Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 70.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 46 (61 mg, yield 70.4%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:41])[CH2:37][C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:38](=[O:39])[CH2:37][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: COCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 95 (136 mg, 0.37 mmol) in dry DMF (7 ml) was added the acid 27 (300 mg, 3.0 eq, 1.1 mmol), HOBT (74 mg, 1.5 eq, 0.55 mmol) and EDC (210 mg, 3.0 eq, 1.1 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and sat NaHCO3 soln, the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was triturated with Et2O to afford title compound 92 (150 mg, 72% yield). 1H NMR (DMSO-d6) δ(ppm): 10.57 (s, 1H), 9.62 (s, 1H), 8.43 (d, J=5.48 Hz, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.85 (m, 1H), 7.76 (s, 1H), 7.45 (m, 2H), 7.05 (m, 2H), 6.90 (m, 1H), 6.58 (m, 1H), 5.35 (s, 2H), 3.84 (m, 3H), 3.63 (s, 2H), 3.25 (s, 3H). MS (m/z): 562.1 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>CCOCC.CCCCCC>[CH3:13][O:12][C:3]1[C:2]([CH:21]=[O:22])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: COc1ncc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ncc(C(F)(F)F)cc1C=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.18 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 50 ml of ether was cooled to -100° C. and blanketed with nitrogen. A solution containing 0.024 mole of butyl lithium in hexane (15.0 ml of 1.6 M) was added slowly with stirring keeping the temperature below about -95° C. and the mixture was allowed to react for another 15 min. Dimethylformamide (7.5 ml, 0.097 mol) was added to the mixture at below -95° C. and stirring continued for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and 1N hydrochloric acid. The mixture that formed was extracted with ether and the extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled in a Kugelrohr apparatus to obtain 3.6 g (86 percent of theory) of the title compound as an oil which solidified to a white crystalline solid. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: OCCc1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
6-(2-Hydroxyethyl)-indole (72.5 mg, 0.45 mmol) was mixed with Et3N (126 mg, 1.35 mmol) in 2 ml of dichloromethane at 0 to 5° C. Methane sulfonyl chloride (61.6 mg, 0.54 mmol) was added and the mixture stirred for 1 hr, diluted with dichloromethane, washed with brine, dried and concentrated to give 107 mg of the title compound (quantitative yield).
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.[CH:21]([CH:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])([CH3:23])[CH3:22]>>[CH:21]([C:24]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])([CH3:23])[CH3:22]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Reactant: CC(C)C1C(=O)CCC1=O
Product: COc1cccc(CCCC(=O)CCC2(C(C)C)C(=O)CCC2=O)c1
Yield: 97.7 %

Procedure:
Condense a mixture (6 g) of 1-diethylamino-6-(m-methoxyphenyl)hexan-3-one and 6-(m-methoxhyphenyl)hex-1-en-3-one with 2-isopropylcyclopentane-1,3-dione (3 g) using a procedure similar to that described for the condensation of the 2-ethyl compound. Obtain the corresponding triketone, 2-isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.2 g) as an uncrystallizable gum.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]O>>[CH3:18][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 90.9 %

Procedure:
A total of 181.5 g (0.825 mol) of 3,5-diphenylpyrazole and 791 g (24.7 mol) of methanol was used. A total of 175.8 g (91%) of 1-methyl- 3,5-diphenylpyrazole was obtained. The holdup of the bubble column was not taken into account.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[CH:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:13]#[CH:14]>O>[CH:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH:12]=[C:13]=[CH2:14])=[CH:21][CH:20]=2)=[CH:23][CH:24]=1)=[C:30]=[CH2:31]
Reactant: C#CCOc1ccc(-c2ccc(OCC#C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C=COc1ccc(-c2ccc(OC=C=C)cc2)cc1
Yield: 35.3 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 2.124 parts of t-BuOK and 12.036 parts of THF and to this, a mixture of 10.000 parts of 4,4'-dipropargyloxybiphenyl and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 4,4'-diallenyloxy biphenyl as pale yellow crystals (M.P.135.2°-138.5° C.)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (45 mg) was coupled to 2-(methylsulfonyl)ethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 26.8 mg of 169. MS (Q1) 487.1 (M)+.
Reaction SMILES: FC1C=CC=CC=1C1[N:9]=[C:10]([CH3:22])[N:11]2C=1[C:15]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[N:14][CH:13]=[N:12]2.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[Cl:34])=O>>[Cl:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:9]=[C:10]([CH3:22])[N:11]2[C:24]=1[C:15]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[N:14][CH:13]=[N:12]2
Reactant: O=C(CBr)c1ccc(F)cc1Cl
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Product: Cc1nc(-c2ccc(F)cc2Cl)c2c(-n3cncn3)ncnn12

Procedure:
5-(2-Chloro-4-fluorophenyl)-7-methyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine was prepared in similar fashion to C6 in Example 1, by employing 2-bromo-1-(2-chloro-4-fluorophenyl)ethanone.
Reaction SMILES: O.[N-:2]=[N+:3]=[N-:4].[Na+].[CH2:6]([Sn:10](Cl)([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>COC(C)(C)C>[CH2:15]([Sn:10]([N:2]=[N+:3]=[N-:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Yield: 64.3 %

Procedure:
Into 40 ml of distilled water was added 9.99 g of sodium azide (0.154 mol, 10.0 equiv), 30 ml tert-butyl methyl ether, and 5.0 g (0.0154 mol, 1.0 equiv) tributyltin chloride. The resultant mixture was stirred at room temperature for one hour. Carbon 13 NMR of an aliquot taken at this point showed absence of the starting tributyltin chloride. Therefore, the organic layer, after being separated from the aqueous layer, was dried over anhydrous sodium sulfate, filtered, concentrated, and distilled to afford 3.29 g (65%) of the desired product (bp.=115°-117° C./0.4 mm): 13C NMR δ27.8, 27.0, 15.2, 13.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Cl)=[C:4]([F:12])[CH:3]=1.[BH4-].[Na+].C[O-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][O:11]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C(CCl)c1ccc(Br)cc1F
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1cc(Br)ccc1C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To a stirred solution of 1-(4-bromo-2-fluorophenyl)-2-chloroethanone (5.57 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (838 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (2.06 ml, 30% solution in methanol) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed the reaction was complete. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; gradient: 5% to 40% EtOAc in heptane) to afford (RS)-2-(4-bromo-2-fluorophenyl)oxirane (1.35 g, 28%) as a light yellow oil which was used in the next step without further purification. MS (EI): 218 ([{81Br}M]+, 216 ([{79Br}M]+).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:20][NH2:21].O>C(O)C>[N+:16]([C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:21][N:20]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: NN
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of 2-chloro-5-nitrobenzophenone (15 g, 57 mmol) in ethanol (300 mL) was added hydrazine monohydrate (50 mL, 1 mol). The resultant solution was stirred overnight (16 hrs.) at ambient temperature, then poured into water (2 L) and stirred for an additional 2 hours. The precipitate that formed was collected by filtration, washed with water (2×100 mL) and air dried to give 5-Nitro-3-phenyl-1H-indazole 11a (13.1 g, 80%) as a yellow solid: 1H NMR (DMSO-d6) δ 7.48 (tt, 1H, J=1.3, 7.4 Hz), 7.58 (dd, 2H, J=7.1, 7.4 Hz), 7.78 (d, 1H, J=9.2 Hz), 8.01 (dd, 2H, J=1.3, 7.1 Hz), 8.25 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d, 1H, J=2.1 Hz), 13.88 (s, 1H). Anal. (C13H9N3O2) C, H, N.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][CH3:34])[N:32]=1)[C:27]([OH:29])=O.[F:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH2:40][CH2:39]2.C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]([N:41]2[C:42]3[C:38](=[CH:37][C:36]([F:35])=[CH:44][CH:43]=3)[CH2:39][CH2:40]2)=[O:29])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.965 g (3.00 mmol) TBTU was added at RT to 0.500 g (2.67 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.366 g (2.67 mmol) 5-fluoroindoline and 0.421 mL (3.00 mmol) triethylamine in 10.0 mL DMF. The mixture was stirred for 2 h at RT and then purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:19]3[CH2:20][CH2:21][CH2:22][CH:18]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: Cc1nnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nnc2ccc(N3CCCC3c3ccccc3)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
A mixture of 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.19 mol), 2-phenylpyrrolidine (200 mg, 1.36 mmol) and K2CO3 (350 mg, 2.5 mmol) in acetonitrile (20 mL) was heated at 100° C. under microwave and stirred for 30 mins. After cooled to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by prep-TLC (silica-gel, DCM: MeOH=20:1) to give product 3-methyl-6-(2-phenylpyrrolidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (Compound 10) as a white solid (30 mg, 12%). 1H NMR (300 MHz, CD3OD) δ 7.73-7.77 (d, 1H, J=10.2 Hz), 7.22-7.34 (m, 5H), 6.84-6.87 (d, 1H, J=10.2 Hz), 5.14-5.18 (m, 1H), 3.92-3.98 (m, 1H), 3.71-3.81 (m, 1H), 2.57 (s, 3H), 2.50-2.54 (M, 1H), 2.03-2.13 (m, 3H); LRMS (M+H+) m/z: calcd 279.15; found 279.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.BrCC1CCCCO1>>[F:31][C:30]([F:33])([F:32])[C:27]1[O:26][C:25]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 64-68° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.8, 7.7, 1.0 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.07 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.76-6.72 (m, 1H), 6.50 (s, 1H), 6.38 (d, J=3.3 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.5 Hz, 1H), 4.89 (d, J=16.5 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (d, J=267 Hz), 112.8 (d, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]([CH2:27]/[C:28](/[CH3:37])=[CH:29]/[CH2:30][CH2:31]/[C:32](/[CH3:36])=[CH:33]/[CH2:34]Br)[CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15]>C1COCC1>[CH2:12]([CH2:27]/[C:28](/[CH3:37])=[CH:29]/[CH2:30][CH2:31]/[C:32](/[CH3:36])=[CH:33]/[CH2:34][NH:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
In 40 ml of THF was dissolved 7.56 g of piperonylamine, a solution of 2.11 g of farnesylgeranyl bromide in 10 ml of THF was added dropwise at room temperature and stirred at room temperature for 12 hours. Then, the THF was concentrated under reduced pressure. The concentrate was dissolved in chloroform and then washed with a 5% sodium hydroxide solution. After the chloroform layer was concentrated under reduced pressure, the concentrate was dissolved in acetonitrile and extracted with hexane (150 ml×2). The hexane layer was washed with acetonitrile (50 ml×2) and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (using ethyl acetate as a developing solvent) to give 2.0 g of N-farnesylgeranylpiperonylamine as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1cc(-c2cn(C3CCN(Cc4ccccc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 90 °C

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), and to which were added potassium carbonate (276 mg, 2 mmol) and benzyl bromide (342 mg, 2 mmol). The reaction mixture was warmed to 90° C. for 5 h. After the reaction mixture was cooled to room temperature, to which was added water. The reaction mixture was extracted with dichloromethane, the organic layer was washed with water for several times, dried over anhydrous sodium sulfate, and then filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane:methanol=10:1) to yield the title compound as gray solid powder.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH:19]1([C:23]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=3)[N:10]=[CH:11][N:12]=2)=[O:22])[CH2:20][CH2:21]1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Agent: [Li]CCCC
Product: C=Cc1ccc(-n2ncnc2C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min To this N-methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d, J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][N:10]1[CH2:15][CH:14]([CH3:16])[NH:13][NH:12][C:11]1=[O:17]>S(=O)(=O)(O)O.C(O)C>[CH3:16][CH:14]1[NH:13][NH:12][C:11](=[O:17])[N:10]([N:9]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:15]1
Reactant: O=Cc1cccnc1
Reactant: CC1CN(N)C(=O)NN1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1CN(N=Cc2cccnc2)C(=O)NN1

Procedure:
2.2 g of pyridine-3-carbaldehyde and 2 drops of sulfuric acid are added to a solution of 3 g of 4-amino-6-methyl-3-oxo-1,4,5,6-tetrahydro-1,2,4-triazine in 30 ml of ethanol. The reaction mixture is then maintained under reflux for 90 minutes and then the resulting suspension is cooled to 200°, filtered and dried. 4.1 g of the title compound having a melting point of 235°-237° are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].CCCC[Sn]([C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)(CCCC)CCCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: CCOC(=O)c1nc(-c2cccnc2)c2onc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to Example 12 from 7-Bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 3-(1,1,1-tributylstannyl)pyridine; ESI MS (m/z): 362.23 (M+H+); 360.13 (M−H+).