Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[CH2:10][C:9]([OH:35])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccccc2)c1)C(C)(C)C
Yield: 100.1 %

Procedure:
According to the procedure described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester (371 mg, 0.781 rnmol) in MeOH (15 mL) was hydrogenolyzed to provide 301 mg (100%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid as a yellow foam. 1H NMR (CDCl3): δ 7.50-7.20 (m, 4H), 7.15 (tt, 1H, J=1.2, 7.3 Hz), 7.06 (dd,1H, J=2.0, 2.0 Hz), 6.78 (dd, 1H, J=2.5, 2.5 Hz), 6.48 (dd, 1H, J=1.6, 2.8 Hz), 5.20 (t, 1H, J=6.9 Hz), 4.20 (d, 1H, J=9.3 Hz), 3.34 (dd, 1H, J=6.9, 17.4 Hz), 3.06 (dd, 1H, J=7.2, 17.4 Hz), 2.69 (d, 3H, J=4.7 Hz), 0.93 (s, 9H); IR (KBr): 3318, 2966, 1718, 1654, 1559, 1542, 1202, 745 cm-1. HRFABMS: Calcd for C21H27N3O4Cs (M+Cs+): 518.1056. Found: 518.1037. Anal. Calculated for C21H27N3O4.0.3 CHCl3 : C, 60.73; H, 6.53; N, 9.97. Found: C, 60.70; H, 6.58; N, 9.84.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)C)=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4]>C(O)C.O>[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)Nc1ccc(-c2cccc(COC(C)(C)C)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Yield: 81.6 %

Procedure:
559 mg of sodium hydroxide in 2 ml of ethanol and 2 ml of water are placed in a round-bottomed flask containing 695 mg of N-[5-(3-tert-butoxymethylphenyl)pyridin-2-yl]acetamide. 1 ml of water and 1 ml of ethanol are added thereto and the mixture is heated at the reflux of the solvent for 1 hour. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is taken up between dichloromethane and water and the organic phase is then separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 487 mg of compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:16]([S:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(Br)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(SCc2ccccc2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a solution of 2-bromo-5-methoxypyridine (1.13 g) in toluene (15 mL) were added phenylmethanethiol (820 mg), N,N-diisopropylethylamine (1.71 g), tris(dibenzylideneacetone)dipalladium(0) (220 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=49:1→19:1) to give the title compound as a yellow oil (yield 1.47 g, quantitative).
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[N:11]([CH3:20])[C:10]=1[CH3:21])=[O:8].B(Br)(Br)Br>>[OH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH3:20])[C:10]=1[CH3:21])=[O:8]
Reactant: COCCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-methoxy-propyl)-amide 63a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ7.52 (1H, d, J=8.6 Hz), 6.73 (1H, d, J=2.1 Hz), 6.68 (1H, dd, J=2.1, 8.6 Hz), 3.69 (2H, t, J=6.1 Hz), 3.57 (3H, s), 3.51 (2H, m), 2.57 (3H, s), 1.85 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 263, found 263.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Cl.[F:32][C:33]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[F:32][C:33]1([F:39])[CH2:38][CH2:37][N:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:35][CH2:34]1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(I)cc2)o1
Reactant: FC1(F)CCNCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCC(F)(F)CC3)cc2)o1
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 2-(4-iodo-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.47 mmol) in toluene (2 mL) were added under an atmosphere of nitrogen 2-(dicyclohexylphosphino)biphenyl (15 mg, 0.04 mmol), tris(dibenzylideneacetone)di-palladium (0) chloroform complex (15 mg, 0.01 mmol), sodium tert-butoxide (107 mg, 1.12 mmol) and 4,4-difluoropiperidine hydrochloride (88 mg, 0.56 mmol). The reaction mixture was stirred for 1 h at 100° C. and was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50) afforded the title compound (138 mg, 70%) as a light yellow solid. MS: m/e=423.3 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)(C)(C)C>[CH2:10]([NH:17][CH2:6][CH2:5][N:4]([CH2:2][CH3:3])[CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CCCl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CCN(CC)CCNCc1ccccc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
2-(diethylamino)-ethyl chloride hydrochloride (1 g, 5.81 mmol) and benzylamine (1.3 ml, 11.62 mmol) were dissolved in t-butanol (40 ml), triethylamine (3.2 ml, 23.24 mmol) was added thereto, and the resulting solution was refluxed for 12 hours. The solution was cooled to room temperature, and distilled under a reduced pressure to remove the solvent. The resulting solid was removed by filtration under a reduced pressure, and the residual solution was extracted with ethylacetate The separated organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, filtered and distilled under a reduced pressure to obtain the title compound 560 mg (yield: 47%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][CH2:10][CH2:11]Cl)[CH3:8].C(N(CC)CC)C>>[CH2:7]([O:9][CH2:10][CH2:11][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH3:8]
Reactant: Cc1ncc[nH]1
Reactant: CCOCCCl
Solvent: CCN(CC)CC
Product: CCOCCn1ccnc1C
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-methylimidazole (19.2 g, 200 mmol) was made reacted with chloroethyl ethyl ether (26.0 g, 240 mmol) at 145 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The obtained product was a transparent liquid which has a boiling point of 171-175 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.96 (d, 1H), 6.72(d, 1H), 4.07-4.04(t, 2H), 3.66-3.63 (t, 2H), 3.45-3.40 (m, 2H), 2.29(s, 3H), and 1.12-1.08(t, 3H), and 1-(2-ethoxyethyl)-2-methyl imidazole was synthesized.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)(=O)C>[C:25]([O:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid (9.0 g., 0.025 mole) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The resulting mixture is cooled to room temperature and dissolved in ethyl acetate providing a clear solution which is extracted with an ice-cold solution of sodium hydroxide (8 g.) in water (150 ml.). The basic solution is quickly separated and acidified with concentrated hydrochloric acid. The oily acid which separates is extracted with ether. The organic extract is washed with water, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. leaves a residual oil which is purified via application to a silica gel (150 g.) column with chloroform. Elution with chloroform-methanol (99:1; v:v) provides the title compound as a colorless, viscous oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[H-].[Li+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>COCCOC>[N:28]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Yield: 42.5 %

Procedure:
To a mixture of 3.63 grams (9.84 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) and 84.75 milligrams (10.7 millimoles) of lithium hydride in 10 milliliters of 1,2-dimethoxyethane was added 1.0 milliliter (10.0 millimoles) of piperidine in 10 milliliters of 1,2-dimethoxyethane. The mixture was heated under reflux for 22 hours, and the resulting heterogeneous mixture filtered to obtain a clear yellow filtrate. The filtrate was concentrated to an orange oil which after evaporative distillation (bath 120° C.; 0.05 torr.) produced 1.18 grams (42.5 percent yield) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine base having infrared and nuclear magnetic resonance spectral characteristics appropriate for said compound. A 286.23 milligram (1.02 millimoles) sample of the free base, 4-(6-piperidinohexyl)-3,5-dioxomorpholine, was dissolved in 1.0 milliliter of 1 N sodium hydroxide (1.0 millimole) and the mixture concentrated to produce 289.63 grams (90 percent yield) of sodium [2-(6-piperidinohexyl)amino-2-oxoethoxy]acetate product with the following spectral characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:11])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:19])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:19][C:10]1[N:9]=[C:8]([I:11])[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nccn2c(I)ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccn2c(I)nc(Br)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-chloro-3-iodo-imidazo[1,5-a]pyrazine (730.0 mg, 2.61 mmol) in DMF (8.00 mL) was added NBS (557.9 mg, 3.13 mol) in 3 portions at 0° C. The resulting mixture was allowed to warm up to rt. and stirred at rt. for 2 hours. To the mixture was added 30 mL saturated NaHCO3 aq. solution, extracted with DCM (20 mL×3). Organic phase was combined and dried (Na2SO4) and evaporated to give crude material which was used in next step without further purification. 1H NMR (400 MHz, MeOD) δ 7.48 (d, J=5.1 Hz, 1H) 8.02 (d, J=5.1 Hz, 1H). MS (ES: m/z: 357.68, 359.67, 361.68 [MH+]. HPLC: tR=3.22 min (OpenLynx: polar—5 min).
Reaction SMILES: [Cl:1][C:2](Cl)([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]=[O:4].[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])([O:4][CH:3]=[C:2]([Cl:1])[CH:5]=[C:6]([Cl:8])[Cl:7])=[O:17]
Reactant: O=CC(Cl)(Cl)C=C(Cl)Cl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OC=C(Cl)C=C(Cl)Cl)OCC
Yield: 62.8 %

Procedure:
184 g of 2,2,4,4-tetrachloro-but-3-enal (prepared in accordance with Example 6) were reacted in a manner analogous to that described in Example 6 with 166 g of triethyl phosphite, and 172 g of product were obtained by distillation at 0.2 to 0.3 torr and 121° to 125° C. NMR-spectrum : δ (CH3) : 1.33 ppm, J = 7 Hz; δ (CH2) : 3.95 - 4.47 ppm; δ (C=CH-C) : 6.67 ppm; δ (CH-O-P) : 7.33 ppm, J = 6 Hz.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:32]1[CH:37]=[N:36][CH:35]=[C:34]([CH3:38])[N:33]=1>CN(C)C(=O)C>[CH3:38][C:34]1[N:33]=[C:32]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:37]=[N:36][CH:35]=1
Reactant: Cc1cncc([Sn](C)(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Temperature: 150 °C
Yield: 58 %

Procedure:
A solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate (90 mg; 0.22 mmol and palladium(0)tetrakis(triphenylphosphine) (25 mg, 0.022 mmol in N,N-dimethylacetamide; 2.0 mL was added trimethyl-(6-methylpyrazin-2-yl)stannane (112 mg; 0.436 mmol). The reaction mixture was heated at 150° C. for 45 min in a microwave (Biotage). The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 50% EtOAc) to give tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate 60 mg in 58% yield.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](OC(=O)C)(=O)[CH3:24]>>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([CH3:24])[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Product: Cc1nc(-c2ccc3nc(N4CCN(C(C)C)CC4)sc3c2)no1
Yield: 16.7 %

Procedure:
A solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (700 mg, 2.19 mmol) in acetic anhydride (20 mL) was heated at 130° C. for 6 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 125 mg (16.7%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-methyl-[1,2,4]oxadiazol-3-yl)benzo-thiazole as a trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.19-3.29 (m, 4H), 3.73-3.89 (m, 3H), 4.11-4.14 (m, 4H), 6.58 (s, 3H), 7.19-7.25 (m, 1H), 7.36-7.64 (m, 2H), 7.67-7.81 (m, 1H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].[C:32]1([C:38](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:38]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCS
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.2 %

Procedure:
To a solution of 2-{2-[2-(2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxyl}-ethoxy)-ethoxy]-ethoxy}-ethanol (3) (1.22 g, 2.6 mmol) prepared according to the method of Pale-Grosdemange et al.†, dissolved in 10 mL of THF was added triphenylmethyl chloride (1.46 g, 5.2 mmol). After stirring at room temperature for 48 hours, the reaction mixture was concentrated. The crude residue was purified by flash chromatography (gradient elution, EtOAc to 20:1 EtOAc/MeOH) to afford 910 mg (49%) of 4. 1H NMR (CDCl3, 400 MHz) d 7.36 (d, J=X Hz, 6H), 7.22 (t, J=X Hz, 6H), 7.15 (t, J=X Hz, 3H), 3.72-3.48 (br m, 24H), 3.40 (t, J=X Hz, 2H), 2.08 (t, J=X Hz, 2H), 1.52 (m, 2H), 1.4-0.9 (br, 16H). ES-MS: m/z 733.4 (M+Na+). †Pale-Grosdemange, C.; Simon, E. S.; Prime, K. L.; Whitesides, G. M. J. Am. Chem. Soc, 1991, 113,12-20.
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of (93) (1.02 g, 3.34 mmol) in dichloromethane was added 1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for 30 min, benzyl alcohol (380 μL, 3.67 mmol) and 4-(dimethylamino)pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature of 16 h. After filtration, the filtrate was washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography of the residue on silica gel, eluting with 10% ethyl acetate/hexane, gave 820 mg (62%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.03 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s, 2H), 5.49 (t, 1H), 6.32 (d, J=4.8 Hz), 1H), 7.34 (m, 5H). MS (ESI) m/z 396.24 (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([NH:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)=[O:35])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]([NH:36][C:37]2[CH:43]=[CH:42][C:40]([NH:41]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:39][CH:38]=2)=[O:35])[CH2:31][CH2:32]1
Reactant: Nc1ccc(NC(=O)CN2CCOCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-morpholinomethylcarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: COC1C=CC([C@H]([N:11]2[CH2:15][C@H:14]([C@H:16]([O:18][C:19]3[C:20]4[N:21]([N:37]=[CH:38][C:39]=4[CH3:40])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:27][CH:26]=4)[N:24]=3)[CH3:17])[CH2:13][C:12]2=[O:41])C)=CC=1>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:40][C:39]1[CH:38]=[N:37][N:21]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:24]=[C:19]([O:18][C@@H:16]([C@H:14]3[CH2:15][NH:11][C:12](=[O:41])[CH2:13]3)[CH3:17])[C:20]=12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCOCC5)cc4)cn4ncc(C)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cnn2cc(-c3ccc(N4CCOCC4)cc3)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Temperature: 60 °C

Procedure:
(R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-4R)-1-(3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.12 (34 mg, 0.061 mmol) was taken up in TFA (1.5 mL) and mixture was heated at 60° C. overnight. After cooling to room temperature, mixture was concentrated under reduced pressure and resulting film was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. Layers were separated and aqueous was extracted with ethyl acetate. Combined organics were washed with 1:1 brine/saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by prep HPLC and then silica gel column chromatography (0-15% methanol in dichloromethane) to yield (R)-4-((R)-1-(3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.13.