Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([OH:50])=O)=[CH:44][C:43]=2[CH3:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH3:52][N:53]1[C:62]2[NH:61][C:60]3[CH:63]=[CH:64][CH:65]=[CH:66][C:59]=3[NH:58][CH2:57][C:56]=2[CH:55]=[N:54]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:58]3[CH2:57][C:56]4[CH:55]=[N:54][N:53]([CH3:52])[C:62]=4[NH:61][C:60]4[CH:63]=[CH:64][CH:65]=[CH:66][C:59]3=4)=[O:50])=[CH:44][C:43]=2[CH3:51])[CH2:36][CH2:37]1)=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: Cc1cc(C(=O)O)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 40 %

Procedure:
PyBroP (224 mg, 0.48 mmol) and DMAP (39 mg, 0.32 mmol) were added to a solution of 4-[3-(4-carboxy-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E68.3 (120 mg, 0.32 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (70 mg, 0.35 mmol) in dichloromethane (5 ml) and DIEA (0.111 ml, 0.64 mmol). The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to yield the title compound (71 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[N+:26]([O-])([OH:28])=[O:27]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:26]([O-:28])=[O:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(OC(C)C)cc12
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.084 mol) was dissolved in chloroform (75 mL) and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in chloroform (75 mL) and cooled in an ice bath. The acid solution was added dropwise to the solution of ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate over 1 hour, and the reaction mixture was then stirred at 0° C. for 1.5 hrs. The reaction mixture was then diluted with water (60 mL) and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (5/1 PE/EA) to afford ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a brown solid (11 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:28](=[O:30])[CH3:29])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials : (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[C:24]([C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:17]3[C:24]([C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:32])=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)cc1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl(4-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)benzyl)carbamate (0.18 g, 0.41 mmol) in DCM (1.5 mL) was added 0.5 mL of TFA. The mixture was heated at 50° C. for 1 hour. The solvent was removed under reduced pressure. The residue was washed with DCM and dried on high vacuum give a yellow solid. M.p.=255-257° C.; 400 MHz 1HNMR (DMSO-d6) δ 13.05 (s, 1H), 11.43 (s, 1H), 8.48 (s, 1H), 7.98-7.96 (m, 3H), 7.85 (d, J=8.4 Hz, 2H), 7.70 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 4.03 (q, J=5.2 Hz, 2H); LCMS [M+H] 344.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[CH:7]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:17]1([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: C(=Cc1ccccc1OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCc1ccccc1
Yield: 89 %

Procedure:
The whole of this 2-benzyloxystilbene was dissolved in 300 ml of ethanol, and the resulting solution was stirred at 60° C. for 3.5 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 1.00 g of 5% w/w palladium-on-charcoal. The catalyst was removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 6.41 g (yield 89%) of the title compound as a colorless solid.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=4)[N:20]=3)=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:32][C:30]1[CH:31]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]4)=[N:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH:27]=[C:28]([Cl:34])[C:29]=1[Cl:33]
Reactant: C=CCOC(=O)N1CCN(c2ccc(-c3ccnc(Nc4cc(Cl)c(Cl)c(Cl)c4)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cc(Nc2nccc(-c3ccc(N4CCNCC4)nc3)n2)cc(Cl)c1Cl
Yield: 41.7 %

Procedure:
A solution of 4-(2-(4-allyloxycarbonylpiperazin-1-yl)pyridin-5-yl)-N-(3,4,5-trichlorophenyl)-2-pyrimidineamine (170 mg,0.33 mmol) in dichloromethane and DMF (3 ml,1:1 mixture) was stirred with acetic acid (1 ml), dichlorobis(triphenylphosphine)palladium (II) (15 mg) and tri-n-butyltin hydride at room temperature for 5 min. The reaction was added to a saturated aqueous NaHCO3 solution, which was extracted with ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with hexane and then subjected to column chromatography (silica gel with 1% ammonium hydroxide-8% methanol-dichloromethane) to give the title compound (60 mg) as an off-white solid m.p. 208-211°. δH(d6 DMSO) 10.03(1H, s), 8.91 (1H, d, J 2.5 Hz), 8.51 (1H, d, J 5.4 Hz), 8.22 (1H, dd , J 9.1, 2.5 Hz),8.16 (2H, s), 7.43 (1H, d, J 5.4 Hz), 3.56 (4H, m) and 2.78 (4H, m).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](O)([C:36]([F:39])([F:38])[F:37])=[O:35]>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:33][C:34](=[O:35])[C:36]([F:39])([F:38])[F:37])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1
Product: O=C(Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1)C(F)(F)F

Procedure:
1-Benzenesulfonyl-N*4*-(1-benzyl-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (500 mg, 1.08 mmol) in TFA (5 mL) was heated to reflux for 5 hours. After cooling the mixture was concentrated under vacuum affording N-[1-benzenesulfonyl-4-(1-benzyl-piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-yl]-2,2,2-trifluoro-acetamide as an orange residue which was used for the next step without further purification. LCMS (Method B, ESI): RT=2.68 min, m+H=558.35.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.CO.[OH-].[Na+].C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc3[nH]ccc23)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1ccc(-c2cccc3[nH]ccc23)cc1Nc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To the obtained tert-butyl 2-(4-fluoroanilino)-4-(1H-indol-4-yl)benzoate were added methanol 1.0 mL,dioxane 1.0 mL and 2.0 mol/L sodium hydroxide aqueous solution 0.23 mL, it was stirred at 50° C. for 2 hours and 30 minutes, subsequently 2.0 mol/L sodium hydroxide aqueous solution 0.23 mL was added, it was stirred at 50° C. for 4 hours, furthermore 2.0 mol/L sodium hydroxide aqueous solution 0.23 mL was added, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, toluene and water were added to it. The water layer was separated and collected, it was adjusted to pH3.0 with 1.0 mol/L hydrochloric acid after washing with toluene, and ethyl acetate was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(1H-indol-4-yl)benzoic acid 23 mg of a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10]2[C:11]3[C:3]([CH3:2])=[CH:4][NH:5][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:32]
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C(=O)NC1CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (70 mg) and DIPEA (0.11 mL, 0.605 mmol) in DCM (1 mL) was added 2-methylbenzoyl chloride (70.2 mg, 0.454 mmol) and the reaction stirred at room temperature for 18 hours. The solvent was removed in vacuo and the mixture purified by MDAP to give the title compound E26 (25 mg) as a pale pink solid, 1H NMR (d6-DMSO) 11.55 (1H, brs), 8.26 (1H, d), 8.21 (1H, s), 7.30 (2H, m), 7.25 (2H, m), 7.06 (1H, s), 4.0 (3H, m), 3.06 (2H, t), 2.35 (3H, s), 2.35 (3H, s), 1.94 (2H, m), 1.67 (2H, m), MS(ES+) 350 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CSc1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(I)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A flask was charged with 10 g of 4-iodothioanisole and 5.5 mL of dimethylsulfate and warmed to ca. 90° C. for 10 min. The resulting solution was dissolved in conc. sulfuric acid (30 mL) and cooled to ca. 0-4° C., whereupon it was treated, with extreme caution, slowly with conc. HNO3 (ca. 2 mL) while maintaining the reaction temperature below 4° C. After stirring it for ca. 10 min, the reaction mixture was stirred at ca. 90° C. for ca. 3 d. The reaction was monitored with HPLC, TLC, and LC-MS, and if needed, smaller portions of nitric acid were added to the reaction mixture to force it to completion. Use of fuming sulfuric acid is also helpful. After the complete consumption of the aromatic starting material, the reaction mixture was cooled, poured over crushed ice, treated with 30% aq. perchloric acid at 4° C. The light colored precipitate was filtered, washed thoroughly with water, and dried under vacuum. The perchlorate salt was stirred with saturated aq. NaCl solution at 95° C. for 3-6 h. Upon cooling to room temperature, the precipitate was filtered, washed thoroughly with water to get rid of any inorganic salts, and dried under vacuum to obtain 4-iodo-3-nitrothioanisole in >80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][C:10]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:9]1.N([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)=[N+]=[N-].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:9]1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)CCc1nn(-c2ccccc2Cl)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 39 %

Procedure:
The alkylation of 2-(2-chlorophenyl)-2,4-dihydro-5-(3-methylbutyl)-3H-1,2,4-triazol-3-one with 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 4, Step D, except that a 20% excess of sodium hydride and 50% excess of the alkylating agent were used. After work-up, the crude product mixture was flash chromatographed on silica gel (72 mL for 0.354 mmol, eluted with 0.3% MeOH/CH2Cl2) to give a 39% yield of the desired material, mass spectrum (FAB) m/e 742 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([OH:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Br:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: Oc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccc(OCCOCCBr)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-ol (229 mg, 1 mmol; compound prepared in the same way as Example 1, Scheme 1-step 1B), 1-bromo-2-(2-bromoethoxy)ethane (515 mg, 2 mmol), potassium carbonate (0.42 g, 3 mmol) and sodium iodide (0.15 g, 1 mmol) in dimethylformamide (12 ml) was stirred, under dry nitrogen atmosphere, at room temperature overnight. The inorganic solid was filtered off and solvent was evaporated to dryness in vacuo. The remaining residue was partitioned between water and ethyl ether. The combined organic phases were washed with water and dried over sodium sulphate, filtered and evaporated in vacuo. The residue was stirred with petroleum ether at 45° C. and decanted for 3 times to yield, after drying, 466 mg of 3-(2-(2-bromoethoxy)ethoxy)-1-(3,4-dichlorophenyl)-1H-pyrazole which was used without further purification in the next step of synthesis.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.CN.[C:13]([BH3-])#[N:14].[Na+].Cl>CO>[CH3:13][NH:14][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCC(C)(C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4,4-dimethylcyclohexanone (25.2 g) in dry methanol under an atmosphere of nitrogen was added methylamine hydrochloride (13.2 g) and 3 Åmol sieves (1 g). The reaction mixture was stirred for 1 hr then sodium cyanoborohydride (12.7 g) added portionwise. The mixture was stirred for 17 hrs. A saturated solution of hydrogen chloride in methanol (200 ml) was added and the reaction mixture stirred for 1 hr the filtered through hyflo and concentrated in vacuo. The residue was partitioned between 1N sodium hydroxide (300 ml) and dichloromethane (200 ml). The layers were separated and the aqueous re-extracted with dichloromethane (2×200 ml). The combined organics were washed with saturated sodium hydrogen concentrated in vacuo. The residue was distilled under reduced pressure. Bpt 40°-45° C. at 0.1 mmHg. 1H NMR (CDCl s) δ0.92 (6H, s), 1.10-1.30 (5H, m), 1.30-1.50 (2H, m), 1.66-1.72 (2H, m), 2.26 (1H, m), 2.42 (3H, s).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:27])[N:13]([C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21](=[O:26])N(OC)C)[CH2:17][CH2:16]1)[CH3:14])([CH3:10])([CH3:9])[CH3:8].OS([O-])(=O)=O.[K+]>C1COCC1>[C:7]([O:11][C:12](=[O:27])[N:13]([C@H:15]1[CH2:16][CH2:17][C@H:18]([CH:21]=[O:26])[CH2:19][CH2:20]1)[CH3:14])([CH3:8])([CH3:10])[CH3:9]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.09 g (55 mmol) LAH in 250 ml THF was cooled (−50° C.) and treated during 25 min with a solution of 15.02 g (50 mmol) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 250 ml THF. The reaction was warmed up to +15° C. for 3.5 h, cooled (−78° C.) and hydrolyzed with a suspension of 15 g MgSO4.7H2O, 15 g silicagel in 50 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was stirred for 30 min and filtered. After evaporation, the residue was dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 12.83 (quantitative) trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, MS: 241 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[C:7]([CH3:11])[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.Br[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+].CI>COCCOC.O.CN(C=O)C.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.CCCCCC>[CH:9]([C:8]1[C:7]([CH3:11])=[C:6]([C:22]2[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])=[O:10]
Reactant: COC(=O)c1cccc(Br)n1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1C=O
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: [Cl-]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(OC)c(C=O)c2C)n1
Temperature: 90 °C
Reaction time: 7 h
Yield: 59.9 %

Procedure:
A suspension of the 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde produced in Example 4-1 (1.01 g, 3.66 mmol), methyl 6-bromopyridine-2-carboxylate (0.79 g, 3.66 mmol), sodium carbonate (1.16 g, 11.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) in 1,2-dimethoxyethane (20.2 ml) and water (8.8 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 7 hours. After air-cooling, an aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with dichloromethane 21 times. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then dissolved in DMF (20.2 ml). Thereafter, potassium carbonate (1.21 g, 8.78 mmol) and methyl iodide (0.27 ml, 4.39 mmol) were added to the resulting solution, and the mixture thus obtained was then stirred at 40° C. for 4 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=40:60, v/v) to obtain the title compound (0.625 g, yield: 60%).