Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:43])([F:44])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCCBr)c2ccccc2-c2ccccc21
Product: CCOC(=O)c1ccc(N2CCN(CCCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 94 were used as the starting compounds. Thus, ethyl 4-[4-[5-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]pentyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[CH3:22][CH:23]([NH2:25])[CH3:24].CCN(C(C)C)C(C)C>>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:25][CH:23]([CH3:24])[CH3:22])[N:11]=2)[CH2:3]1
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C[C@H]1O
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To the solution of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (446 mg, 1.437 mmol) from the previous step was added propan-2-amine (0.367 mL, 4.31 mmol) and DIEA (1.004 mL, 5.75 mmol). The reaction was stirred at 80° C. for 4 h and then allowed to cool to ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-90% ethyl acetate in hexanes) to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(isopropylamino)pyrimidine-5-carbonitrile (381 mg, 1.317 mmol, 92% yield). MS (ESI) m/z 290.2 [M+1]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31]([N:33]2[CH:37]([C:38]3[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=3)[CH2:36][O:35][C:34]2=[O:46])=[O:30])[CH2:6][CH2:7]1
Reactant: O=C1OCC(c2cc(F)cc(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccccc1N1CCN(CCCN)CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1N1CCN(CCCNC(=O)N2C(=O)OCC2c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine (25 mg, 0.090 mmol) in 10 mL of THF, 4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester(30 mg, 0.082 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf=0.75, MeOH/EtOAc=1:3 ) to obtain 2-[4-(3-{[4-(3,5-difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-amino)-propyl)-piperazin-1-yl]-benzoic acid methyl ester (31 mg, 69%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P. 93-96° C.; [α]D=+45.3, (c=0.29, MeOH); Anal. Calcd. For C25H30N4O 5F2Cl2 .0.58 CH2Cl2: C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56; N, 8.91.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:10]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=2)=[N:2][N:12]=[N:11]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nnn[nH]2)nc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammonium chloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].C1(C=O)CC1>C1COCC1>[CH3:15][N:3]([O:2][CH3:1])[C:4](=[O:14])/[CH:5]=[CH:16]/[CH:17]1[CH2:19][CH2:18]1
Reactant: [Li]CCCC
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Agent: O=CC1CC1
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of N-methoxy-N-methyl diethylphosphonoacetamide (34.56 g, 144.5 mmol) in THF (200 mls) at -78° C., was added n-butyllithium (57.8 mls of a 2.5M solution in hexanes, 144.5 mmol) dropwise. Upon completion of addition, the mixture was stirred for 30 mins at -78° C. A solution of cyclopropanecarboxaldehyde (6.75 g, 96.3 mmol) in THF (50 mls) was then added dropwise. Upon completion of addition, the cooling bath was withdrawn and the reaction allowed to warm to r.t. It was then diluted with aqueous sat'd NH4Cl (200 mls) and the THF was stripped off in vacuo. The aqueous residue was extracted with ethylacetate (3×200 mls). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 3:2) to afford 14.09 g (94%) of trans-N-methyl-N-methoxy-3-cyclopropylpropenamide as a colorless oil.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[C:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:2]([OH:5])(=[O:4])=[O:3])=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(OC(=O)c2ccccc2)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(OC(=O)c2ccccc2)ccc1S(=O)(=O)O
Yield: 13.9 %

Procedure:
A solution of 0.47 mL (7.01 mmol) of chlorosulfonic acid in 7 mL of dichloromethane was added drop by drop to a solution of 1.6 g (7.01 mmol) of 3-methoxyphenyl benzoate in 12 mL of dichloromethane at 0° C. Once the addition was completed, the mixture was left to react for 18 h at room temperature. The formed precipitate was filtered, giving 300 mg of 4-benzoyloxy-2-methoxybenzenesulfonic acid. Yield 15%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([CH3:26])[N:19]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([CH3:26])=[CH:21][CH:22]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: Cc1ccc(CO)c(C)n1
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (110 mg) and THF (dry) (5 mL) were added (2,6-dimethylpyridin-3-yl)methanol (58.8 mg), tri-n-butylphosphine (0.159 mL) and ADDP (130 mg) at room temperature. The mixture was stirred at room temperature for 12 h. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (139 mg).
Reaction SMILES: [CH2:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([OH:18])=[O:17])[CH:2]=[CH2:3].CCN=C=NCCCN(C)C.Cl.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][O:17][C:16]([C@@H:5]2[C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:7](=[O:8])[N:6]2[Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])=[O:18])=[CH:35][CH:34]=1
Reactant: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Reactant: COc1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of 900 mg of crude compound 57 (3.34 mmol) above, EDC hydrochloride salt (1.34 g, 7.01 mmol), DMAP (83 mg, 0.67 mmol) and 4-methoxybenzyl alcohol (1.40 g, 10.1 mmol) in dichloromethane (9 mL) was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved with ethyl acetate, washed with 5% aqueous KHSO4, water (×2) and brine (×1). The organic layer was dried over Na2SO4, then concentrated to yield the crude 58 with LC purity: 60%. Purification by ISCO silica gel column using 0-20% AcOEt in Hexanes afforded 630 mg of compound 58 (49% yield, 81% purity): 1HNMR (300 MHz, CDCl3): 0.13 (s, 3H), 0.32 (s, 3H), 0.95 (s, 9H), 2.56 (m, 2H), 3.43 (m, 1H), 3.81 (d, J=2.60 Hz, 1H), 3.82 (s, 3H), 4.67 (s, 2H), 5.17 (m, 2H), 5.72 (m, 1H), 6.94 (d, 2H), 7.34 (d, 2H). Anal. C21H31NO4Si, Mol. Wt.: 389.56. Found: ESI-MS: 390.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[Br:27]CCBr>C1COCC1>[Br:27][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: BrCCBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 25 g (140 mmol) of the product from Step A and 52.2 mL (350 mmol) of redistilled N,N,N′,N′-tetramethylethylenediamine in 350 mL of dry THF under nitrogen at −78° C. was slowly added via cannula 140 mL (350 mmol) of n-butyllithium (2.5N in hexane). The reaction mixture was stirred at −78° C. for 30 min then at −10° C. for 90 min. The reaction mixture was then cooled to −78° C. and 30.2 mL (350 mmol) of 1,2-dibromoethane was slowly added. The mixture was stirred at −78° C. for 30 min, at −10° C. for 90 min then quenched with saturated aqueous ammonium chloride solution. A 600 mL portion of ethyl acetate was next added and the mixture was washed sequentially with water and saturated aqueous brine (400 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes gradient) to give the title compound. 1H NMR (500 MHz, CDCl3): δ 9.54 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.86 (br s, 1H), 7.51 (d, J=5.3 Hz, 1H), 1.39 (s, 9H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]4=[CH:20][CH:21]=[C:22]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:38][S:39]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)=[N:15]3)=[CH:20][CH:21]=2)[CH2:28][CH2:27]1)(=[O:41])=[O:40]
Reactant: C1=C(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CCNC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CC=C(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CC1
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
Into a 8-dram vial, (4-Morpholin-4-yl-phenyl)-[7-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (0.080 g, 0.21 mmol), Acetonitrile (15 mL, 290 mmol), Potassium carbonate (0.0587 g, 0.425 mmol) were added and stirred for 5 minutes. Methanesulfonyl chloride (0.0256 g, 0.223 mmol) was added. The reaction was stirred at room temperature over night. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine as a yellow solid (35 mg, 36%). LCMS (E/I+) 455.10 (M+H). MP 238-240° C. NMR 1H (DMSO-d6)-9.18 (s, 1H), 8.90 (s, 1H), 7.56 (d, 2H, J=8.88 Hz), 7.19 (bs, 1H), 6.94 (d, 2H, J=8.88 Hz), 6.83 (d, 1H, J=4.72 Hz), 6.81 (d, 1H, J=4.72 Hz), 4.00 (bs, 2H), 3.75 (t, 4H, J=5.26 Hz), 3.42 (t, 2H, J=5.96 Hz), 3.05 (t, 4H, J=5.26 Hz), 2.97 (s, 3H), 2.72 (bs, 2H).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH2:6][CH:5]=1.[C:16](Cl)(=[O:20])[C:17](Cl)=[O:18]>CCOCC>[O:3]1[C:17](=[O:18])[C:16](=[O:20])[C:5]2[CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:4]1=2
Reactant: C[Si](C)(C)OC1=CCSc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: O=C1OC2=C(CSc3ccccc32)C1=O
Yield: 82.3 %

Procedure:
To a stirred mixture of 4-[trimethyl[silyl]oxy]-2H-benzothiopyran (380.5 g,1.609 mol), prepared according to the method of L. Hellberg et al, Tet. Letters, 3553-3554 (1974), and one liter of diethyl ether, were added 103.8 g (0.818 mol) of oxalyl chloride in a dropwise manner over a period of 50 minutes at room temperature under nitrogen. The mixture was stirred at room temperature for 17 hours after which time the ether was removed under reduced pressure. The residue was triturated with isopropyl ether/hexane to give 146.9 g (82.3%) of a brown crystalline solid, mp 156° C. (dec).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:19][OH:20]>C(O)C>[OH:20]/[N:19]=[C:9](\[NH2:10])/[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(CC#N)ccc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C/C(N)=N/O)ccc1I
Yield: 50.3 %

Procedure:
2-(4-Iodo-3-methylphenyl)acetonitrile (2 g, 7.78 mmol) in ethanol (30 mL) was added dropwise to potassium carbonate (6.67 g, 48.24 mmol) and hydroxylamine hydrochloride (0.541 g, 7.78 mmol) in ethanol (30 mL) at reflux over a period of 5 minutes. The resulting suspension was stirred at reflux for 8 hours. The reaction mixture was allowed to cool overnight and the salts were filtered and washed with DCM (2×50 mL). The filtrate was evaporated to give crude product. The crude product was purified by flash silica chromatography on a combi flash companion 40 g cartridge, elution gradient 0 to 30% MeOH in DCM. Pure fractions were evaporated to dryness to afford (Z)—N′-hydroxy-2-(4-iodo-3-methylphenyl)acetimidamide (1.135 g, 50.3%) as a yellow gum.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:57])[CH2:17][CH2:18][C:19](=[O:56])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:27](=[O:47])[CH2:28][CH2:29][C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:58](OC(=O)C)(=[O:60])[CH3:59]>N1C=CC=CC=1>[CH2:1]([O:8][N:9]([C:16](=[O:57])[CH2:17][CH2:18][C:19](=[O:56])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:27](=[O:47])[CH2:28][CH2:29][C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:58](=[O:60])[CH3:59])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Reaction time: 12 h
Yield: 91 %

Procedure:
6,17,28-Tris (benzyloxy)-7,10,18,21,29-pentaoxo-6,11,17,22,28-pentaazatriacontanenitrile (13 ) was prepared by dissolving compound (12) (1.1 g, 1.4 mmol) in pyridine (16 ) mL), adding acetic anhydride (4 mL) and stirring the solution for 12 hours. After removal of solvents under high vacuum, water was added, followed by extraction with CHCl3. The organic extracts were washed with 1 N HCl and saturated NaHCO3. Column chromatography (5% CH3OH/CHCl3) gave 1.05 g (91%) of (13): NMR δ 1.4-1.59 (m, 4 H), 1.59-1.70 (m, 6 H), 1.70-1.85 (m, 6 H), 2.1 (s, 3 H), 2.35 (t, 2 H), 2.40-2.55 (m, 4 H), 2.75-2.90 (m, 4 H), 3.18-3.28 (m, 4 H), 3.6-3.7 (m, 6 H), 4.8 (s, 2 H), 4.82 (s, 2 H), 4.84 (s, 2 H), 6.20-6.75 (m, 2 H), 7.4 (s, 15 H) . Anal. calcd. for C46H62N6O8 : C, 66.30; H, 7.68. Found: C, 66.44; H, 7.66 [Bergeron et al, J. Org. Chem., supra].
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29].CC(C)([O-])C.[K+]>O1CCCC1>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[CH:2]=[C:7]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]3=[O:29])[C:6]=2[CH:8]=1)[C:13]([F:14])([F:15])[F:16]
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: O=C1CCCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 3 %

Procedure:
To a mixture of 0.54 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.24 g of 2-piperidinone and 10 ml of tetrahydrofuran was added 0.27 g of potassium tert-butoxide with stirring under ice-cooling. The mixture was stirred for 6 hours under ice-cooling and then stirred at room temperature for 16 hours. Ice water was added to the mixture, which was then extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.02 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-oxo-1-piperidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 149°-150° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[O:5].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]4[O:13][CH2:14][O:15][C:9]=4[CH:8]=3)=[O:5])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCl)Nc1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCN1CCN(c2ccccc2)CC1)Nc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 109.5 %

Procedure:
To N-(3-chloropropionyl)-3,4-methylenedioxyaniline (2.0 g) dissolved in N,N-dimethylformamide (20 ml) were added N-phenylpiperazine (1.6 g) and triethylamine (3 ml) and the mixture was stirred at 80° C. for 20 hours in a nitrogen atmosphere. The reaction mixture was evaporated in vacuo and to the residue were added ethyl acetate and 2N sodium hydroxide solution. After the aqueous layer was removed, the ethyl acetate layer was washed twice with water and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off and the residual solid was recrystallized from ethanol to give N-[3-(4-phenyl-1-piperazinyl)propionyl]-3,4-methylenedioxyaniline (3.4 g, 90% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13].[NH2:14][OH:15]>CO>[OH:15]/[N:14]=[C:12](\[NH2:13])/[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: N#CCCCCNc1ccccn1
Reactant: NO
Solvent: CO
Product: N/C(CCCCNc1ccccn1)=N\O
Temperature: 40 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
5-(Pyridin-2-ylamino)pentanenitrile (1.00 g; 5.71 mmoles) was dissolved in methanol (10 mL) and hydroxylamine (1.4 mL of a 50% aqueous solution; 22.83 mmoles) was added. The reaction mixture was stirred at 40° C. under nitrogen for 2 days. The solvent was removed under vacuum and the resulting oil was placed under vacuum at 40° C. for 6 hours. The product (1Z)-N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (A) (1.16 g; 98%) was obtained as a pale yellow oil. 1H NMR (DMSO-d6) δ 8.68 (1H, s, br), 7.91-7.95 (1H, m), 7.29-7.35 (1H, m), 6.35-6.45 (3H, m), 5.25-5.35 (2H, s, br), 3.15-3.23 (2H, m), 1.97 (2H, t, J=7.5 Hz), 1.45-1.60 (4H, m).
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.N=[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH2:33]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:16]2[C:15]([NH:5][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:29][CH:28]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: N=C1C=CC=NC1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2Nc2cccnc2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-iminopyridine ([462-08-8]) in N-methyl 2-pyrrolidone for 4 days at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=321.1 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccc(C)cc2n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCC(=O)OC(C)(C)C)c2ccc(C)cc2n1
Reaction time: 16 h

Procedure:
To a solution of 3.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of DMF, 3.0 g of potassium carbonate and 3.8 g of Bromo-acetic acid tert-butyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 4.9 g.