Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 4-hydroxy benzaldehyde, (1.22 g, 0.01 m), methyl glycolate (0.97 g, 0.01 m), and triphenylphosphine, (3.93 g, 0.015 m), in dry tetrahydrofuran, (50 ml) was stirred with cooling in ice and diethylazodicarboxylate, (2.61 g, 0.015 m), added dropwise. The solution was stirred at room temperature for 0.5 hours, then evaporated in vacuo to dryness. Column chromatography of the residue on silica gel eluting with chloroform yielded 1.30 g (67%) of the title compound as an oil which crystallized on standing, mp 39°-41° C., νmax (mull) 1750, 1680, 1595, 1575, 1505 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[CH:8]=[C:9]3[C:14](=[O:15])O[C:11](=[O:12])[C:10]3=[CH:16][C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.O.C([NH2:31])=O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[CH:16]=[C:10]3[C:11](=[O:12])[NH:31][C:14](=[O:15])[C:9]3=[CH:8][C:7]=2[NH:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)=[CH:20][CH:21]=1
Reactant: O=C1OC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21
Reactant: NC=O
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21

Procedure:
A suspension of 1000 mg (2.73 mmol) of 4,5-bis(4-fluoroanilino)phthalic anhydride in 5 ml of formamide under argon atmosphere is heated at 125°-130° for 5 hours. The reaction mixture is cooled to 60°, and 20 ml of water are slowly added. This mixture is cooled to 0° for 3 hours, and the reddish crystals are filtered off, washed with water and dried. Recrystallization from dichloromethane yields the title compound in the form of orange crystals, m.p. 244°-246° C., FAB-MS: 366 [M+ +H].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccnc2)cn1
Yield: 19 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-pyridylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (18 mg, 19%) which was obtained as an off-white solid. MS: m/e=321.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[O:15]([CH2:22][C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:23]([CH3:24])[CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)COc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)COc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-phenoxy-propan-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH:27]([N:25]([CH3:26])[C:24]1[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:30]([O:32][CH3:33])=[O:31])=[CH:19][CH:18]=2)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 1-methyl-1H-indazol-5-ylboronic acid (180 mg, 1.02 mmol) in dioxane (3 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 109 mg, 0.37 mmol), K3PO4 (175 mg, 0.83 mmol), Pd(PPh3)4 (29 mg, 0.03 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (110 mg, 76%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([CH3:3])[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13]>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:13][CH2:12][C:11]([OH:15])=[O:14])([CH3:3])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CC(C)c1ccccc1S
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1SCCC(=O)O
Temperature: 25 °C
Reaction time: 71.8 h
Yield: 98.5 %

Procedure:
2-Isopropylthiophenol (4.77 g, 31 mmol) was placed in a flask with acrylic acid (2.37 g, 33 mmol) and stirred at room temperature for 71.8 hours. The reaction mixture solidified, was dissolved in ethyl acetate and extracted with 5% NaOH. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo to give 3-(2-isopropylphenylthio)propanoic acid (6.85 g), contaminated with some acrylic acid, as a yellow solid which was used without further purification in the next step.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.[N:14]1([C:19]2[N:24]=[CH:23][N:22]=[C:21]([N:25]=[C:26](SC)SC)[CH:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:14]1([C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[CH:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CSC(=Nc1cc(-n2ccnc2)ncn1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cn(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)cn1
Yield: 85.4 %

Procedure:
A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (419 mg, 1.8 mmol), dimethyl 6-(1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (404 mg, 1.5 mmol), and cesium carbonate (1.24 g, 3.8 mmol) was stirred in DMF (3.8 mL) at 75° C. for 2 h. The reaction was concentrated and purified by flash chromatography on a 40 g silica gel cartridge with 0 to 3% [9:1 MeOH/NH4OH] in CHCl3 to yield (R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (417 mg, 83% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.40 (1H, br. s.), 8.60 (1H, d, J=1.01 Hz), 8.37 (1H, t, J=1.01 Hz), 7.55 (1H, t, J=1.39 Hz), 7.16 (1H, dd, J=1.39, 0.88 Hz), 6.84 (1H, br. s.), 3.98 (1H, d, J=9.57 Hz), 3.64 (1H, d, J=9.57 Hz), 3.34 (1H, dd, J=14.98, 1.64 Hz), 2.69-3.04 (5H, m), 2.08-2.21 (2H, m), 1.67-1.78 (1H, m), 1.43-1.62 (2H, m). LCMS: RT=0.26 min, MH+=326.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: Nc1cc(O)cc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cc(O)cc(Br)c1)c1ccc(F)cc1F
Yield: 121.5 %

Procedure:
3-Amino-5-bromophenol (600 mg, 2.87 mmol, prepared according to WO 2011119704 A1 20110929) was treated with 2,4-difluorobenzene-1-sulfonyl chloride (386 μl, 2.87 mmol) according to the method described in Preparation 15b to give 1.27 g (99% yield) of the title compound as an oil. Purity 70%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[C:8]([F:15])[C:7]=1[F:16])[CH2:2][CH2:3][CH3:4].C(O)(=[O:19])C.OO.S([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:19])=[C:8]([F:15])[C:7]=1[F:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCOc1ccc(B(O)O)c(F)c1F
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(O)c(F)c1F
Reaction time: 2 h

Procedure:
The compound (23) (40.0 g) and acetic acid (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and hydrogen peroxide (31% aqueous solution; 40.4 ml) was added dropwise in the temperature range of 25° C. to 30° C., and the stirring was continued for another 2 hours. Then the reaction mixture was poured into a vessel containing sodium hydrogen sulfite solution (100 ml) and ethyl acetate (300 ml), and mixed. Then the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The organic phase obtained was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, giving 31.7 g of 4-butoxy-2,3-difluorophenol (24). The yield based on the compound (23) was 90.2%.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[C:3]([F:6])([F:5])[F:4].[H][H]>[Pd].C(OCC)(=O)C>[NH2:14][C:9]1[CH:8]=[C:7]([C:2]([F:1])([F:17])[C:3]([F:4])([F:5])[F:6])[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)C(F)(F)F)ccc1O
Yield: 83.7 %

Procedure:
A mixture of 1.38 g of 4-(pentafluoroethyl)-2-nitrophenol, 15 ml of ethyl acetate and 0.15 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for four hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was washed with hexane to give 1.02 g of 2-amino-4-(pentafluoroethyl)phenol.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2>>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: c1cnc2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc2c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 6-bromoquinoline (312 mg, 1.5 mmol; TCI-US) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.22 (m, 4H) 2.94-2.99 (m, 1H) 3.09-3.28 (m, 4H) 4.36 (s, 2H) 7.06-7.13 (m, 3H) 7.39-7.47 (m, 1H) 7.64 (dd, J=8, 4 Hz, 1H) 7.74 (dd, J=9, 2 Hz, 1H) 7.96 (d, J=2 Hz, 1H) 8.23 (d, J=9 Hz, 1H) 8.47 (d, J=8 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])=[C:3]([O:2][CH3:1])[CH:19]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)NCc1ccc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1

Procedure:
A solution of 2-methoxy-N-(6-methylpyridin-3-yl)methyl-4-nitrobenzamide (448 mg, 1.49 mmol) in EtOH and EtOAc (8 mL each) is stirred and ammonium formate (375 mg, 6 mmol) and 10% Pd/C (100 mg) are added. The mixture is heated at reflux for 20 min, cooled, filtered through celite, the solid is washed with EtOH and the combined solvents are evaporated to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH2:23][OH:24])[CH:10]=[C:11]([C:13]3[N:14]([CH:19]([CH3:21])[CH3:20])[N:15]=[C:16]([CH3:18])[N:17]=3)[N:12]=2)=[C:4](F)[CH:3]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH2:22][CH2:23][O:24][C:4]=2[CH:3]=1)[CH:10]=[C:11]([C:13]1[N:14]([CH:19]([CH3:21])[CH3:20])[N:15]=[C:16]([CH3:18])[N:17]=1)[N:12]=3
Reactant: Cc1nc(-c2cn(CCO)c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A suspension of 2-[2-(4-bromo-2-fluoro-phenyl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (2.3 g, 5.6 mmol) in DMF (50 mL) was treated with sodium hydride (60% dispersion, 247 mg, 6.2 mmol) portionwise over 5 min and the mixture stirred at RT for 1 h. The reaction was quenched by the slow addition of water (200 mL). The precipitate formed was filtered off, washed with water to give 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a white solid (1.64 g, 53%). LCMS: RT=3.43 min, [M+H]+=388/390. 1H NMR 400 MHz (CDCl3) δ: 8.37 (1 H, d, J=8.61 Hz), 7.70 (1 H, s), 7.26-7.25 (2 H, m), 5.87-5.86 (1 H, m), 4.50-4.48 (2 H, m), 4.46-4.42 (2 H, m), 2.42 (3 H, s), 1.57 (6 H, d, J=6.64 Hz)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH:11]([C:10]([CH3:18])([CH3:17])[CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(C)(C)C
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)(C)C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 627.7 %

Procedure:
Lithium diisopropylamide (21.7 mL of 1.8M solution, 40 mmol) was added to a solution of ethyl 3,3-dimethylbutyrate (5.76 g, 40 mmol) in 40 mL of tetrahydrofuran at -35° C. After stirring for 30 minutes and further cooling to -50° C., 4,4'-difluorobenzophenone (4.36 g, 2 mmol) was added. The reaction was stirred for 2 hours at -50° and for 2 hours at -20° C. The mixture was quenched with 2N hydrochloric acid and extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was crystallized from petroleum ether to give 4.55 g of the title compound; m.p. =93°-96° C.
Reaction SMILES: CCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-].O.CC[O:15][C:16]([CH:18]1[C:20]([CH3:22])([CH3:21])[CH:19]1[CH:23]=[C:24]([CH3:26])[CH3:25])=[O:17]>>[CH3:25][C:24]([CH3:26])=[CH:23][C@H:19]1[C:20]([CH3:21])([CH3:22])[C@@H:18]1[C:16]([OH:17])=[O:15]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: O
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
In a 100 ml flask, 2.0 g of an ethyl chrysanthemate having the optical isomer ratio of 3.6% of (-)-cis, 19.1% of (+)-cis, 10.5% of (-)-trans and 66.9% of (+)-trans forms by weight, was dissolved into 18.0 g of n-heptane under nitrogen. To the solution was added 0.7 g of aluminum chloride, and the mixture was stirred at a temperature of 70° C. for 3 hours. Thereafter, water was added to the reaction mixture to decompose the aluminum chloride. The organic layer separated was evaporated to remove the solvent, and the residue was mixed with 6.1 g of an aqueous 10% sodium hydroxide solution and stirred at a temperature of 100° C. for 2.5 hours to effect the hydrolysis. The reaction mixture was extracted with toluene to separate the neutral substance. The aqueous layer was acidified with a diluted sulfuric acid and then extracted with toluene. The toluene layer was washed with water, dried and evaporated to remove the solvent. Distillation in vacuo yielded 1.32 g of a trans-chrysanthemic acid boiling at 110° to 116° C./2 mmHg. Its analysis by gas-chromatography showed the optical isomer ratio of 0.9% of (-)-cis, 6.3% of (+)-cis, 12.4% of (-)-trans and 80.4% of (+)-trans forms by weight.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:25]=[C:24]([CH2:23][Cl:22])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: C1COCCO1
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Yield: 8.8 %

Procedure:
A yellow suspension of 7.91 g (0.0248 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-thiocarboxamide in 160 ml of dioxan was treated with 3.46 g (0.0273 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 24 hrs. The suspension obtained was cooled and filtered. The solution was completely freed from the solvents. The crude product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:2 as the eluent and recrystallized from hot acetonitrile. There was obtained 0.85 g (8.7%) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as white crystals; m.p. 221-223 and [α]D20 =-163.0° (MeOH, c=1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:12]1[CH:11]=[C:10]([CH:9]([NH:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C(NCC(O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCC(O)c2ccccc2)c2cccc(N)c2)cc1
Yield: 73.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution of 2-{[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amino}-1-phenylethanol (3.26 g) [prepared as described in step (b) above] in methanol (60 m), nickel chloride hexahydrate (4.09 g) and sodium borohydride (1.3 g) were reacted, to afford the title compound (2.2 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[Cl:1][C:2]1[N:3]([NH:13][C:21](=[O:23])[CH3:22])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: CC(=O)Cl
Reactant: Nn1cc(-c2cccnc2)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nn1cc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To a solution of 2-Chloro-4-(pyridin-3-yl)-1H-imidazol-1-amine (30 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) in dichloromethane (5 mL) was added acetyl chloride (12 mg, 0.15 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. The solvent was removed in vacuum and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:2) to give the title compound (10 mg, 27%) as a yellow solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 10.69 (br, 1H), 8.81-8.80 (m, 1H), 8.44-8.43 (m, 1H), 8.02-8.00 (m, 1H), 7.33 (br s, 2H), 2.20 (s, 3H); ESIMS m/z 237 [(M+H)]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-pyrrolidin-1-yl-piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O2 [(M+H)+] 676.318, observed 676.3176.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[N:38]1([C:44](=[O:52])[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:9]([C:27]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][C:44]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[O:52])[CH2:47][CH2:48]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 751.3 [(M+H)+]