Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(O)C.O>N1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Yield: 62.4 %

Procedure:
Treatment of 4-(4-aminophenoxy)-1-(4-pyridyl)piperidine (see Preparation 3) (0.323 g) with methanesulphonyl chloride (0.151 g) in pyridine (10 ml) according to the method of Example 1 gave the title compound, (0.260 g), m.p. 191°-192° (from ethanol/water).
Reaction SMILES: [CH3:1][N:2]([O:21][CH3:22])[S:3]([N:6]([S:8]([NH:11][C:12](=O)[O:13]C1C=CC=CC=1)(=[O:10])=[O:9])[CH3:7])(=[O:5])=[O:4].[CH3:23][C:24]1[CH2:28][CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][N:25]=1>C1C=CC=CC=1>[CH3:1][N:2]([O:21][CH3:22])[S:3]([N:6]([S:8]([NH:11][C:12]([N:26]1[CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][C:24]([CH3:23])=[N:25]1)=[O:13])(=[O:9])=[O:10])[CH3:7])(=[O:5])=[O:4]
Reactant: CC1=NNC(c2ccccc2)C1
Reactant: CON(C)S(=O)(=O)N(C)S(=O)(=O)NC(=O)Oc1ccccc1
Solvent: c1ccccc1
Product: CON(C)S(=O)(=O)N(C)S(=O)(=O)NC(=O)N1N=C(C)CC1c1ccccc1
Yield: 42.4 %

Procedure:
A mixture comprising 1 g (2.83 mmol) of phenyl N-[(N-(N-methyl-N-methoxyaminosulfonyl)-N-methylamino)sulfonyl]-carbamate, 0.45 g (2.81 mmol) of 3-methyl-5-phenyl-2-pyrazoline and 30 ml of dry benzene was heated at 80° C. for 5 minutes. The mixture was left to cool, and then the solvent was distilled off under reduced pressure. The residue was purified by reverse phase column chromatography (CH3CN: H2O=7:3) to obtain 0.5 g of the desired 1-[(N-(N-methyl-N-methoxyaminosulfonyl)-N-methyl-amino)sulfonylcarbamoyl]-3-methyl-5-phenyl-2-pyrazoline as glassy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9](Cl)[N:8]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9]([N:28]2[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]2)[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1c(Cl)nc(N2CCC(O)CC2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-2,6-dichloropyrimidine (prepared in the above (2)) 1.01 g in dimethylformamide 10 ml are added 4-hydroxypiperidine 338 mg and triethylamine 411 mg at room temperature, and the mixture is stirred for 15 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give a slightly yellow oil. The oil is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=8:1→5:1), and further separated with silica gel chromatography (solvent; hexane:ethyl acetate=1:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidine as colorless crystals 540 mg (mp 138-139° C.) and 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-chloropyrimidine as a colorless foam, 617 mg.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:8]([C:11]1[N:16]2[N:17]=[C:18]([CH3:25])[C:19]([C:20]3[S:24][CH:23]=[N:22][CH:21]=3)=[C:15]2[N:14]=[C:13]([CH3:26])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[CH3:27][O:28][CH2:29]I.[Cl-].[NH4+]>C1COCC1>[CH2:6]([CH:8]([C:11]1[N:16]2[N:17]=[C:18]([CH3:25])[C:19]([C:20]3[S:24][C:23]([CH2:27][O:28][CH3:29])=[N:22][CH:21]=3)=[C:15]2[N:14]=[C:13]([CH3:26])[CH:12]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: CCC(CC)c1cc(C)nc2c(-c3cncs3)c(C)nn12
Reactant: COCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3cnc(COC)s3)c(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.4 mL, 1.0 mmol) to a solution of 7-(1-ethyl-propyl)-2,5-dimethyl-3-thiazol-5-yl-pyrazolo[1,5-a]pyrimidine (300 mg, 1.0 mmol) in THF (3 mL) at −78° C. Stir 30 min and add 1-iodomethyl methyl ether (205 mg, 1.2 mmol). Continue stirring for one hour and then slowly warm up to room temperature and stir overnight. Quench the reaction by adding saturated ammonium chloride solution and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate under vacuum to a residue. Purify the crude material by flash chromatography, eluting with hexanes/ethyl acetate (10/2) to give the title compound as a yellow foam (184 mg). MS (APCI) m/z 345.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:42])[C:7]=1[CH:8]([OH:41])[CH2:9][N:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:42][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8](=[O:41])[CH2:9][N:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3ccc(F)cc3)CC(O)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3ccc(F)cc3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 1-2 (9.9 g, 15.6 mmol) in DCM (120 mL) was added Dess-Martin periodinane (21.9 g, 21.9 mmol) in portions, and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with NaHCO3 (50 mL, sat. aq.) and Na2S2O3 (50 mL, sat. aq.), then extracted with DCM (2×150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: 10% EtOAc/hexane) to yield compound 1-3 (9.12 g, 92%) as a white solid. 1H NMR (CDCl3) rotomers present δ 8.74 and 8.67 (2H, 2×s); 7.85 and 7.79 (1H, 2×s); 7.30-7.26 (1H, m); 7.41-7.37 and 7.22-7.15 (3H, 2×m); 4.73-4.51 (4H, m); 4.27-4.21 (1H, m); 4.07 (2H, q, J=7.2 Hz); 2.50-2.48 (1H, m); 2.06-1.93 (6H, m); 1.59-1.54 (2H, m); 1.18 (3H, t, J=6.9 Hz); LCMS: 629 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]([NH:7]1)[CH2:5][C:4]1[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:3]2=1.Cl.[NH+]1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]([NH:7]1)[CH2:5][C:4]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:3]2=1
Reactant: COc1ccc2c(c1)CC1NC2(C)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC12NC(Cc3cc(O)ccc31)c1ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
A mixture of 2-methoxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (2.7 g, 0.0107 mol) and pyridinium hydrochloride (16.2 g) is stirred at 200° for 2 hours. The melt is cooled to 50° C. and slurried with water (75 ml). The slurry is made basic with aqueous saturated NaHCO3 and extracted with ether (3×100 ml). The combined extracts are dried over MgSO4 and filtered, and the filtrate evaporated to dryness under reduced pressure to give 2.19 g of crude product. Column chromatography (silica gel with 2% methanol in chloroform) provides a solid which is recrystallized from ethyl acetate to give 1.20 g (47%) of pure title compound; m.p. 215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:27]([N:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[C:31]([CH3:37])=[N:30]1)[CH3:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:35][C:32]3[C:31]([CH3:37])=[N:30][N:29]([CH2:27][CH3:28])[C:33]=3[CH3:34])=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCn1nc(C)c(C=O)c1C
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Solvent: CO
Product: CCn1nc(C)c(CC2=C(O)CC(CCc3ccc(OC(C)C)c(Cl)c3)(C3CCCC3)OC2=O)c1C
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 38.1 %

Procedure:
A solution of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (379 mg; 1.0 mmol from step 1 below) and 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (152 mg; 1.1 mmol) in methanol was heated at 40° C. overnight. The reaction mixture was treated with (CH3)2NHBH3 (65 mg, 1.1 equiv), and heated at 40° C. overnight again. The reaction was partitioned between EtOAc and H2O. The EtOAc layer was dried with Na2SO4, concentrated, and purified by reverse phase HPLC using 0.1% HOAc in H2O and CH3CN. (Column: Water's Bondapak, C18, particle size: 37–55 micron column size: 47×300 mm; Flow rate: 70 ml/min; Detector: was set at 254 nm; Buffer A: 0.1% HOAc in H2O; Buffer B: 0.1% HOAc in CH3CN. The column was equilibrated in A for 20 minutes. The sample was dissolved in 5 ml of DMSO, filtered, and injected onto the column. The gradient was held at 75% A/25% for 5 minutes and then increased linearly to 55% A/45% B in 15 minutes and then continued isocratically at 45% B for another 25 minutes. The desired product eluted at 28 minutes.) The product-containing fractions were lyophilized to afford the title compound as a powder (196.2 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, 3H), 1.26 (d, m overlap, 8H), 1.35–1.63 (m, 6H), 1.75 (m, 2H), 2.02 (s, 3H), 2.10 (s, 3H), 2.21 (m, 1H), 2.39 (m, overlap, 3H), 2.61 (d, J=16.4 Hz, 1H), 3.1 (m, 2H, overlap with H2O peak), 3.81 (q, 2H), 4.56 (7 line pattern, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.11 (s, 1H). LC-MS (APCI) calcd for C29H39ClN2O4: 514.26, found (M+H+): 515.3 m/z.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]([C:18]([OH:20])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:14]([C:18]([O:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)CBr
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OCC(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl bromoacetate (263 μL, 2.37 mmol) was added to a solution of 2-butyl-4-chloro- 1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 1000 mg, 1.48 mmol), and potassium carbonate (347 mg, 2,51 mmol) in N,N-dimethylformamide (10 mL). The solution was stirred for 2 hours at room temperature. Water was added and the solution was extracted with diethyl ether (2×). The organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was used crude in the following step. LC-MS: m/z 787.1 (M+Na).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:17]=2)[C:12]2[CH:28]=[CH:29][C:30]([C:32]([O:34]C)=[O:33])=[CH:31][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+]>[CH2:1]([S:8][C:9]1[N:13]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](=[O:25])(=[O:26])[NH2:24])[CH:17]=2)[C:12]2[CH:28]=[CH:29][C:30]([C:32]([OH:34])=[O:33])=[CH:31][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(SCc1ccccc1)n2NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)Nn2c(SCc3ccccc3)nc3cc(C(=O)O)ccc32)ccc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A suspension containing 5.3 g of 2-benzylthio-1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-methoxycarbonylbenzimidazole in 30 ml of 2N sodium hydroxide solution was stirred at 50° C. for 4 hours. Meanwhile most part of the starting substance dissolved. After filtering off the insoluble part, the filtrate was neutralized by adding 30 ml of 2N hydrochloric acid. The white precipitate was filtered by suction, washed with water and dried to yield 4.9 g (94.8%) of 2-benzylthio-1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-carboxybenzimidazole, m.p.: 190°-196° C. (with decomposition).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[S:23]1C=[N:26][N:25]=[C:24]1N>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[S:23][CH:24]=[N:25][N:26]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1nncs1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2nncs2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1,3,4-thiadiazol-2-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 2.25 (s, 3H), 4.68 (d, J=2.0 Hz, 2H), 7.18-7.51 (m, 3H), 7.70 (t, J=7.8 Hz, 1H), 8.50 (s, 1H), 9.01 (s, 1H), 10.93 (bs, 1H); MS (ESI) m/z 314.1 (M+1)+.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([O:36][C:37](=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44])[CH3:35]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:46])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOC(=O)CCCCCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82-84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86-7.65 (m, 3H), 5.18-5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97-2.83 (m, 1H), 2.64-2.48 (m, 2H), 2.30-2.15 (m, 4H), 2.08-2.04 (m, 1H), 1.56-1.47 (m, 4H), 1.32-1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>>[CH2:11]([CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([OH:18])[CH2:2][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(CCl)CN1CCC(Cc2ccccc2)CC1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCC(Cc2ccccc2)CC1
Yield: 86 %

Procedure:
Treatment of 1-chloro-3-(4-benzylpiperidin-1-yl)propan-2-ol with potassium phthalimide, following the procedure described in Example 12, Step 2, gave 2-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]isoindole-1,3-dione (32.44 g, 86%) as a white solid:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9])([O-])=O>CO.[Pd]>[ClH:1].[NH2:2][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)=[O:9]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C1CCNCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc(C(=O)C2CCNCC2)c1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A Parr bottle of 220 mL thermostated at 28-29° C. was charged with a suspension of Pd/C 10% (18.2 mg) in methanol (20 mL) followed by 4-(3-nitrobenzoyl)piperidine HCl (1 g 3.69 mmol). The reactor was placed under hydrogen atmosphere(40 PSI). The hydrogenation was complete within 1 hour. The catalyst was removed by filtration and rinsed with methanol (2×5 mL). The filtrate was rota-evaporated and the solid dried under vacuum at 50° C. for 8 hours to give 890 mg (100%) of crude 4-(3-aminobenzoyl)piperidine HCl.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.[CH2:45]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.O>[CH2:45]([N:52]1[CH2:57][CH2:56][N:55]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:32])[F:31])=[O:26])[CH2:54][CH2:53]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(Cc2ccccc2)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
HOBt (4.26 g, 31.5 mmol) and DIEA (10.19 g, 78.89 mmol) were added to a stirred solution of 2-trifluoromethylbenzoic acid (5 g, 26.3 mmol) in DMF (20 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (12.6 g, 65.7 mmol) followed by 1-benzyl-piperazine (5.56 g, 31.55 mmol) were then added. The reaction mixture was stirred at room temperature overnight, then diluted with water and the product extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh with (30% ethyl acetate in hexane) to afford 8.6 g (93%) of (4-benzyl-piperazin-1-yl)-(2-trifluoromethyl-phenyl)-methanone. 1H NMR: (DMSO-d6): δ 7.8 (m, 2H), 7.6 (t, 1H), 7.4 (d, 1H), 7.3 (m, 5H), 3.6 (m, 2H), 3.5 (s, 2H), 3.1 (m, 2H), 2.4 (m, 1H), 2.3 (m, 2H), 2.2 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]([CH3:9])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)CNC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CN(C)c1nccc(Cl)n1

Procedure:
30.0 g (0.20 mol) of 2,4-dichloropyrimidine, 30.9 g (0.20 mol) of ethyl N-methylglycinate and 61.0 g (0.60 mol) of triethylamine in 200 ml of dioxane are stirred at 50° C. for 10 min. The mixture is filtered off with suction and the mother liquor is concentrated to half the original volume. A solid crystallizes out, which is filtered off with suction. The mother liquor is concentrated, the residue is stirred with petroleum ether and the product is filtered off.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: OCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(hydroxymethyl)phenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>O1CCCC1>[Cl:34][CH2:35][CH2:36][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:38]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
2 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)-ethyl]piperazine and 0.82 g of Hunig base are introduced into 40 ml of tetrahydrofuran, and a solution of 0.8 g of 3-chloropropionic acid chloride is added dropwise thereto. The solution is left to stand overnight. The resulting suspension is concentrated by evaporation and taken up in methylene chloride and water. There is obtained from the organic phase 1-[4-(3-chloropropionylamino)benzoyl]-4-[2-(4-chlorophenyl)-ethyl]piperazine having a melting point of 190°-191°.