Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)NCCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)NCCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2-phenylethylamino-carbonyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(OCC)(OCC)OCC.C[O-].[Na+].[CH3:25][O:26][C:27]([CH3:37])([CH3:36])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:35])[CH2:32][CH2:33]O>O.CN(C)C=O>[CH3:25][O:26][C:27]([CH3:36])([CH3:37])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:35])[CH2:32][CH:33]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(C)(C)CCCC(C)CCO
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)CCCC(C)CC=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture consisting of 5.4 g (0.025 mol) of p-nitrobenzyl bromide and 4.15 g (0.025 mol) of triethyl phosphite is stirred at 90°, over the course of 1 hour and under nitrogen. The resulting ethyl bromide is distilled off from the reaction vessel. The obtained solution is then evacuated and stirred at a bath temperature of 110° for one further hour in a water jet vacuum. A suspension consisting of 1.68 g (0.030 mol) of sodium methylate and 10 cc of absolute dimethylformamide is carefully added at 0° to the residue. 4.65 g (0.025 mol) of 7-methoxy-3,7-dimethyloctanol in a small amount of dimethylformamide are subsequently added over the course of 5 minutes to the red reaction mixture which is stirred at 0° for 1 hour and at room temperature for 90 minutes. The ruby-coloured solution gradually turns dark brown. 60 cc of water are added and the reaction mixture is extracted with hexane. The extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated at 40° /20 mm Hg. After chromatography of the residue on silica gel with hexane/ethyl acetate (97:3) and (94:6), pure 1-(8-methoxy-4,8-dimethyl-1-nonenyl)-4-nitrobenzene is obtained as a slightly yellow oil. nD20 = 1.5473
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C@@H:6]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH2:7][OH:8].C(N(CC)CC)C.O>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C@@H:6]([CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)[CH:7]=[O:8]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@H](CO)Cc1cc(F)cc(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CN(Cc1ccccc1C)[C@H](C=O)Cc1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
Dissolve 2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-propan-1-ol (1.34 g, 3.38 mmol) in DMSO (3 mL) and cool in an ice bath. Add triethylamine (1.9 mL, 13.51 mmol) followed by sulfur trioxide-pyridine complex (1.07 g, 6.76 mmol). Stir 30 min then slowly add water (1.5 mL). Dilute with ethyl acetate and wash with 5% aqueous citric acid (3×), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a light yellow residue.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:25]([N:27]1[CH2:32][CH2:31][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([CH3:41])=[CH:33]2)[CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C>C(O)C.[C].[Pd]>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:25]([N:27]1[CH2:28][CH2:29][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]([CH3:41])[CH2:33]2)[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC1CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.5 %

Procedure:
N-[7-Benzylamino-6-(3-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]methanesulfonamide (0.035 g, 0.061 mmol) obtained in Example 111, step 3 was dissolved in ethanol (2.0 ml), 10% palladium-carbon (0.079 g, 0.382 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through celite and washed with chloroform, and the filtrate was concentrated under reduced pressure to give a residue. Diisopropyl ether was added to the residue and the precipitated crystals were collected by filtration to give the title compound (0.011 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[C:10](=[O:44])[CH2:11][N:12]([CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=1)[C:13]([C:15]1[CH:16]=[N:17][N:18]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]2)[C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:14].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:10](=[O:44])[CH2:11][N:12]([CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=1)[C:13]([C:15]1[CH:16]=[N:17][N:18]([C@H:24]2[CH2:25][CH2:26][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]2)[C:19]=1[C:20]([F:22])([F:23])[F:21])=[O:14]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cccc3OC)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(O)cccc3Cl)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Reaction time: 16 h

Procedure:
To a stirred solution of compound 15-3 (0.25 g, 0.39 mmol) in DCM (10 mL) was added BBr3 (1.0 M in DCM, 3.9 mL, 3.9 mmol) at room temperature and the mixture was stirred for 16 h. Solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 15-4 (85 mg, 35%) as a yellow oil.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20][O:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[C:11]=2[CH:40]=1)([O-:6])=[O:5]>C(O)C>[NH2:22][O:21][CH2:20][C:17]1[N:16]2[C:10]3[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:40][C:11]=3[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[N:13][CH2:14][C:15]2=[N:19][N:18]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-nitro-1-[(phthalimidooxy)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[CH:23][CH:22]=1)[CH3:30]
Reactant: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
1 mol of 4-[4-(1-adamantyl)-phenoxy]-butyric acid is dissolved in excess ethanol and boiled, with addition of 3% of concentrated sulphuric acid, for 3 hours under reflux, with exclusion of moisture. The product is concentrated to half its volume and partitioned between methylene chloride and water. The organic phase is washed until neutral, dried with sodium sulphate and evaporated in vacuo to give 4-[4-(1-adamantyl)-phenoxy]-butyric acid ethyl ester of melting point 45°-46° C.
Reaction SMILES: [CH:1]1([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][N:16]([CH2:23][CH:24]4[CH2:28][O:27]C(C)(C)[O:25]4)[C:17](=[O:22])[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(Cl)Cl>CCOCC>[CH:1]1([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][N:16]([CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[C:17](=[O:22])[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCC(Cn2ccc3c(C(=O)NCC4CCCCCC4)cccc3c2=O)O1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCC1CCCCCC1)c1cccc2c(=O)n(CC(O)CO)ccc12

Procedure:
N-(Cycloheptylmethyl)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-oxo-1,2-dihydroisoquinoline-5-carboxamide (110 mg, 0.00028 mol), hydrogen chloride (5 mL, 0.006 mol) as 2M solution in ether and methylene chloride (5 mL, 0.08 mol) were stirred at room temperature for 2 hours. The volatiles were removed under vacuum, the residue was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2) to give a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:21]([CH3:23])[CH3:22])[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2.CCN=C=NCCCN(C)C.[NH2:35][C:36]1[N:37]([CH3:42])[CH2:38][C:39](=[O:41])[N:40]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][C:36]2[N:37]([CH3:42])[CH2:38][C:39](=[O:41])[N:40]=2)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:21]([CH3:22])[CH3:23])[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2
Reactant: CC(C)c1cc(-c2cc(C(=O)O)ccc2F)c2ncccc2c1
Reactant: CN1CC(=O)N=C1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)c1cc(-c2cc(C(=O)NC3=NC(=O)CN3C)ccc2F)c2ncccc2c1
Reaction time: 12 h

Procedure:
To solution of the 4-fluoro-3-(6-isopropyl-quinolin-8-yl)-benzoic acid from Step 2 (1.0 eq), EDCI (1.1 eq) and DMAP (1.1 eq) in CH2Cl2 (0.07M) was added 2-amino-1-methyl-1,5-dihydro-imidazol-4-one (1.1 eq). The resulting mixture was stirred for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (EtOAc) afforded the compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:31][C:32]([O:34][CH2:35]I)=[O:33])[CH:28]([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:35][O:34][C:32]([O:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)COC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)COC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 67.4 %

Procedure:
In the same manner as in Example 81, 294 mg of the title compound was prepared from 344 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 264 mg of isobutyloxycarbonyloxymethyl iodide.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]21[CH2:19][CH2:18][C:17]1[C:12](=[CH:13][C:14]([N+:20]([O-])=O)=[CH:15][CH:16]=1)[C:11]2=[O:23])=[O:4].[ClH:26]>C(O)C.[C].[Pd]>[ClH:26].[NH2:20][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][C:6]3([C:11]2=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][N:5]3[C:3](=[O:4])[C:2]([F:25])([F:1])[F:24])=[CH:16][CH:15]=1
Reactant: O=C(N1CCCCC12CCc1ccc([N+](=O)[O-])cc1C2=O)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)C1(CCCCN1C(=O)C(F)(F)F)CC2
Reaction time: 3 h

Procedure:
To a solution of 3.0 g of 1'-trifluoroacetyl-3,4-dihydro-7-nitrospiro[naphthalene-2(1H),2'-piperidine]-1-one in 50 ml of ethanol, 0.30 g of 10% palladium-carbon catalyst and 2 ml of concentrate hydrochloric acid were added, followed by 3 hours of catalytic reduction at normal pressure and temperature. After the catalyst was filtered off, the filtrate was distilled to remove the solvent. The residue was dissolved in methylene chloride and washed with water. The methylene chloride layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was distilled off. The residue was treated with 2.2 ml of 4 N-methanolic hydrochloric acid to yield a solid, which was then recrystallized from ethanol-ether to yield 2.37 g of 7-amino-1'-trifluoroacetyl-3,4-dihydrospiro[naphthalene-2(1H),2'-piperidine]-1-one hydrochloride as a white crystal.
Reaction SMILES: C(OC([C:6]1[CH:38]=[CH:37][CH:36]=C[C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.OC1C=CC=C[N:41]=1>>[N:41]1[CH:36]=[CH:37][CH:38]=[CH:6][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccccn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccn2)cc1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-hydroxypyridine.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11]([F:25])=[C:12](C2C(O)=CC=CC=2F)[C:13](O)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(OC1C=CC(Br)=CC=1F)C1C=CC=CC=1.BrCCCCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:27]([F:26])[CH:28]=2)=[CH:12][C:11]=1[F:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(O)c(-c2c(O)cccc2F)c1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Agent: Fc1cc(Br)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCCCCCCCBr
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)c(F)c2)cc1F
Reaction time: 20 h

Procedure:
A mixture of 4'-octyloxy-3,3'-difluorobiphenol (0.1 mol, obtained by coupling 3-fluoro-4-octyloxyphenyl boronic acid with 4-benzyloxy-3-fluoro-brombenzene followed by hydrogenolytic cleavage of the benzylic ether), 1-bromooctane (0.12 mol), potassium carbonate (30 g) and butanone (125 ml) is heated under reflux and stirred for 20 hrs. After cooling the reaction mixture is filtered and the filtrate evaporated off, distillation under reduced pressure affords the required product, m.p. 84°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[CH3:26])=[C:11]([CH2:13][C:14]([O:16]C)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[CH3:26])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1cc(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(C)c(Oc2oc(-c3ccc(Cl)cc3)nc2CC(=O)O)c1
Reaction time: 3.5 h
Yield: 72.3 %

Procedure:
To a stirred solution of 13 g of methyl 2-p-chlorophenyl-5-(2,5-dimethylphenoxy)-4-oxazoleacetate prepared in Example 4 in 150 ml of acetone at room temperature was dropwise added a 15 ml aqueous solution of 2.0 g of sodium hydroxide. The mixture was further stirred for 3.5 hours. After the solvent was evaporated under reduced pressure, water was added to the remaining aqueous solution. The resulting solution was cooled and acidified to pH 3 with hydrochloric acid. The crystalline precipitate was filtered off and recrystallized from ethanol to give 9.05 g of the title compound as bulky needles, melting at 185° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([C:48]([F:51])([F:50])[F:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:61])=[C:36]([C:48]([F:51])([F:49])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (355 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (205 mg), and the mixture was stirred overnight under nitrogen atmosphere. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (176 mg) as colorless amorphous.
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[NH2:12][C:13]1[CH:14]=[C:15]([C:19](=[N:24][C:25]#[N:26])OCCC)[CH:16]=[N:17][CH:18]=1>CN(C=O)C.CO>[NH2:12][C:13]1[CH:14]=[C:15]([C:19](=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])[NH:24][C:25]#[N:26])[CH:16]=[N:17][CH:18]=1
Reactant: CCCOC(=NC#N)c1cncc(N)c1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#CNC(=NCCO[N+](=O)[O-])c1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (140 mg, 0.98 mmol) in DMF (1 ml) was added sodium methoxide (42 mg, 0.78 mmol) followed by a solution of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg, 0.49 mmol) in methanol (1 ml) described in Example 6 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (77 mg, yield 63%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.[NH2:28][C:29]1[N:34]=[C:33]([N:35]([C:37]2[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=2)[CH3:36])[N:32]=[C:31]([C:44](=[N:46]O)[NH2:45])[N:30]=1>N1C=CC=CC=1.CCOC(C)=O>[F:43][C:40]1[N:39]=[CH:38][C:37]([N:35]([CH3:36])[C:33]2[N:34]=[C:29]([NH2:28])[N:30]=[C:31]([C:44]3[N:45]=[C:11]([C:8]4[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:6][CH:7]=4)[O:13][N:46]=3)[N:32]=2)=[CH:42][CH:41]=1
Reactant: CN(c1ccc(F)nc1)c1nc(N)nc(C(N)=NO)n1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)nc1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
6-(2,2,2-Trifluoroethoxy)pyridine-3-carboxylic acid (prepared in an analogous manner to Intermediate 206, 0.216 g, 0.051 mmol) was added to a solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.049 g, 0.252 mmol) in pyridine (1 mL) and the mixture was stirred at room temperature for 16 h. Further N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0255 g, 0.1 mmol) was added and the mixture was stirred at 50 C for 4 h. 4-Amino-6-[(6-fluoropyridin-3-yl)(methyl)amino]-N′-hydroxy-1,3,5-triazine-2-carboximidamide (Intermediate 156, 0.05 g, 0.18 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0163 g, 0.09 mmol) were added and the mixture was stirred at 50 C for 16 h and then at 60 C for 5 h. The mixture was dissolved in EtOAc and washed with water, and then saturated aq. ammonium chloride, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC, Method B, to afford the title compound (0.002 g, 3%).
Reaction SMILES: [C-]#N.[Na+].[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].[N:17]1C=CC(C)=C[CH:18]=1>[Cu]I>[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([C:18]#[N:17])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: Cc1ccncc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 155 °C

Procedure:
A 250-mL, four-necked flask equipped with a mechanical stirrer and condenser was charged with copper(I) iodide (1.97 g, 10.3 mmol), sodium cyanide (95% purity, 3.30 g, 64.0 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (10.0 g, 40.9 mmol), 4-picoline (distilled prior to use) (1.16 g, 12.5 mmol) and oxygen-free anisole (20 mL), and then purged with nitrogen, after which time the reaction mixture was maintained under a nitrogen atmosphere. The reaction mixture was heated at about 155° C. for 12 h and then allowed to cool to room temperature overnight. Toluene (20 mL) was added to the solid-containing reaction mixture, the mixture was heated at about 100° C., and then water (60 mL) was added over 20 minutes with stirring. The reaction mixture was stirred for 1 h at 85° C., cooled to room temperature, and then filtered. The solid collected was washed with water (3×mL) and toluene (1×20 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (7.34 g).