to yield the desired compound as a very hygroscopic white foam, 64 mg (89% yield).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[N:27][CH:28]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[N:27][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:43])=[O:44])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 91.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (140 mg, 0.199 mmol) was deprotected with TFA/DCM (2/1 ml). This afforded 110 mg (91.6% yield) of the titled compound. MS: m/z=604.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:14][CH2:13][CH:12](OS(C)(=O)=O)[CH2:11][CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O>[C:20]([S:22][CH:12]1[CH2:11][CH2:10][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:14][CH2:13]1)(=[O:23])[CH3:21]
Reactant: CS(=O)(=O)OC1CCN(c2nc(C(N)=O)cs2)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(c2nc(C(N)=O)cs2)CC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 67.9 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-methanesulfonyloxypiperidine (1.59 g, 5.21 mmol) (obtained as described in Reference Example 15(3)) in dimethylformamide (80 ml) was added potassium thioacetate (1.19 g, 10.4 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (90° C.) for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:n-hexane (10:1) as the eluant to afford 4-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)piperidine (1.01 g, yield 68%) as a brown solid.
Reaction SMILES: [CH2:1]([Sn:11](Cl)([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[S-:33][C:34]#[N:35].[K+].C1C=CC=CC=1>O>[CH2:1]([Sn:11]([N:35]=[C:34]=[S:33])([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: N#C[S-]
Reactant: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccccc1C(F)(F)F)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(N=C=S)c1ccccc1C(F)(F)F)c1ccccc1
Yield: 96.2 %

Procedure:
Dineophyl-orthotrifluoromethylphenyltin chloride (6 g, 10.6 mmol) prepared in Example 5, potassium thiocyanate (1.5 g, 15.9 mmol), benzene (40 g) and water (10 g) were charged into a flask and the mixture was refluxed for 2 hours. The aqueous layer was removed and the organic layer was washed with water and filtered. Evaporation of the benzene under reduced pressure gave 6.0 g of dineophyl-orthotrifluoromethylphenyltin isothiocyanate as a colorless viscous liquid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8](OS(C)(=O)=O)[CH2:9][CH:3]1[CH2:4][CH2:5]2.C([O:17][C:18]([S-:20])=[S:19])C.[Na+].C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C@@H:3]2[CH2:9][CH:8]([S:19][C:18]([SH:20])=[O:17])[CH2:7][C@H:6]1[CH2:5][CH2:4]2
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Reactant: CCOC(=S)[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1[C@@H]2CC[C@H]1CC(SC(=O)S)C2
Temperature: 30 °C

Procedure:
Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b.
Reaction SMILES: [C:1]([CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)#[N:2].S(Cl)([Cl:24])=O.O>O1CCCC1>[Cl:24][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: N#CC(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#CC(Cl)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a suspension of 2-[4-[cyano(hydroxy)methyl]phenyl]-5,6-dichlorobenzimidazole (275 mg, 0.865 mmol) in tetrahydrofuran (20 mL) was added thionyl chloride (0.38 mL, 5.2 mmol), and the mixture was heated to reflux for 3 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (14:1 chloroform/acetonitrile) to afford of 2-[4-[chloro(cyano)methyl]phenyl]-5,6-dichlorobenzimidazole (73 mg, 25%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](OC=C)(=O)[CH3:18].[OH-].[K+]>[Pd].C(OCC)C>[CH:17]([O:15][C:14](=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH2:18]
Reactant: CC(C)(C)OC(=O)NCCOCCC(=O)O
Reactant: C=COC(C)=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C=COC(=O)CCOCCNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 60 %

Procedure:
3-(2-tert-Butoxycarbonylamino-ethoxy)-propionic acid (3.72 g, 15.95 mmol) was dissolved in vinyl acetate (147 mL, 1595 mmol). Pd (II) acetate (716 mg, 3.19 mmol) and KOH (89 mg, 1.59 mmol) were added to the reaction mixture and stirred overnight. The reaction mixture was transferred into a large excess of diethyl ether to fully precipitate the black Pd byproduct. The solution plus precipitate was then filtered through celite to remove the black precipitate. The resulting solution was then concentrated to dryness and the product purified on a silica column using ethyl acetate/hexane eluent. Yield=60%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (3.28 g, 7.94 mmol) was dissolved in TFA (40 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (1.1 g, 15.9 mmol) was added with stirring to give a red mixture with gas evolution. After 20 min, solid sodium azide (5.16 g, 79 mmol) was added over 5 min followed immediately by Et2O (40 mL). After 20 minutes water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×), and saturated Na2CO3 solution (until the aqueous phase was basic) and brine. After drying the solvent with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with hexane containing 10 to 40% DCM) afforded methyl 3-azido-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (2.23 g, 5.08 mmol, 64% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.68-7.79 (3H, m), 7.29-7.49 (5H, m), 7.06 (2H, d, J=8.55 Hz), 4.00 (3H, s).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:14])=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:2].Cl.[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.CCN=C=NCCCN(C)C>O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[N:14]=[C:16]1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCNc1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
A mixture of 1.0 g of N1-ethyl-4-trifluoromethylbenzene-1,2-diamine, 1.05 g of isonicotinoyl chloride hydrochloride and 15 ml of pyridine was stirred for 4 hours at 60° C. Then, 0.94 g of WSC was added, and the mixture was stirred for 8 hours at 80° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, then, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 1-ethyl-2-(pyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 221).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]2[N:16]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)[N:14]=2)[CH:17]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)cn2c1

Procedure:
59.5 g (0.2 mole) of 1-bromo-2-(4-nitrophenyl)-2-ethanone, 21.6 g (0.2 mole) of 2-amino-5-methylpyridine and 34 g of sodium bicarbonate are reacted in 200 ml of 95% strength ethanol. Stirring and refluxing are maintained for 3 hours, and the reaction mixture is then cooled and the ethanol evaporated off under reduced pressure. The evaporation residue is stirred in 700 ml of water at 70° C. for 3 hours, and the insoluble material is then filtered off, washed with 50 ml of ethanol and then ether and dried. M.p. 237°-239° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]([CH3:26])[NH:7][C:8](=[O:25])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH3:2].[O:27]1[C:31]2[CH:32]=[CH:33][C:34](B(O)O)=[CH:35][C:30]=2[CH2:29][CH2:28]1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([N:7]3[C:8](=[O:25])[C:9]([CH2:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]5[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=5)=[CH:13][CH:12]=4)=[C:4]([O:3][CH2:1][CH3:2])[N:5]=[C:6]3[CH3:26])=[CH:35][C:30]=2[CH2:29][CH2:28]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCOc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 24 h
Yield: 92 %

Procedure:
To a suspension of 4′-[(4-ethoxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.17 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.16 g), triethylamine (0.17 mL), pyridine (0.34 mL) and molecular sieves 4 A (0.34 g) in tetrahydrofuran (5 mL) was added copper(II) acetate (0.17 g), and the mixture was stirred for 1 day. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: [H][H]
Reactant: COc1cc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC2CCN(C)CC2)ccc1N
Reaction time: 8 h

Procedure:
To a solution of 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine (3.0 g, 11.3 mmol) in ethanol (50 mL), 5% palladium on carbon (300 mg) is added under a nitrogen atmosphere. The reaction vessel is fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction is under a hydrogen atmosphere. The reaction is allowed to stir overnight. The reaction mixture is filtered through a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo to afford 2-Methoxy-4-(1-methyl -piperidin-4-yloxy)-phenylamine in quantitative yield (2.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[N:37]2[CH2:38][CH2:39][NH:40][CH2:41][C:36]2=[CH:35][N:34]=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11](=[O:13])[N:40]1[CH2:39][CH2:38][N:37]2[C:33]([C:32]([F:43])([F:31])[F:42])=[N:34][CH:35]=[C:36]2[CH2:41]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ncc2n1CCNC2
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F

Procedure:
Under a nitrogen atmosphere, 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1k (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane under stirring. After stirring at room temperature for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine if (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]carbamic acid tert-butyl ester 1l (20.0 g, yield 88%) as a white solid.