Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH:22]([F:24])[F:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH:22]([F:23])[F:24])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2=CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18.25 h

Procedure:
4-[5-(1-Cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 mL), 10% palladium on charcoal was added, and the suspension was stirred at room temperature under hydrogen (36 psi) for 18.25 hours. The reaction was filtered through celite, and the ethanol removed in vacuo to give a white solid, which was recrystallized from methylene chloride/isooctane (0.31 g, 99%): mp 199-203° C.; 1H NMR (acetone-d6) 300 MHz 8.05 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 6.69 (t, J=55.0 Hz 1H), 6.47 (s, 1H), 5.02 (br s, 2H), 2.67 (m, 1H), 1.71-1.88 (m, 5H), 1.24-1.43 (m, 5H); 19F NMR (acetone-d6) 300 MHz: −112.86 (d).
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9](=[N:31]O)[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[CH2:1]([C:5]1[N:13]2[C:8]([CH:9]([NH2:31])[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=NO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2N

Procedure:
Alternatively, the title compound of Example 1955 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1953) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1955.
Reaction SMILES: ClC(Cl)C(O)=O.N[C:8]1[N:9]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=3)[C:31]([CH:40]3[CH2:42][CH2:41]3)=[CH:30][CH:29]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1.N([O-])=O.[Na+].[Br:47]CBr>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:47][C:8]1[N:9]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=3)[C:31]([CH:40]3[CH2:42][CH2:41]3)=[CH:30][CH:29]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1
Reactant: BrCBr
Reactant: COc1ccc2c(C3CC3)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Product: COc1ccc2c(C3CC3)ccc(-n3c(Br)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
Dichloroacetic acid (0.063 mL, 0.76 mmol) was added to a mixture of compound 12 (200 mg, 0.38 mmol), benzyltriethyl ammonium bromide (311 mg, 1.14 mmol) and sodium nitrite (526 mg, 7.63 mmol) in dibromomethane (3 mL). The mixture was stirred at room temperature for 18 hours in the dark. The reaction mixture was then concentrated and the resulting residue was purified by prep. TLC (95% dichloromethane/5% methanol) to afford 90.4 mg of 4-[2-(5-bromo-4-[4-cyclopropyl-7-methoxynaphthalen-1-yl]-4H-1,2,4-triazol-3-ylthio)acetamido]-3-chlorobenzoic acid (13), 40% yield.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][N:7]([C:9]([O:11][CH3:12])=[O:10])[C@H:6]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])[C@@H:5]([C:27](OC)=[O:28])[CH2:4]1.[OH:31][NH2:32].Cl.NO.C[O-].[Na+].Cl>CO>[OH:31][NH:32][C:27]([C@H:5]1[CH2:4][C@H:3]([O:2][CH3:1])[CH2:8][N:7]([C:9]([O:11][CH3:12])=[O:10])[C@@H:6]1[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20]1)=[O:14])=[O:28]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](OC)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (0.027 g, 0.000064 mol) in methanol (0.30 mL, 0.0074 mol) was added 1.640 M of N-hydroxyamine in methanol (0.7850 mL), freshly made from the corresponding hydroxylamine HCl salt and sodium methoxide. The mixture was stirred at rt for 1 h, then acidified with 1N HCl. The crude mixture was applied directly on RP-HPLC to afford the product as a TFA salt (23 mg, 68%). MS (ESI): (M+H)+=421.2.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.O[C:26]1([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][C:50]=2[OH:51])[CH2:47][CH2:46][CH2:45]3)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]1=[O:41]>>[OH:51][C:50]1[CH:49]=[C:48]2[C:44]([CH2:45][CH2:46][CH2:47]2)=[CH:43][C:42]=1[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]1=[O:41]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCC3)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-hydroxy-3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: 1H NMR (300 MHz, CDCl3) δ 8.50-7.90 (br, 1H), 7.40-7.32 (m, 2H), 7.38 (td, 1H), 6.94 (s, 1H), 6.84 (d, 1H), 6.75 (s, 1H), 5.16 (s, 1H), 4.48 (ABq, 2H), 4.21 (q, 2H), 2.85 (t, 2H), 2.81-2.61 (m, 2H), 2.09-1.92 (m, 2H), 1.25 (t, 3H); MS (ES+) m/z 352 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH2:24]O)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[CH:13][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P([N:73]=[N+:74]=[N-:75])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:73]([CH2:24][C:22]1[CH:21]=[CH:20][C:19]2[N:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH:10]=3)[CH:16]=[N:17][C:18]=2[CH:23]=1)=[N+:74]=[N-:75]
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(COCc2nccs2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc2c(c1)ncn2-c1cccc(COCc2nccs2)c1
Reaction time: 2 h

Procedure:
To a mixture of 10g (0.1 g; 0.28 mmol) and PPh3 (0.11 g; 0.43 mmol) in THF (3 ml) was added DIAD (0.09 g; 0.43 mmol) at 0° C. After 5 min. diphenylphosphorylazide (0.12 g; 0.43 mmol) was added and the mixture was allowed to reach room temperature. Stirring was continued for 2 hours. The solvent was removed by evaporation and the residue was eluted through silica gel with a mixture of dichloromethane and methanol (50:1 v/v) to afford 25g. LC-ESI-HRMS of [M+H]+ shows 377.1188 Da. Calc. 377.118455 Da, dev. 0.9 ppm In analogy herewith the following compounds were prepared 5-Azidomethyl-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole (25c) from 10c. LC-ESI-HRMS of [M+H]+ shows 375.1671 Da. Calc. 375.168182 Da, dev. −2.9 ppm 5-Azidomethyl-1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole (25e) from 10e. LC-ESI-HRMS of [M+H]+ shows 374.1732 Da. Calc. 374.172925 Da, dev. 0.7 ppm
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20](/[CH:19]=[CH:18]/[C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)=[N:21][NH:22]2)=[CH:27][CH:26]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 82.3 %

Procedure:
The title compound (E:Z=1:4, 73 mg, 83%) was synthesized as a dark yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-bromoindolin-2-one (44.5 mg, 0.21 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 10.84 (s, 1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.16-8.10 (m, 3H), 8.04 (s, 1H), 7.71 (d, J=16.8 Hz, 1H), 7.59 (d, J=17.2 Hz, 1H), 7.43 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 7.39 (dd, J=8.0 Hz, J=1.2 Hz, 1H); MS ESI 443.3 [M+H]+, calcd for [C23H15BrN4O+H]+ 443.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([NH:18][C:15]2[O:16][C:17]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[CH:4][CH:5]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)[CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(CN)cc4)c3o2)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cccc(-c4ccc(CNC(C)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.070 g (0.173 mmol) [7-(4-aminomethyl-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 29), 1 ml pyridine and 0.016 g (0.199 mmol) acetyl chloride is stirred for 1.5 h at room temperature. Then the reaction mixture is poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and 0.1N NaOH solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo and co-evaporated twice with toluene. The residue is purified by crystallization from dichloromethane/diethyl ether to afford the title compound as a light brown solid. Rt=2.12 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 448 (M+1)+; m.p. 237-239° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C)C=O.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>S(Cl)(Cl)=O>[CH2:15]([N:17]([CH2:18][CH3:19])[C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:16]
Reactant: CCNCC
Reactant: O=C(O)c1ccccn1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A slurry of picolinic acid (10.2 g, 83.3 mmol) in 100 mL of thionyl chloride was stirred at ambient temperature for 10 min. Dimethylformamide (0.5 mL) was carefully added dropwise via a syringe. After 3 hours the mixture became a clear, homogeneous solution. Excess thionyl chloride and dimethylformamide were removed under reduced pressure. The residue was azeotroped 3× with dry toluene, dissolved in 100 mL of dichloromethane, cooled to 0° C. and treated dropwise with diethylamine (34.5 mL, 330 mmol) over a 12 minute period. The reaction mixture was stirred for 72 hours at ambient temperature and then filtered through a pad of Celite® filter aid. The filtrate was poured into 200 mL of water. The organic phase was collected and the aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic extracts were washed successively with 1N NaOH, water, and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by normal phase flash chromatography eluting with 100% ethyl acetate. Like fractions containing product were combined and concentrated under reduced pressure to give N,N diethylpicolinamide 14. (12.6 g, 70.8 mmol). 1H NMR (400 MHz, Chloroform-d) δ 8.47 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.71-7.62 (m, 1H), 7.45 (ddd, J=7.8, 1.9, 0.8 Hz, 1H), 7.27-7.17 (m, 1H), 3.46 (q, J=7.1 Hz, 2H), 3.26 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H). LCMS: (M+H)+, 179.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:22][C:23]([O:26][C:27]([NH:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[CH2:32][CH2:33]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Yield: 99.8 %

Procedure:
A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.584 mmol), 4-N-Boc-aminomethylpiperidine (125 mg, 0.584 mmol) and triethylamine (0.160 mL, 1.15 mmol) in dioxane (5 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (303 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:14]([Mg]Br)[CH3:15].[Cl-].[NH4+]>O1CCCC1>[OH:13][CH:12]([CH2:14][CH3:15])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CC[Mg]Br
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 65 %

Procedure:
N-Methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (2.00 g, 10.7 mmol) was dissolved in tetrahydrofuran (20 ml) under nitrogen and cooled to 0° C. with stirring. To the resulting solution was added ethylmagnesium bromide and the mixture stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature with stirring over 20 h. The mixture was then poured into saturated ammonium chloride solution and then extracted with diethyl ether three times. The combined organic fractions were then washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 40% diethyl ether/isohexane as eluent to give 1.70 g (65%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][C:28]([OH:30])=O)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]4[O:25][C:28](=[O:30])[CH2:27][N:26]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: ClCCl
Product: O=C1CN=C(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of N—[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (510 mg) and PS (polymer supported)-carbodiimide (1.69 g, 123 mmol/g) in dichloromethane (25 mL) was stirred at room temperature overnight. The reaction mixture was filtered through a short pad of Celite® diatomaceous filter aid and rinsed with dichloromethane. The filtrate was concentrated to provide the title compound (400 mg, 81% yield) as a pale yellow solid used directly for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-cyano-1H-imidazole-4-carboxylate (2.57 gram, 5.73 mmol) in dichloromethane (40 mL) is added trifluoroacetic acid and the resulting solution is stirred at room temperature for 20 hours and concentrated in vacuo. The residue is crystallised from diisopropyl ether to give pure 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.95 gram, 87% yield). Melting point: 200–202° C. (dec.).
Reaction SMILES: C(OC([NH:11][NH:12][C:13]([CH:15]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][Cl:19])=[O:14])=O)C1C=CC=CC=1>CO.[C].[Pd]>[Cl:19][CH2:18][CH2:17][CH2:16][CH:15]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:13]([NH:12][NH2:11])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)NNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)NN)CC1
Reaction time: 4.5 h
Yield: 100.1 %

Procedure:
10% palladium-carbon (50% wet, 200 mg) was added to a solution of tert-butyl 4-[1-(N′-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]piperidine-1-carboxylate (928 mg) in methanol (15 ml), and the reaction solution was hydrogenated at normal pressure at room temperature for 4.5 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to obtain 663 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[H][H]>C(O)C.[Pt]=O>[OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1
Reactant: [H][H]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Agent: O=[Pt]
Solvent: CCO
Product: CC1=C2CCC(O)CC(C)C2CC1
Yield: 60.1 %

Procedure:
500 mg of platinum oxide were pre-hydrogenated in 300 ml of ethanol. After addition of 2.14 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a, 4,5,6,7,8-octahydroazulene, the mixture was hydrogenated until hydrogen was no longer taken up. The reaction mixture was filtered, the filtrate evaporated and the crude product distilled under reduced pressure in a bulb-tube. There were obtained 1.3 g of pure 6-hydroxy-1,4-dimethyl-2,3,3a, 4,5,6,7,8-octahydroazulene; b.p.0.001 ca 85°; IR(film):νmax 3380, 1460, 1440, 1095, 1078, 1035/30, 985/75, 940 cm-1. The substance has a woody, flowery, fresh green odour.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[OH:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C1CCCN1CCO
Product: CC1=C(C(=O)OCCN2CCCC2=O)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 1-(2-hydroxyethyl)-2-pyrrolidinone. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1c(Br)ccc(N)c1C#N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc(N)c1C#N
Yield: 36.3 %

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-6-methylbenzonitrile, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene was heated at 90° C. for about 20 hours. After this time, the reaction mixture was stirred with 100 mL of water, and the organic layer was separated. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 30/65/5 and 20/60/20 methylene chloride/petroleum ether/ethyl acetate as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 1.0 gram of 2-amino-6-methyl-5-[3,5-di(trifluoromethyl)phenyl]benzonitrile. The NMR spectrum was consistent with the proposed structure.