Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:14][OH:15]>C(O)C.N1C=CC=CC=1>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[N:14][OH:15])[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCOc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CCCOc2ccccc21
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine was heated under reflux for 5 h. After distilling off the solvents on a rotary evaporator, the residue was treated with water, adjusted to pH 2 with dil hydrochloric acid and stirred for 3 h. After filtering off the precipitated product with suction and drying it, 10.2 g of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime were obtained, m.p. 96-98° C. b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0° C. under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borohydride in 50 ml of DME over the course of 20 min. After stirring at RT for 2 days, 100 ml of water were added dropwise and the mixture was rendered alkaline using conc. ammonia solution. After filtering off the precipitate with suction, the filtrate was extracted three times with EA. After washing with sodium chloride solution, drying over magnesium sulfate and concentrating, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine were obtained. c) 0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-berzoxepine were obtained, m.p. 109-111° C. d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-Bromo-pyridin-2-yl)-methanol (60 mg, 0.32 mmol) in dichloromethane (2 ml) was cooled in as ice bath. To the mixture was then added triethylamine (0.13 mL, 0.96 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and the aqueous phase extracted further with dichloromethane (2×5 mL). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give the product as a pale brown oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:3][CH:4]=1)#[N:7]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Temperature: 120 °C
Yield: 94.4 %

Procedure:
Combine 6-chloro-nicotinonitrile (1.0 g, 7.22 mmol), 4-hydroxybenzamide (1.09 g, 7.94 mmol), and potassium carbonate (1.49 g, 10.83 mmol) in toluene (8 mL). Add DMA (24 mL) to the reaction mixture. Heat the reaction mixture for 1.5 hour at 120° C. Let the reaction mixture cool to room temperature. Pour the reaction mixture onto water and filter the precipitate washing with water. Dry the solid under vacuum to provide the title compound (1.63 g, 94%)
Reaction SMILES: [CH2:1]([S:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[F:21][Sb-:22]([F:27])([F:26])([F:25])([F:24])[F:23].[Na+]>CC(C)=O>[F:21][Sb-:22]([F:27])([F:26])([F:25])([F:24])[F:23].[CH3:10][S+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CCCCCCCCSC
Reactant: O=C(CBr)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCC[S+](C)CC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Into a 100 mL round bottom flask equipped with a magnetic stirrer and reflux condenser were placed 16.0 g (0.1 mol) methyl octyl sulfide (obtained from the Aldrich Chemical Co.), 19.9 g (0.1 mol) phenacyl bromide, 25.87 g (0.1 mol) sodium hexafluoroantimonate and 40 mL acetone. The reaction mixture was brought to reflux and held at this temperature for 15 minutes. The mixture was filtered through a plug of glass wool (to remove the sodium bromide which was formed during the reaction) and the solvent was removed on a rotary evaporator, leaving 43.1 g (83.6% yield) of the desired methyl octylphenacylsulfonium hexafluoroantimonate as a tan colored solid. The product was further purified by recrystallization, first from a 1:3 mixture of water and ethanol, then, isopropanol. The pure, colorless, crystalline initiator had a melting point of 75-76° C. The initiator was soluble in a wide variety of common solvents such as acetone, methyl ethyl ketone, chloroform and methylene chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH2:2][CH2:3][N:4]6[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: NCCN1CCNCC1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNCCN4CCNCC4)cc3)cc2n1

Procedure:
The title compound was prepared from N-(2-aminoethyl)-piperazine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by the procedure analogous to example 17. M.P. 178-191° C.; LC-MS: 484 (MH+); HPLC RT: 3.41 minutes.
Reaction SMILES: [NH2:1][C:2]([CH:17]([F:19])[F:18])([CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O)[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:22])[CH3:21].Cl>[OH-].[Na+]>[C:20]([NH:1][C:2]([CH:17]([F:18])[F:19])([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCC(N)(C(=O)O)C(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(CCCN)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.9 g of 2-amino-5-tert-butoxycarbonylamino-2-difluoromethylpentanoic acid in 10.5 ml of 1 M sodium hydroxide is added at 0° C. simultaneously 0.19 g of acetylchloride and 5 ml of 2 M aqueous sodium hydroxide. The reaction mixture is stirred for 3 hours at room temperature. The alkaline aqueous solution is then adjusted to a pH of 2 with hydrochloric acid and extracted with ethylacetate. After usual work-up the solvent is evaporated and the residue taken up in trifluoroacetic acid. After concentration and purification by ion exchange chromatography on a resin 5-amino-2-acetylamino-2-difluoromethylpentanoic acid is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 50 °C
Yield: 78.4 %

Procedure:
To a solution of 2-hydroxy-4-nitro-benzonitrile [164 mg, 1.0 mmol, prepared as described in Yasubiro Imakura et. al. Chem. Pharm. Bull 40 (7), 1691-1696 (1992)] in anhydrous DMF (2 mL) was added allyl bromide (0.11 mL, 1.3 mmol), followed by K2CO3 (166 mg, 1.2 mmol). The resulting suspension was heated to 50° C. under Argon for 4 h. After cooling to rt, the reaction mixture was poured into ice/water, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 30% to 60% EtOAc/hexane to furnish the title compound (160 mg, 80% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O-:18])=[O:17])[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetate from Step A (170 mg, 0.501 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH monohydrate (36 mg, 0.858 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 1 N HCl (1 mL, 1 mmol), concentrated in vacuo and dried to afford the title compound. MS: m/z=312 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[NH2:8])(=[O:3])[CH3:2].[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20]([OH:27])=[C:21]([C:24](=O)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:8][C:24](=[C:21]2[C:22]([OH:23])=[C:17]([C:14](=[O:16])[CH3:15])[C:18](=[O:28])[O:19][C:20]2=[O:27])[CH3:25])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=[O:3])[CH3:2]
Reactant: COc1ccc(N)cc1NC(C)=O
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: COc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1NC(C)=O

Procedure:
The aniline thus prepared (0.8 g., 0.0045 mol) is added to a hot suspension of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 50 ml. of methanol. The mixture is refluxed for one hour and filtered to obtain 3-[1-(3-acetamido-4-methoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 252°-253° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1(C)[O:21][C:19](=O)[CH2:18][C:16](=O)[O:15]1.C1CCC(N=C=NC2CCCCC2)CC1.C(O)C=C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH2:13][C:14]([O:15][CH2:16][CH:18]=[CH2:19])=[O:21]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C=CCO
Product: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a CH2Cl2 (40 mL) solution of 2,4-difluorophenyl acetic acid (6.89 g, 40.03 mmol) at 0° C. was added DMAP (4.89 g, 40.03 mmol), and Meldrum's Acid (5.77 g, 40.03 mmol) followed by DCC (8.26 g, 40.03 mmol). The reaction mixture was warmed to ambient temperature and stirred for 4 h. The reaction was filtered to remove the DCU and the filtrate washed with 1N HCl, H2O, and brine. The organics were dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was redissolved in THF (40 mL) and allyl alcohol (8 mL, 117.63 mmol). The reaction mixture was refluxed for 3 h and then concentrated to deliver 9.67 g (95% yield) of the title compound as a pale yellow oil and used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.16–7.10 (m, 1H), 6.82 (dd, J=16.6, 8.2 Hz, 2H), 5.91–5.82 (m, 1H), 5.31 (dd, J=17.3, 1.4 Hz, 1H), 5.25 (dd, J=10.3, 1.0 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H), 3.82 (s, 2H), 3.52 (s, 2H).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][C:8]([OH:10])=[O:9].[CH3:21]O>>[NH2:5][C@@H:6]([CH2:7][C:8]([O:10][CH3:21])=[O:9])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CO
Reactant: N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 29 h

Procedure:
SOCl2 (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled (ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid (10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removed and the reaction mixture was stirred at ambient condition for 29 hr. Most of the volatile component was removed in vacuo and the residue was carefully partitioned between EtOAc (150 mL) and saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorless oil (9.706 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd, J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond. 1): RT=0.90 min; LC/MS: Anal. Calcd. for [M+H]+ C12H16NO4: 238.11. found 238.22.
Reaction SMILES: [OH:1][C:2]1C=CC(O)=C[C:3]=1[OH:9].[C:10](OCC)([O:15]CC)([O:12][CH2:13][CH3:14])[CH3:11]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:13]([O:12][C:10]1([CH3:11])[O:9][CH2:3][CH:2]([OH:1])[O:15]1)[CH3:14]
Reactant: Oc1ccc(O)c(O)c1
Reactant: CCOC(C)(OCC)OCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC1(C)OCC(O)O1
Yield: 114.1 %

Procedure:
A solution composed of 5.0 g of 1,2,4-trihydroxybenzene, 9.7 g of triethyl orthoacetate and 50 ml of toluene-carbon tetrachloride (1:1) was refluxed for 1.5 hours. The solvent was evaporated, and the residue was purified by column chromatography to give 6.7 g (yield 86%) of the desired product as pale brown crystals having a melting point of 86° to 87° C.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](N3CCNCC3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].ClCP(=O)(C)C.O>CN(C)C=O>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-n2ncc3ccccc32)cc1
Temperature: 90 °C

Procedure:
A stirred mixture of 4.3 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole (prepared as in Example 2), 2.3 g of potassium carbonate, and 2.3 g of chloromethyldimethylphosphine oxide in 75 ml of dimethylformamide was heated at 90°, under nitrogen, for 16 hrs. Additional chloromethyldimethylphosphine oxide (0.6 g) was added, and the reaction mixture heated at 90° C. for 24 hrs. The reaction mixture was poured into water and the aqueous solution extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to an oil. Flash chromatography of the oil on silica gel, eluting with dichloromethane/methanol (10%) followed by concentration of the appropriate fractions and trituration with diethyl ether gave 2.5 g (45%) of 3-[4-(dimethylphosphinylmethyl)-1-piperazinyl)]-1-phenyl-1H-indazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([Li])CCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]C.C(Br)CCCC>CN1C(=O)N(C)CCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC
Reactant: C#CCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCBr
Solvent: CN1CCCN(C)C1=O
Product: CCCCCC#CCCCOC1CCCCO1
Yield: 58 %

Procedure:
1-(Tetrahydopyran-2-yloxy)-4-pentyne (1) (0.66 g, 3.90 mmol) was metallated with n-butyllithium solution (2.5M) in hexane (1.87 ml, 1.2 eq.). Addition of a solution of n-pentyl bromide (0.725 ml, 1.5 eq.) in DMPU (2 ml) produced 0.54 g (58% yield) of the title compound (15). 1H NMR (200 MHz) δ: 4.60 (m, 1H, CH-2'), 3.65 (m, 4H, CH2 -1, 6'), 2.26 (tt, J=7.0, 7.0, 2.0, 2.0 Hz, 2H, CH2 -3), 2.13 (tt, J=7.0, 7.0, 2.5, 2.5 Hz, 2H, CH2 -6), 1.77 (tt, J=6.8, 6.8, 7.07 7.0 Hz, 2H, CH2 -2), 1.33 (m, 6H, CH2 -7, 8, 9), 1.52 (m, 6H, CH2 -3', 4', 5'), 0.89 (t, J=7.0 Hz, 3H, CH3). MS [FAB, m/z(%)] 237 (M+ -1), 85 (100). IR (CCl4, cm-1) 2229, 1322, 1331, 1201, 1138, 1121, 1034.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:9])[CH3:8].CN(C=O)C.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:25]=[CH:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:18]=1>COC(C)(C)C>[C:7]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:25]=[CH:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1

Procedure:
Potassium carbonate (0.075 g) and acetyl chloride (0.035 ml) were added to DMF (3 ml) solution of phenyl N-(4-hydroxyphenyl)-3-(phenoxy)acrylimidate (0.15 g) at room temperature and stirred for two hours at the same temperature and for three hours at 50° C. t-Butyl methyl ether (80 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain phenyl N-(4-acetoxyphenyl)-3-(phenoxy)acrylimidate (0.11 g) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]2=[O:23].IC1C(C=O)=C(OC)N=CC=1>CO.CC(O)=O.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]2=[O:23]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(CCCN1CCCC1)C2=O
Agent: [Pd]
Agent: COc1nccc(I)c1C=O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc2c(cc1N)C(=O)N(CCCN1CCCC1)C2=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Pd/C (250 mg) was added to a solution of crude 5-amino-6-nitro-2-(3-(pyrrolidin-1-yl)propyl)isoindoline-1,3-dione in MeOH/AcOH (100 mL/5 mL) and hydrogenated for 5 h. The mixture was filtered through Celite and the filtrate was treated with 4-iodo-2-methoxynicotinaldehyde (3.2 g, 12.07 mmol) and stirred at ambient temperature open to air for 12 h and at 80° C. for 5 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to dryness. Purification by flash chromatography gave the title 5,6-diamino-2-(3-(pyrrolidin-1-yl)propyl)isoindoline-1,3-dione as a solid (2.02 g, 32% through 4 steps). 1H NMR (MeOD): δ 8.15 (s, 2H), 8.01-8.08 (t, J=3 Hz 1H), 7.64 (t, J=3 Hz, 1H), 3.89-3.78 (m, 2H), 3.41-3.22 (m, 2H), 2.95-2.81 (m, 6H), 2.15-1.82 (m, 7H). ESMS (m/z) 532 (M+H)+.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:4][CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([N:4]1[CH:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:6][CH2:7][N:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of Intermediate 3-2 (4.21 g) and TEA (2.0 g) in DCM (50 mL) was added benzoyl chloride (2.11 g) slowly. After stirring at room temperature for 1 hour and then the reaction was quenched with saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. Purification was achieved by chromatography on an ISCO column (RediSep 12, gradient elution with 10% to 70% EtOAc/Hex providing pure Intermediate 3-3 (2.82 g, 49% yield for the three steps).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:24][O:23][C:21](=[O:22])[C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 0.92 mmol) in dichloromethane (5.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organics were separated and dried over sodium sulfate and concentrated in vacuo. The product used without any further purification. ESI-MS m/z: 255 (M+1), UV retention time: 1.14 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22](SC)=[N:23][CH:24]=2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]3[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:23][CH:24]=2)=[CH:28][CH:29]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: NCCCNc1ncccc1Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(NCCCNc2ncccc2Cl)ncc1Cc1ccc(Cl)cc1

Procedure:
2-(3-Aminopropylamino)-3-chloropyridine (1 g) and 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.3 g) were heated together under reflux in pyridine (20 ml) for 48 hr. The mixture was stripped and recrystallised from dimethyl formamide/ethanol/water to give 5-(4-chlorobenzyl)-2-[3-(3-chloropyrid-2-ylamino)propylamino]-4-pyrimidone 0.7H2O, (1.55 g; 76%) m.p. 180°-81° C.