Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>CN(C=O)C>[N:8]1([C:4]2[N:3]=[C:2]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]3[CH2:19][CH2:20][OH:21])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: OCCC1CCCCN1
Reactant: Clc1ccnc(-n2ccnc2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCCC1CCCCN1c1ccnc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
The above synthesis may be carried out as follows: To DMF (100 ml) was added 4-chloro-2-imidazol-1-ylpyrimidine (0.50 g, 2.77 mmol), 2-piperidineethanol (0.359 g, 2.77 mmol), and Hünig's base (0.536 g, 4.15 mmol). After heating at 80° C. for 5 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 349 mg (46% ) of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (the compound of formula (XVI)), (1H NMR (CDCl3) δ8.54 (s, 2), 8.11 (d, 1), 7.82 (t, 1), 7.11 (d, 1), 6.44 (d, 1), 3.60 (m, 2), 3.03 (m, 1), 1.77 (m,); MS: 2.74 (M+H)+). To a solution of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (25 mg, 0.092 mmol) dissolve in DMF (5 ml) was added NaH (60% dispersion in oil, 5.5 mg, 0.14 mmol) followed by piperonyl chloride (17 mg, 0.10 mmol) and t-butyl ammonium chloride. After stirring for 16 hours at 80° C., the solvent was removed in vacuo and the residue was partitioned with saturated NH4Cl and CH2Cl2. The organic layer was separated, dried (MgSO4), the solvent removed in vacuo, and the residue chromatographed (CH2Cl2/MeOH, 19/1) to give 13 mg (35%) of 4-[2-[[(1,3-benzodioxol-5-yl)methoxy]ethyl]piperidin-1-yl]-2-(1H-imidazol-1-yl)pyrimidine (the compound of formula (Icc)); 1H NMR (CDCl3) δ8.52 (s, 1), 8.05 (d, 1), 7.80 (s, 1), 7.09 (s, 1), 6.73 (m, 3), 6.45 (d, 1), 5.93 (s, 2), 4.30 (s, 2), 3.45 (m, 2), 2.95 (m, 1), 1.55 (m); MS: 408.7 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O.O>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCCC1CCCOC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(Tetrahydro-2H-pyran-3-yl)ethyl methanesulfonate (142 mg) was added and the stirring mixture heated at 60° C. for 3 h. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-70%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a brown oil, yield 108 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])(=[O:21])[NH2:2]
Reactant: N#Cc1cc2n(c1)CCc1ccccc1C2=O
Reactant: CC(=O)O
Agent: Cl
Product: NC(=O)c1cc2n(c1)CCc1ccccc1C2=O
Temperature: 25 °C
Yield: 83 %

Procedure:
2-Cyano-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid was refluxed for 2 hours. It was then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution, from which crystals deposited during the extraction, was left to cool to room temperature and filtered to afford 2-carbamoyl-6,11-dihydro-11-oxo-5H-pyrrolo[2,1-b]-[3]benzazepine (27 g. 83%), m.p. 228° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])OC)=[N:6]1.C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:27])[NH2:17])=[N:6]1
Reactant: [NH4+]
Reactant: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
The solution of methyl (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanol obtained from Example 33 A-5 is mixed with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride and stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly triturated with acetone, and the precipitated solid is filtered off with suction.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]1([C:50]2[NH:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:55]([C:53]2[NH:54][C:50]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:51][CH:52]=2)=[O:56])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Reactant: CC(C)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2ccc(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-isopropyl-piperidin-4-ylamine (350 mg) in DCM (15 mL) was added DIEA (1.67 mL), followed by HATU (935 mg) and 5-phenyl-1H-pyrrole-2-carboxylic acid (461 mg). The mixture was stirred for 1 h at RT whereupon it was washed two times with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated to give crude 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide which was used directly in the following step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH:24]=[N:23][C:22]3[C:21](=[O:25])[NH:20][C:19]([NH2:26])=[N:18][C:17]2=3)[CH:10]=1>C(O)(=O)C>[Br:1][C:24]1[N:16]([CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:17]2[N:18]=[C:19]([NH2:26])[NH:20][C:21](=[O:25])[C:22]=2[N:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc2c(ncn2Cc2cccnc2)c(=O)[nH]1
Solvent: CC(=O)O
Product: Nc1nc2c(nc(Br)n2Cc2cccnc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-Bromosuccinimide (1.59 g; 8.95 mmol) was added to a suspension of 9-[(3-pyridyl)methyl]guanine (2.0 g; 8.14 mmol) in glacial acetic acid (20 ml) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water and filtered. The crude product was triturated with water, filtered, and washed with water and dried. Yield 1.91 g; mp >300° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:18]=[C:13]1[CH2:14][CH2:15][C:16](=[O:17])[N:12]1[O:9][C:8](=[O:10])[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CN1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CN1CCCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6 g (42 mMol) (piperidine-1-yl)-acetic acid 10 was added to 4.83 g (42 mMol) N-hydroxysuccinimide and 9.53 g (46.2 mMol) dicylohexyl-carbodiimide in 100 ml CH2Cl2. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated in vacuum to dryness. The residue was then dissolved in diethylether and the solution was filtered off. The filtrate was reduced once again and the residue was dissolved in Diisopropylether. After filtration of the solution and evaporation of the solvent, the compound was then recrystallised from diisopropylether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:23])([CH3:22])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10]2)=[CH:5][C:4]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.[NH2:35][S:36](Cl)(=[O:38])=[O:37]>CC(N(C)C)=O>[S:36](=[O:38])(=[O:37])([O:24][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[CH2:10][N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:8]([CH3:23])([CH3:22])[CH2:7]2)[NH2:35]
Reactant: COc1cccc(CN2Cc3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: COc1cccc(CN2Cc3cc(OC)c(OS(N)(=O)=O)cc3CC2(C)C)c1
Yield: 89 %

Procedure:
Sulfamoylation of 226 with H2NSO2Cl and DMA as described above afforded the title compound (86 mg, 89%) as a colourless foam. 1H NMR (400 MHz; DMSO-d6) 1.14 (6H, s, 2×CH3), 2.69 (2H, s, CH2), 3.43 (2H, s, CH2), 3.62 (2H, s, CH2), 3.73 (3H, s, OCH3), 3.75 (3H, s, OCH3), 6.80 (1H, dd, J=8.0, 2.0 Hz, CH), 6.83 (1H, s, CH), 6.89-6.94 (3H, m, 3×CH), 7.23 (1H, t, J=8.0 Hz, CH), 7.79 (2H, s, NH2). 13C NMR (100 MHz; DMSO-d6) 42.80 (CH2), 49.42 (CH2), 52.05 (C), 53.0 (CH2), 54.94 (OCH3), 55.79 (OCH3), 111.83 (CH), 112.97 (CH), 114.10 (CH), 120.30 (CH), 120.61 (CH), 125.77 (C), 129.25 (CH), 133.04 (C), 136.80 (C), 142.19 (C), 149.88 (C), 159.28 (C). LC/MS (ES+) tr=1.14 min, m/z 407.28 (M++H). HRMS (ES+) cald. for C20H27N2O5S (M++H) 407.1635, found 407.1636. HPLC tr=2.10 min (>98%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: CC(C)c1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 168A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69-11.71 (bs, 1H), 8.38-8.41 (m, 1H), 7.89-8.03 (m, 2H), 7.75-7.77 (m, 1H), 7.50-7.53 (m, 2H), 7.42-7.46 (m, 2H), 7.37-7.43 (m, 4H), 3.70 (s, 2H), 2.93-3.06 (m, 1H), 1.27 (d, J=6.9 Hz, 6H); MS (APCI+) M/Z 432 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl:11][C:12]1[CH:17]=[C:16]([NH:18][C:19]2[C:24]([NH2:25])=[C:23]([Cl:26])[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:14][N:13]=1>N1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:26][C:23]1[C:24]([NH:25][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[C:19]([NH:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)[N:20]=[CH:21][N:22]=1
Reactant: Nc1c(Cl)ncnc1Nc1ccnc(Cl)c1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1c(Cl)ncnc1Nc1ccnc(Cl)c1)c1cccc(F)c1
Reaction time: 12 h
Yield: 62.1 %

Procedure:
3-Fluorobenzoyl chloride (1.3 mL, 10.7 mmol) was added dropwise to a suspension of N4-(2-chloro-4-pyridyl)-6-chloro-4,5-pyrimidine diamine (2.5 g, 9.8 mmol) in pyridine (50 mL) over 5 minutes in a nitrogen atmosphere at 0 to 5° C., and the mixture was stirred as such for 12 hours. The reaction solution was diluted with water and ethyl acetate (100 mL). The organic layer was washed with 1N hydrochloric acid (×1). After the 1N hydrochloric acid layer was extracted with ethyl acetate (×2), the combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (×1), dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether, to give the title compound (2.3 g, 62%) as a colorless solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9]([C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH2:1]([C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@@H:9]([OH:10])[C@H:11]([CH:13]1[CH2:15][CH2:14]1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
2.83 g (8.77 mmol) tert-butyl [(1S,2R)-1-benzyl-2-(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate were dissolved in 130 ml of methylene chloride, 3 ml of acetic acid were added thereto and the mixture was finally treated portionwise at 0°-10° C. with 0.332 g (8.78 mmol) of sodium borohydride. The reaction solution was stirred at 50 for a further 2 hours and was then partitioned between 2N sodium hydrogen carbonate solution and methylene chloride. The organic phase was separated, washed with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. Crystallization of the residue from ether/hexane yielded 2.1 g of tert-butyl [(1S,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydroxypropyl]carbamate as colourless needles, m.p. 83-85°.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH3:35][N:36]([CH3:51])[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[C:42]2[S:47]([NH2:50])(=[O:49])=[O:48]>>[Cl:24][C:17]1[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:34])[NH:50][S:47]([C:42]4[C:43]5[C:38](=[C:37]([N:36]([CH3:51])[CH3:35])[CH:46]=[CH:45][CH:44]=5)[CH:39]=[CH:40][CH:41]=4)(=[O:48])=[O:49])=[CH:10][CH:9]=3)[C:15]=2[CH:16]=1
Reactant: CN(C)c1cccc2c(S(N)(=O)=O)cccc12
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 5-(dimethylamino)-1-naphthylsulfonamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:28])(=[O:29])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (350 mg, 0.68 mmol) in N,N-dimethylformamide (6.54 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (318 mg, 0.719 mmol) at 0° C. under an atmosphere of nitrogen. After stirring for 15 min, methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (196 mg, 0.821 mmol) and N,N-diisopropylethylamine (358 μL, 2.05 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was diluted with ethyl acetate and quenched with sat. sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative LCMS to afford product as a white solid (361 mg, 72% two steps). 1H NMR (500 MHz, CD3OD): δ 7.63 (d, J=15.6 Hz, 1H), 7.44 (m, 1H), 7.31 (m, 7H), 6.48 (t, J=8.0 Hz, 2H), 5.56 (m, 1H), 5.03 (d, J=13.9 Hz, 2H), 4.31 (m, 1H), 3.97 (t, J=5.6 Hz, 2H), 3.86 (s, 3H), 3.44 (m, 1H), 3.25 (m, 3H), 2.95 (m, 1H), 1.66 (m, 4H). LCMS found for C32H35BrN3O10S (M+H)+: m/z=732, 734.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:42][C:43]1[O:47][N:46]=[C:45]([CH3:48])[CH:44]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:42][C:43]2[O:47][N:46]=[C:45]([CH3:48])[CH:44]=2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)on1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 5-amino-3-methylisoxazole (15 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (9.8 mg, yield 17.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[ClH:14].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][Cl:14]
Reactant: CNc1ccc(C)cc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CNc1ccc(C)cc1CCl
Product: Cl
Yield: 22 %

Procedure:
Ethyl 2-amino-5-methylbenzoate was treated with dimethylsulfuric acid to give a N-methylated product. The N-methylated product was reduced using lithium aluminum hydride to give 5-methyl-2-methylaminobenzyl alcohol. The obtained alcohol was reacted with thionyl chloride in benzene to give the desired compound, yield 22% (based on the amount of the starting benzoate).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[N:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:17]=2)[N:12]([CH3:34])[C:11](=[O:35])[C:10]=1[C:36](=[O:38])[CH3:37])=[O:7])(=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CO.CCOC(C)=O>[C:36]([C:10]1[C:11](=[O:35])[N:12]([CH3:34])[C:13]2[C:18]([C:9]=1[NH:8][C:6](=[O:7])[CH2:5][OH:4])=[CH:17][C:16]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:15]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[N:14]=2)(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1c(NC(=O)CO)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the product of EXAMPLE 33 (77 mg) in CH2Cl2 (2 mL) was added Cs2CO3 (43.7 mg) in methanol (1 mL). The reaction stirred at room temperature for 2.5 hours before diluting with EtOAc. The reaction was washed with brine and 10% aqueous NaHSO4 solution. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-65% EtOAc in hexane affording the title compound. HPLC/MS: 530.1 (M+1), 532.1 (M+3); Rt=3.85 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH3:18])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([Br:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br-:26].[CH2:19]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:10]([CH3:18])=[CH:9]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cn1cnc(-c2ccccc2)c1-c1ccccc1
Solvent: Cc1ccccc1
Product: C[n+]1cn(Cc2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Product: [Br-]

Procedure:
In a 25 ml one-necked flask, there is dissolved 0.240 g (1.024 mmol) of 4,5-diphenyl-1-methylimidazole, which was obtained according to Zeitschrift fuer Naturforschung, B: Chemical Sciences (2003), 58(4), 305-310, in 10 ml of toluene and then 183 μl (1.536 mmol) of benzyl bromide are added. After 2 days of heating under reflux, the reaction medium is concentrated under reduced pressure. The residue is taken up in 50 ml of diisopropyl ether. The precipitate formed is drained, washed twice with 5 ml of diisopropyl ether and then dried under reduced pressure. There is thus obtained 0.480 g (100%) of 3-benzyl-4,5-diphenyl-1-methylimidazolium bromide, in the form of a yellow solid, used as it is in the next step, whose characteristic is the following:
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:10]1=[O:35])C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[OH:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)(=[O:17])=[O:18])[C:10]1=[O:35]
Reactant: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1O
Reaction time: 1 h

Procedure:
4-(4Trifluoromethyl-phenyl)-piperazine-1-sulfonic acid ((3S)-1-benzyloxy-2,5-dioxo-pyrrolidin-3-yl)-amid (67 mg; 0.13 mmol) was dissolved in EtOAc (4 ml) +MeOH (4 ml). A slurry of 10% Pd/C (30 mg) in MeOH (1 ml) was added under a stream of nitrogen. The mixture was hydrogenated at room temperature at 1 atm. pressure of H2 for 1 h. The reaction mixture was filtered through celite and the filtercake was washed with EtOAc and MeOH. The filtrate was evaporated and the crude product were purified twice by flash chromatography on Si-60-gel using EtOAc:Heptane (1:1) as eluent 1 to remove impurities, and EtOAc to elute the product. The fractions containing the product is evaporated and the residue is trituated with Et2O, the resulting colourless solid was dried to give the title compound. Obtained 20 mg (36% yield) of the title compound.