Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)=C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[O:35])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: Cc1ccc(NC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-p-tolylurea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (66 mg, 0.22 mmol) and 1-isocyanato-4-methylbenzene (29.4 mg, 0.22 mmol) according to General Procedure G to give 30 mg (31.4%) of white solid. Anal. Calcd. for C26H33N5O m/z 431.3, found: 432.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (m, 2H), 7.39 (d, J=8.9 Hz, 2H), 7.25 (m, 2H), 7.03 (d, J=8.3 Hz, 2H), 6.93 (d, J=7.6 Hz, 2H), 6.02 (s, 1H), 3.81 (m, 2H), 2.22 (s, 3H), 1.91 (m, 3H), 1.64 (m, 4H), 1.48 (m, 2H), 1.2 (m, 5H), 1.19 (m, 1H).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.N#N.FC(F)(F)C(O)=O.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([N:24]1[CH2:30][CH:2]2[C:1](=[O:7])[NH:5][C:4](=[O:6])[CH:3]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the maleimide (80.4 g, 0.83 mol) in 1.5 L of CH2Cl2 in a 3-neck, 3-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at 0° C. was added trifluoroacetic acid (TFA) (6.4 mL, 83 mmol). Benzyl(methoxymethyl)trimethylsilylmethylamine (261 g, 1.1 mol) in 500 mL CH2Cl2 was added dropwise via addition funnel over 3 hours with the reaction temperature being maintained below 5° C. After the addition was complete, the mixture was allowed to warm slowly to ambient temperature and then was stirred for 16 h. The mixture was concentrated and the residue was dissolved in 500 mL CH2Cl2 and was washed with 2×50 mL saturated NaHCO3. The layers were separated and the aqueous layer was extracted 2×25 mL CH2Cl2. The combined organics were washed with 25 mL brine, dried over saturated, aqueous Na2SO3, and concentrated under reduced pressure to give the title compound which was carried on to the next step without further purification. MS (DCl/NH3) m/z 231 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Li+].I[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26]I)=[CH:19][CH:18]=1>CN(C)C=O>[C:5]([CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])=[CH:19][CH:18]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: ICCCOc1ccc(OCCCI)cc1
Reactant: CCC(=O)CC(=O)CC
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCCOc1ccc(OCCCC(C(=O)CC)C(=O)CC)cc1)C(=O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
A solution of 16.1 g (0.126 m) of 3,5-heptanedione in 50 ml of dimethylformamide was added during 15 minutes to a stirred suspension of 1.2 g of lithium hydride in 100 ml of dimethylformamide. The mixture was stirred one hour at room temperature and then a solution of 27.6 g (0.0619 m) of 1,4-bis(3-iodopropyloxy)benzene in 100 ml of dimethylformaide was added. The reaction mixture was heated at 60°-70° C. for about 16 hours and then concentrated in vacuo. The residue was distilled to remove volatiles (150° C., 0.05 mm) and chromatographed on 400 g of silica with chloroform:acetonitrile 95:5. The product was distilled at 250° C. (0.02 mm) and crystallized from ether to give 4.4 g of 1,4-bis(4,4-dipropionylbutyloxy)benzene, m.p. 57°-58° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].CN1CCCC1=O.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=1)[CH:20]=[CH2:21]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN(CC=C)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98.6 %

Procedure:
A mixture of 3-fluoro-4-nitroaniline (1.56 g, 10 mmol), 1-methylpyrrolidinone (10 mL), diallylamine (1.94 g, 20 mmol) and potassium carbonate (1.38 g, 10 mmol) was heated to 115-125° C. for 9.5 h. The mixture was diluted with water, and extracted with ethyl ether. The combined extracts were washed with water, washed with saturated brine solution, and dried over magnesium sulfate. The extract was concentrated to give N,N-diallyl-6-nitro-1,3-benzenediamine as an orange oil (2.3 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH2:21]OS(C)(=O)=O)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:27]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CC#N>[N:30]([CH2:21][C@@H:19]1[CH2:20][C@H:18]1[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:27][C:7]=3[S:8][CH:9]=2)[CH2:16][CH2:15]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Temperature: 47 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A mixture of Methanesulfonic acid (1R, 2R )-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl )-piperazin-1-ylmethyl]-cyclopropylmethyl ester (3.995 g, 8.92 mmol), NaN3 (1.16 g, 17.85 mmol ) and anhydrous CH3CN (60 mL ) was stirred at 47° C. under N2 for 4 h, then an additional quantity of NaN3 (580 mg, 8.92 mmol ) was added. Stirring was continued at 47° C. for a further 4 h. After cooling to rt, the mixture was filtered through Celite 545, washed with CH3CN. The combined filtrate and washings were concentrated and then separated by Prep LC (heptane/EtOAc—70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 100% EtOAc) to give the desired product (1.5 g, 43%).
Reaction SMILES: [CH3:1][CH:2]([C@@:4]12[C@@H:19]([OH:20])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1.CCCCCC>N1C=CC=CC=1>[CH3:3][CH:2]([C@@:4]12[C@@H:19]([OH:20])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:1].[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:6])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@@H]2O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 30 h

Procedure:
Triptolide (100 mg) in 10 ml of pyridine was treated with succinic anhydride (150 mg) at room temperature. The reaction was carried out at 85° C. for 30 hours under a nitrogen atmosphere. Hexane (50 ml) was added to the resultant mixture to precipitate a crude product, which was collected by filtration and washed with hexane. The crude product was recrystallized from ether/hexane to yield 90 mg (70%) of triptolide succinate (YM-262), m.p. 111°-113° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:18]1([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC.C1COCC1>[CH:18]1([CH:23]([OH:24])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC1CCCC1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (2.01 g, 0.00905 mol) in tetrahydrofuran (30 mL, 0.4 mol) was added 2.5 M of n-butyllithium in hexane (4.0 mL) at −78° C. and the mixture was stirred at −30° C. for 30 minutes. A solution of cyclopentanecarbaldehyde (0.972 g, 0.00990 mol) in THF (2 mL) was added to the above mixture and the resulting mixture was stirred at −78° C. for 2 hours. The reaction was then quenched with a small amount of saturated aqueous NH4Cl solution followed by extraction with ethyl acetate, drying with MgSO4, and concentrating under reduced pressure. The crude product was purified by flash chromatography, eluting with 30% AcOEt in hexanes.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([F:9])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
The starting material 5-benzyloxy-2-fluoro-4-methylnitrobenzene was obtained by adding benzyl bromide (3 ml, 25 mmol) to a solution of 2-fluoro-5-hydroxy-4-methylnitrobenzene (3.92 mg, 23 mmol) in DMF (70 ml) containing potassium carbonate (9.5 g, 68 mmol). After stirring for 3 hours at 60° C., the mixture was diluted with water and adjusted to pH2. After extraction with ethyl acetate, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The solid was filtered off, washed with hexane and dried under vacuum to give 5-benzyloxy-2-fluoro-4-methylnitrobenzene (4.83 g, 80%).
Reaction SMILES: [OH:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4].[CH3:10]O.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[OH:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: O=C(O)C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(O)C(F)(F)F

Procedure:
A mixture of (±)-2-hydroxy-3,3,3-trifluoropropionic acid (7.8 g.), methanol (10 ml.) and concentrated sulphuric acid (0.5 ml.) is heated under reflux for 2 days. The cooled solution is poured into water (100 ml.), the mixture is saturated with sodium sulphate, and is extracted three times with ether. The extract is dried with sodium sulphate and evaporated. The residual oil (8.6 g.) is fractionally distilled to give (±)-methyl 2-hydroxy-3,3,3-trifluoropropionate b.p. 60°-64° C. at 12 mm. pressure, m.p. 50°-53° C. (3.9 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:10]=2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(Cc2n[nH]c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Yield: 48.6 %

Procedure:
Into a dry reaction vessel, 2.15 g (8.49 mmol) 3-(4-nitrobenzyl)-1H-indazole, 10 mL DMF, 1.70 g (10.2 mmol) ethyl bromoacetate, 5.54 g (17.0 mmol) cesium carbonate were respectively added, and reacted at room temperature overnight. It was chromatographed on a column to obtain 1.4 g red solid, at a yield of 48.5%.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].CS(C)=O.[CH3:20][C:21]1[O:25][N:24]=[C:23]([OH:26])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][C:21]1[O:25][N:24]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:23](=[O:26])[CH:22]=1
Reactant: Cc1cc(O)no1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2oc(C)cc2=O)c([N+](=O)[O-])c1
Reaction time: 10 h
Yield: 58.9 %

Procedure:
After mixing 400 g of ethyl 4-chloro-3-nitrobenzoate, 1.2 liters of dimethyl sulfoxide, 270 g of 5-methyl-3-hydroxyisoxazole, and 292 g of potassium carbonate, the reaction was performed for 10 hours at 60° C. After the reaction was over, the reaction mixture was poured into water and crystals thus deposited were recovered by filtration and recrystallized from ethyl acetate to provide 300.1 g of the desired compound with a yield of 59.0%. The melting point thereof was 122° C. to 123° C.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:4][CH:3]1[CH2:5][S:6][CH2:7][CH2:8][C:9](O)=[O:10].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2]1([F:12])[CH2:4][CH:3]1[CH2:5][S:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCSCC1CC1(F)F
Solvent: ClCCl
Product: O=C(Cl)CCSCC1CC1(F)F
Temperature: 40 °C
Yield: 96.4 %

Procedure:
In a 3 L 3 neck round bottomed-flask equipped with an overhead stirrer, a temperature probe, and addition funnel and an nitrogen inlet was charged with 3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid (90.0 g, 459 mmol) that was immediately taken up in dichloromethane (140 mL) with stirring. At room temperature, thionyl chloride (170 mL, 2293 mmol) in dichloromethane (100 mL) was added drop-wise with stirring. The reaction mixture was heated to 40° C. and heated for 2 hours. The reaction was determined to be complete by 1H NMR (An aliquot of the reaction mixture was taken, and concentrated down via rotary evaporator). The reaction was allowed to cool to room temperature and the mixture was transferred to a dry 3 L round-bottom and concentrated via the rotary evaporator. This resulted in 95 g of a honey-colored oil. The contents were gravity filtered through paper and the paper rinsed with diethyl ether (10 mL). The rinse was added to the flask. This gave a clear yellow liquid. The liquid was placed on a rotary evaporator to remove the ether. This gave 92.4 g of a yellow oil. The oil was Kugelrohr distilled (bp 100-110° C./0.8-0.9 mm Hg) to provide the title compound as a colorless oil (81.4 g, 81%): 1H NMR (400 MHz, CDCl3) δ 3.27-3.12 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.67 (ddd, J=6.8, 2.6, 1.0 Hz, 2H), 1.78 (ddq, J=13.0, 11.3, 7.4 Hz, 1H), 1.64-1.46 (m, 1H), 1.09 (dtd, J=13.2, 7.7, 3.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[OH-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: COc1cccc(CCN)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCNC(C)=O)c1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
3-methoxyphenethylamine(50 g, 0.33 mol) was dissolved in a soultion of water(130 ml), dichloromethane(210 ml) and sodium hydroxide(17.6 g). Acetyl chloride(25.9 ml, 0.36 mol) was added dropwise at a room temperature to the mixture solution, which was then stirred for 1 hour. The separated dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure to give 63.6 g of the titled compound.
Reaction SMILES: Cl.[C:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)([O:4][CH3:5])=[O:3].C(N(CC)CC)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:2]([O:4][CH3:5])=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC1CCCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
In 13 ml of acetonitrile was dissolved 1.0 g (5.16 mol) of 2-carbomethoxymethylpiperidine hydrochloride, and 1.77 ml (12.72 mmol) of triethylamine and 0.76 ml (6.36 mmol) of benzyl bromide were added to the solution at room temperature, and the resulting mixture was reacted at the same temperature under stirring for 5 hours. After completion of the reaction, the obtained reaction mixture was filtered and then concentrated under reduced pressure, then, 25 ml of ethyl acetate and 15 ml of a saturated aqueous sodium hydrogen carbonate solution were added to the residue and the organic layer was extracted. The obtained organic layer was washed with 15 ml of a saturated aqueous sodium hydrogen carbonate solution, and saturated saline solution, dried over anhydrous magnesium sulfate, then, filtered and the filtrate was concentrated under reduced pressure to obtain 0.97 g of an oily substance. The resulting oily substance was purified by silica gel column chromatography (WAKOGEL C-200 (trade name), n-hexane/ethyl acetate=4/1(volume ratio)) to obtain 0.75 g (Isolated yield based on 2-carbomethoxymethylpiperidine hydrochloride=59%) of N-benzyl-2-carbomethoxymethylpiperidine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCNc1ccc(F)cc1F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 68.4 %

Procedure:
A solution of 14.8 g of N-butyl-2,4-difluoroaniline, 16.2 g of triethylamine and 0 5 g of dimethylaminopyridine in 150 ml of toluene is treated dropwise at 0-5° C. with a solution of 15.2 g of p-toluenesulphonyl chloride in 80 ml of toluene. The reaction mixture is then warmed to 90° C. and stirred at this temperature for 48 hours. After cooling, the mixture is washed with 5% strength HCl and with water, and the toluene solution is dried over Na2SO4 and evaporated. The residue is distilled at 0.01 mbar. 18.5 g of N-butyl-N-(2,4-difluorophenyl)-p-toluenesulphonamide are obtained at 150°-160° as a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C@H:45]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:46](O)=[O:47])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C@@H:45]([C@@H:41]2[CH2:42][CH2:43][CH2:44][N:40]2[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:46](=[O:47])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:54][CH:53]=1
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (d 0.742; 0.0410 mL, 0.235 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.0311 g, 0.0883 mmol, See Example 1), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.020 g, 0.0589 mmol, see Example C) and TBTU (0.0227 g, 0.0706 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-carboxylate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.008 g, 24%). MS APCI (+) m/z 501.3 detected.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC(COC3C=CC=CC=3)=O)C(=[O:9])N2[C@H]1C(O)=O.CN(C1C=CC=CN=1)C.[CH2:34]1[CH2:39][CH2:38][CH:37]([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:36][CH2:35]1>C(Cl)Cl>[CH:43]1([NH:42][C:41]([NH:40][CH:37]2[CH2:36][CH2:35][CH2:34][CH2:39][CH2:38]2)=[O:9])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 4 °C
Reaction time: 144 h

Procedure:
In a 10 mL round-bottomed flask, 0.400 g (0.178 mmol) of the poly(PEG-Lys) having ethanolamide pendant functional groups of Example 6 was dissolved in 4 mL of methylene chloride. To this solution was added 0.094 g (0.267 mmol) of Penicillin V (Sigma) and 0.008 g (0.065 mmol) of dimethylaminopyridine (Aldrich). The reaction mixture was cooled in an ice water bath and then 0.048 g (0.232 mmol) of DCC was added. After a few hours at 0° C., the reaction vessel was moved to a cold room maintained at 4° C. and allowed to stir for almost six days. A precipitate of dicyclohexyl urea formed and was removed by filtration. The drug conjugate was precipitated with cold ether. About 0.250 g of crude product was obtained which was purified by reprecipitation twice from isopropanol. TLC in methanol showed absence of free drug.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O-:24])=[O:23])[CH2:18][CH:17]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C(OCC)(=O)C>[N:37]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:13]([CH3:16])([CH3:14])[CH3:12])=[O:23])[CH2:18][CH:17]3[O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:12][CH:11]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CS(=O)(=O)OCCCOc1ccc(C2CCN(C(=O)[O-])CC2OCc2ccc3ccccc3c2)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCN3CCOCC3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A solution of 200 mg (0.35 mmol) of tert-butyl 3RS,4RS)-4-[4-(3-methylsulphonyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 1 ml of ethyl acetate was treated with 60 μl of morpholine and boiled under reflux for 3 hours. Subsequently, the reaction solution was diluted with 5 ml of ethyl acetate and extracted twice with 1 ml of saturated sodium hydrogen carbonate solution each time. The organic phases were dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The colourless oil (169 mg) was chromatographed on silica gel using ethyl acetate and the eluent. There were obtained 142 mg of tert-butyl (3RS,4RS)-4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in the form of white crystals; MS: 561 (M+H)+.