Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1[CH:34]=[C:35]([CH2:39][CH2:40]O)[CH:36]=[CH:37][CH:38]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:40][CH2:39][C:35]2[CH:34]=[C:33]([CH3:32])[CH:38]=[CH:37][CH:36]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: Cc1cccc(CCO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(OCCc2cccc(C)c2)c1
Yield: 102.7 %

Procedure:
4-Bromo-3-hydroxy-benzoic acid methyl ester (1.00 g, 4.32 mmol) and triphenylphosphine (1.36 g, 5.19 mmol) were dissolved in THF. 2-(3-Methylphenyl)-ethanol (2-m-tolyl-ethanol) (0.707 g, 5.19 mmol) was added, the mixture was cooled in an ice bath, and DIAD (1.05 g, 5.19 mmol) was added slowly with stirring. The ice bath was removed and stirring continued overnight at room temperature. The volatiles were evaporated in vacuo, and the residue was purified by silica gel chromatography (HEP/EA gradient) to give 1.55 g of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O:21][C:22](=O)[C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C>C(O)C>[OH:31][C:23]1[C:22](=[O:21])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]([C:14]2[CH:17]=[CH:18][C:11]([CH3:10])=[CH:12][CH:13]=2)[C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C2C(c3ccccc3)=C(O)C(=O)N2CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 4-Methyl-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethylester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[CH:9][N:10]=2)[N:7]=1.[C:21]([Cu])#[N:22].[CH3:24]N1C(=O)CCC1>CCOC(C)=O>[N:12]1[C:13]2[C:14](=[CH:24][C:20]([CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[CH:19][CH:18]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc2ncc(-c3ccc4ccccc4n3)n2n1
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinoline (Example 14) (50 mg, 0.17 mmol) and CuCN (23 mg, 0.26 mmol) in 0.5 mL NMP were heated under microwave irradiation at 230° C. for 9.5 h. The RM was diluted with EtOAc and washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to yield the title compound as a yellow solid (tR 2.16 min (conditions 8), MH+=286).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[OH:17])[C:5]1=[O:28])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH3:34][O+](C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[O:17][CH3:34])[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: C[O+](C)C
Reactant: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1OC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccc(OC)c(OC)c1
Reaction time: 3 h

Procedure:
4.0 g (10.5 mmol) 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V) are suspended in 100 ml methylene chloride and combined with 3.1 g (21 mmol) trimethyloxonium tetrafluoroborate as well as 7.2 ml Hünig base (ethyldiisopropylamine) at ambient temperature. The solution is stirred for 3 h, then a further 1.55 g trimethyloxonium tetrafluoroborate and 3.5 ml Hünig base are added and the mixture is stirred overnight. After the same amount of reagent has been added again and the mixture has been stirred for a further 5 h, the reaction is washed three times with water, the organic phase is dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.COC1C=CC(C[CH2:30][NH2:31])=CC=1.C1CCN2C(=NCCC2)CC1.FC(F)(F)C(O)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH3:30])[CH:12]=3)[CH:7]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CCn1c(=O)c(-c2cc(N)ccc2C)cc2cnc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)c(-c2cc(N)ccc2C)cc2cnc(NC)cc21
Yield: 42.6 %

Procedure:
Using a procedure analogous to Example A26, 3-(5-amino-2-methylphenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (1.9 g, 6.4 mmol), 4-methoxybenzylmethylamine (1.5 g, 9.6 mmol), DBU (1.6 g, 9.6 mmol), and trifluoroacetic acid (10 mL, 134 mmol) were combined to give 3-(5-amino-2-methylphenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.84 g, 43% yield, 2 steps). 1H NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1 H), 7.56 (s, 1 H), 6.91-6.82 (m, 2 H), 6.47-6.39 (m, 2 H), 6.22 (s, 1 H), 4.80 (s, 2 H), 4.13 (q, J=6.9 Hz, 2 H), 2.84 (d, J=4.8 Hz, 3 H), 1.92 (s, 3 H), 1.19 (t, J=6.9 Hz, 3 H); MS (ESI) m/z: 308.9 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)CCC>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:26]2[CH:25]=[CH:24][CH:23]=[C:28]([CH2:2][CH2:3][CH2:4][CH3:5])[CH:27]=2)=[CH:8][CH:9]=1
Reactant: CCCCc1ccncc1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Product: CCCCc1ccc[n+](CCCCCc2ccc(-c3ccccc3)cc2)c1
Product: [Br-]
Temperature: 65 °C
Yield: 72 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (360 mg, 1.19 mmol) and 4-n-butylpyridine (0.5 mL) was heated at 60-70° C. for 12 hrs. The resulting mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with ethyl acetate (30 mL×3). Water was removed by lyophilization to afford 377 mg of the title compound. Yield: 72%. 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 3H), 1.29-1.53 (m, 4H), 1.60-1.80 (m, 4H), 2.08 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.8 Hz, 2H), 4.94 (t, J=7.5 Hz, 2H), 7.18-7.60 (m, 9H), 8.00 (t, J=7.2 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 9.29 (d, J=6.0 Hz, 1H), 9.30 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.9, 22.3, 25.7, 30.8, 32.0, 32.5, 32.6, 35.2, 61.7, 126.8, 127.0, 127.1, 128.0, 128.8, 128.9, 138.6, 140.8, 141.1, 142.5, 144.0, 144.1, 144.6 ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13]Cl)[CH:7]=[C:6]([CH3:15])[N:5]=2.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH3:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13][NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:7]=[C:6]([CH3:15])[N:5]=2
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NCCCl)cc(C)nc32)c(C)c1
Reactant: NC1CCCCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-n2c(C)nc3c(NCCNC4CCCCC4)cc(C)nc32)c(C)c1

Procedure:
Heat a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-y1](2-chloroethyl)amine (0.04 g, 0.12 mmol), and cyclohexyl amine (0.13 mL g, 1.16 mmol) in dry NMP (2 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (20 mL) and extract twice with ethyl acetate (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% methanol in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>ClCCCl.CCOC(C)=O>[CH3:27][O:26][C:24](=[O:25])[NH:13][C:12]1[CH:14]=[CH:15][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: COC(=O)Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 104.3 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 0.685 mmol) and pyridine (0.277 mL, 3.43 mmol) in 1,2-dichloroethane (3.5 mL) was added methyl chloroformate (0.058 mL, 0.754 mmol) at 0° C. and stirred at 60° C. for 6 hours. The mixture was diluted with AcOEt, washed with 1N HCl, brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated to afford the desired product (198 mg, quant) as a pale yellow oil. 1HNMR (CDCl3) 400 MHz δ: 7.75 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.64 (br s, 1H), 3.78 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[O:26])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(OC2CC2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-bromo-4-(cyclopropoxy)benzene (492 mg, 2.31 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 2.66 mol/L n-butyllithium in hexane (0.955 ml, 2.54 mmol) at −78° C. under argon atmosphere, and the mixture was stirred for 2.5 hours. Then, thereto was added dropwise N,N-dimethylformamide (0.358 ml, 4.62 mmol) at the same temperature, and the mixture was stirred for 3.5 hours with slowly warming to room temperature. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was stirred, and then extracted with ethyl acetate three times. The organic layer was combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude 4-(cyclopropoxy)benzaldehyde as a pale yellow liquid. The resulting compound was used in the next step without further purification. (2) A solution of the above crude product in methanol (5 ml) was cooled to 0° C., and then thereto was added sodium borohydride (175 mg, 4.62 mmol), and the mixture was stirred for 1 hour. Then, thereto was added saturated brine, and then the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give the title compound, [4-(cyclopropoxy)phenyl]methanol (216 mg, 57%, yields for 2 steps) as a white solid.
Reaction SMILES: [P:1]([O-:12])([O:7][C:8](C)(C)[CH3:9])[O:2][C:3](C)(C)[CH3:4].[CH:13]([N:16](C(C)C)P(Cl)(N)=O)(C)C.[O-]P(OP([O-])([O-])=O)(=O)[O-].C(OP([O-])(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>>[CH2:3]([O:2][P:1]([C:13]#[N:16])(=[O:12])[O:7][CH2:8][CH3:9])[CH3:4]
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Reactant: CC(C)N(C(C)C)P(N)(=O)Cl
Agent: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: CCOP(=O)(C#N)OCC

Procedure:
In order to try different protecting groups on the phosphate, several other methods of phosphorylation were attempted. These included the use of alkylamidophosphines, which have been shown to readily phosphorylate alcohols and phenols in high yield. For example, di-tert-butyloxy (N,N-diisopropylamido)phosphine, prepared from dichloro(N,N-diisopropylamido)phosphine and tert-butanol was allowed to react with diphenol 1 in the presence of 1H-tetrazole. After phosphorylating diphenol 1, subsequent in situ oxidation of the trivalent phosphorous to the pentavalent species with meta-chloroperoxybenzoic acid did not result in the desired phosphate. Perhaps this unpromising result arose from the steric crowding involved with four tert-butyl groups in the 2′- and 3′- positions, or from the oxidation step which may have effected the stilbene olefin. Interestingly, the use of dibenzyloxy(N,N-diisopropylamido)phosphine under the reaction conditions just described did afford phosphate 10 but only in 10% yield. Two other phosphorylation methods were attempted using di-tert-butyl phosphite with an in situ generation of the appropriate halide (Br, Cl), and N,N-diisopropylphosphorodiamidic chloride. Neither method led to the corresponding diphosphate analog of dibenzylphosphate 10. Diphosphorylation of 1 was also achieved in good yield with diethylcyano-phosphonate. However, this method proved to be problematic due to harsh conditions needed to remove an ethyl group.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].N[C:28]1[CH:29]=C2C(=C[CH:37]=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CCCCC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:29][CH2:28][CH2:37][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: O=C(O)C(=O)CC1(c2ccccc2)CCCCC1
Product: O=C(CC1(c2ccccc2)CCCCC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclohexyl)-2-oxo-propionic acid, melting point 120-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl.N1C=CC=CC=1>[C:27](=[O:28])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 104, 3.90 g, 10.6 mmol) in dichloromethane (20 mL) and pyridine (2 ml) was added dropwise phenyl chloroformate (1.6 mL, 12.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography eluting with hexane/ethyl acetate (3:1) afforded 4.2 g (82%) of the title compound as a colorless syrup.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[N:15]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=[N:15]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: c1c[nH]nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(CCn3ccnn3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), 1,2,3-triazole (2.07 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (70 ml) was boiled under reflux for 24 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with EA/cyclohexane (1:1→4:1).).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>C(O)C>[NH2:21][C:20]1[NH:22][C:4](=[O:3])[C:5]([CH3:13])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:19]=1
Reactant: CCOC(=O)C(C)C(=O)c1ccco1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Cc1c(-c2ccco2)nc(N)[nH]c1=O
Temperature: 100 °C
Yield: 123.1 %

Procedure:
Following the method of Rorig and Nicholson (U.S. Pat. No. 2,710,867), a mixture of 3.00 g (15.3 mmol) (RS)-3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester and 1,38 g (7.65 mmol) guanidine carbonate in 20 ml ethanol was heated at 100° C. for 16 hours. The reaction mixture was then cooled to 0° C., whereupon the resulting crystals were collected by filtration and washed sequentially with water and with ice-cold ethanol to afford 1.80 g (62%) 2-amino-6-furan-2-yl-5-methyl-3H-pyrimidin-4-one as a white crystalline solid. ES-MS m/e (%): 190 ([M—H]−, 100).
Reaction SMILES: C1(S([C:10]2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C[OH:27].Cl>C(OCC)(=O)C.CCCCCC>[Cl:23][C:18]1[CH:17]=[C:16]([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:10](=[O:27])[CH2:11]3)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CO
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(3,4-dichlorophenyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (1.4 g, 3.3 mmol), methanol (6 mL) and concentrated hydrochloric acid (1.5 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)). The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (100 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 1.1 g of crude oil, which was purified by preparative HPLC to yield 560 mg (70%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.67-0.70 (1H,t, J=4 Hz), 1.25-1.35 (1H,m), 1.94-2.15 (1H,m), 2.36-2.42 (1H,d ,J=18 Hz), 2.59-2.65 (1H,d,J=18 Hz), 2.83-2.89 (2H,m),6.99-7.03 (1H,dd,J=9.3 Hz), 7.25-7.26 (1H,d,J=3 Hz),7.36-7.39 (1H,d,J=9 Hz). 13CNMR(CDCl3) δ: 215.25, 143.49, 132.55, 130.39, 130.06, 128.07, 125.40, 45.34, 42.08, 27.18, 23.32, 22.24.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[N+:15]([O-:18])(O)=[O:16].[C:19](OC(=O)C)(=[O:21])C>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:11]([N+:15]([O-:18])=[O:16])=[CH:10][C:5]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:19](=[O:21])[NH:12][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(C)n1c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
The compound of Example 4 (1.0 g, 5.0 mmol) was suspended in acetic anhydride (10 mL) and cooled in an ice bath. To this mixture was added dropwise 1.5 mL of a 1:2 mixture of nitric acid/acetic anhydride. The reaction mixture was stirred for 5 minutes before being poured into ice-water. The solid was filtered and washed well with water and suction-dried to afford 1.01 g (80%) of the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:7]=1[C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[NH:10]2.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[C:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[C:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]3[C:7]=2[C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[NH:10]3)[CH2:34][CH2:35]1
Reactant: C(=C1CCNCC1)c1ccc2ccccc2n1
Reactant: Cc1ccc(OCCCCl)c2c1NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCCN2CCC(=Cc3ccc4ccccc4n3)CC2)c2c1NC(=O)C2(C)C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
4-(3-Chloropropoxy)-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-one (268 mg) and 4-(2-quinolylmethylene)piperidine (224 mg) were dissolved in DMF (10 ml), and potassium carbonate (145 mg) and potassium iodide (173 mg) were added to the solution. The mixture was stirred at 100° C. for 90 minutes under argon and concentrated under reduced pressure. Chloroform was added to the residue. The mixture was washed with water, dried over magnesium sulfate anhydrate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developer: chloroform-methanol (20:1)), to thereby obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(Cl)Cl>C(O)C.O.NN>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: NN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
In a suspension of 1.4 g of N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenylmethyl]phthalimide in 20 mL of ethanol, 1.0 mL of 80% hydrazine monohydrate aqueous solution was added, and stirred under reflux with heating for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 50 mL of chloroform was added therein, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The procedure comprising adding 50 mL of chloroform in the residue, filtering off insoluble material and distilling off the solvent was repeated twice to obtain 1.1 g of the aimed product as yellow resinous substance.