Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[C:5]([O:11][CH3:12])[C:4]=1B(O)O.[CH2:16]([O:18][C:19](=[O:40])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:40])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:4]2[C:5]([O:11][CH3:12])=[CH:6][CH:7]=[C:8]([CH2:9][OH:10])[C:3]=2[O:2][CH3:1])=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29])[CH3:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1ccc(CO)c(OC)c1B(O)O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(CO)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-Dimethoxy-3-(hydroxymethyl)benzeneboronic acid was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester in a similar method as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-3-(hydroxymethyl)phenyl]-L-phenylalanine ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45]Cl)[N:44]=2)[CH:41]=1>O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=4[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[CH:6][CH:7]=3)[N:44]=2)[CH:41]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5cc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (300 mg, 0.96 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.8 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes, upon which 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (201 mg, 1.4 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxy phenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 39.3%) as a white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.85 (s, 1H), 8.0 (s, 1H), 7.6 (d, 3H), 7.3 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.15 (s, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]+: m/z=475. HPLC: (98.0%, Condition-A).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[F:34][C:35]([F:44])([F:43])[C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:39][C:38]1[CH:40]=[CH:41][CH:42]=[C:36]([C:35]([F:34])([F:43])[F:44])[CH:37]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(COCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 mL round-bottomed flask was added benzyloxyacetic acid (4.80 g, 28.9 mmol, 1.0 eq.), EDC (8.30 g, 43.3 mmol, 1.5 eq.), HOBt (5.85 g, 43.3 mmol, 1.5 eq.), and DMF (200 mL). N-methylmorpholine (6.5 mL, 57.7 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature for 30 min. 3-Trifluoromethylaniline (6.12 mL, 49.1 mmol, 1.7 eq.) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (500 mL) and then washed with H2O (1×100 mL), 10% aqueous LiCl (3×100 mL), H2O (1×100 mL), and brine (1×50 mL). The combined aqueous phases were extracted with EtOAc (3×75 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give an oil which was used in the next step without further purification. LC/MSD (HP Series 1100 MSD) Expected MW: 309.10, Observed M+H, 310.1, Retention time: 1.67. 1H-NMR, DMSO-d6, Varian 400 MHz δ 10.15 (s, 1H), 8.13 (s, 1H), 7.86 (d, 1H), 7.54 (t, 1H), 7.39-6.72 (m, 5H) 5.55 (s, 1H), 4.62 (s, 2H), 4.12 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[C@@H:10]([NH:35]C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20](CC3C=CC(OC)=CC=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](C)C)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:8][C:9](=[O:43])[C@@H:10]([NH2:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Agent: C[SiH](C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)cc1)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
The title B compound, (S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (40 mg, 0.066 mmol) is dissolved in TFA (1.32 mL) containing t-butyidimethylsilane (0.033 mL, 0.198 mmol) in a 1 dram vial. The reaction is monitored by reverse phase HPLC (YMC CombiScreen Pro C18, 50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 at 7.0 min. Starting material has a retention time of 4.97 min and a new peak has a retention time of 3.09 min, the starting material without the t-butoxylcarbonyl group as an “intermediate”, [M+H]+=510. After 25 min at RT, the reaction is heated at 80° C. for an additional 25 min. A new peak by HPLC has a retention time of 2.02 min, corresponding to the desired product. The reaction is cooled, filtered through florisil to remove a black precipitate and concentrated on a Savant Speedvac. The resulting residue is triturated with Et2O to give a white solid. This material is purified on a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in two equal aliquots and eluted at 30 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) 10:90 over 5.0 min, then held at 10:90 until 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac to yield (S)-2-amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid benzyl ester as a white foam: [M−1]−=388.0.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:17][C:16]=2[C:29](N(OC)C)=[O:30])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:35]1COC[CH2:36]1>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[S:17][C:16]([C:29](=[O:30])[CH2:35][CH3:36])=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=3)[C:19]=2[CH3:20])=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)c(-c3ccc(S(=O)(=O)N=CN(C)C)cc3)c2C)cc1
Product: CCC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Yield: 37 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 3.59 g, 26.8 ml, 26.94 mmol) was added drop wise to a stirred solution of 3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-5-(4-methoxyphenyl)-N,4-dimethylthiophene-2-carboxamide (compound 7f, 2.7 g, 5.8 mmol) in anhydrous THF (100 ml) at 25° C., and the reaction mixture was heated at about 70 to about 75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by adding a solution of saturated ammonium chloride (50 ml) and the resulting mixture was extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by Preparative HPLC to obtain the title compound (0.84 g, 37%).
Reaction SMILES: [CH2:1]([C:5](=[CH2:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)C(C)(C)C)=[C:10]([F:21])[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].OS(O)(=O)=O>C(Cl)Cl>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[F:21])[C:6](=[O:7])[CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:22]2
Reactant: C=C(CCCC)C(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCC1Cc2cc(N)c(F)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.9 %

Procedure:
A solution of the product mixture from step 4 (19.5 g, approx. 60.7 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath and treated with ice-cold, conc. H2SO4 (300 mL). The resulting mixture was removed from the cooling bath and stirred at room temperature for 18 hours. The mixture was cautiously added to an ice-cold mixture of CH2Cl2 (300 mL) and chopped ice (1 L). Excess acid was neutralized by portionwise addition of saturated Na2CO3 solution (approx. 1 L) followed by solid Na2CO3 (approx. 500 g). Additional water and CH2Cl2 were occasionally added to dissolve the red/purple solids that formed during the neutralization. When the pH was neutral, the organic phase was separated and the aqueous portion was extracted with more CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residual dark red oil was purified by flash chromatography on a Biotage 75 L KP-Sil column, eluting with 4:1 hexanes-EtOAc. The product containing fractions were combined and evaporated under vacuum to provide 5-amino-2-butyl-6-fluoro-1-indanone (5.5 g, 37%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[NH2:22][C:23]1[C:24]([F:32])=[C:25]([OH:31])[CH:26]=[C:27]([CH3:30])[C:28]=1[F:29].O>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:32][C:24]1[C:25]([OH:31])=[CH:26][C:27]([CH3:30])=[C:28]([F:29])[C:23]=1[NH:22][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: Cc1cc(O)c(F)c(N)c1F
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(O)c(F)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (Intermediate III(a)) (437 mg, 1.87 mmol, 1.1 eq) in CH2Cl2 (10 mL) and DMF (3 drops) was added SOCl2 (15 mL) dropwise at 0° C. The solution was stirred at room temperature for 1 h, then concentrated in vacuo. The residue obtained was dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-2,4-difluoro-5-methyl-phenol (270 mg, 1.70 mmol, 1.0 eq) in THF (10 mL) at 0° C. After addition was completed, the reaction mixture was stirred at room temperature for 2 h, then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 10:1 to 3:1) to give the title compound as a white solid (285 mg, 45%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[NH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])=[CH:18][C:13]=2[N:12]=[C:11]1[NH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1.[O:43]1C[CH:44]1[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])O>C(#N)C.ClCCl>[OH:43][CH:44]([NH:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:20])=[CH:18][C:13]=2[N:12]=[C:11]1[NH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCN)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCNC(O)Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Lithium perchlorate (16 mg, 3 eq) then after 5 minutes 1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxy phenyl)amino]-1H-benzimidazole-5-carboxamide (25 mg, 1 eq) are added, at a temperature of approximately 20° C. to a solution of 2,3-epoxypropylbenzene (7 mg, 1 eq) in acetonitrile (0.5 ml). The mixture is heated under reflux for 24 hours then cooled down to ambient temperature and hydrogen carbonate and dichloromethane saturated water is added. After decanting and extracting, the organic phases are combined and washed with salt water, followed by drying over sodium sulphate and evaporating under reduced pressure at 40° C. Purification of the oil obtained by flash chromatography on silica gel (100% dichloromethane to dichloromethane/methanol 80:20) produces the expected compound in the form of an oil (31 mg, 55% yield)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:14][OH:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][O:9]2)=[N:3][CH:4]=1
Reactant: OCC1CCCO1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCC2CCCO2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydrofuran-2-methanol by the method of Example 10 (b).
Reaction SMILES: [CH3:1][C@@H:2]1[N:8]([C:9](=[O:15])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4](=[O:20])[C@H:3]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36]([CH2:40]Cl)=[C:35]([O:42][CH3:43])[CH:34]=[CH:33]2.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36]([CH2:40][N:5]1[C:4](=[O:20])[C@@H:3]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:2]([CH3:1])[N:8]([C:9](=[O:15])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=3)=[C:35]([O:42][CH3:43])[CH:34]=[CH:33]2
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccccc2N1C(=O)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a rt solution of tert-butyl(2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (60.3 mg, 147 μmol) in DMF (366 μl) was added 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (50.2 mg, 176 μmol), cesium carbonate (62.1 mg, 191 μmol), and sodium iodide (28.6 mg, 191 μmol). The reaction was stirred at rt for 4 h, then diluted with EtOAc (30 mL), washed with H2O (30 mL) and sat. aq. NaCl (30 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (75 mg, 78% yield) as a white solid. MS m/z 682/684 (MNa)+
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>CN(C=O)C>[Br:39][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCCCCC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCCCCC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of 6-cyclopentyl-hexan-1-ol (1.20 g, 7.06 mmol) in DMF (20 mL) was added triphenylphosphine (2.08 g, 7.93 mmol). The solution was cooled to 0° C. and NBS (1.36 g, 7.64 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford (6-bromo-hexyl)-cyclopentane (1.55 g, 94%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, t, J=6.9 Hz), 1.85 (2H, m), 1.73 (3H, m), 1.38–1.64 (6H, m), 1.24–1.38 (6H, m), 1.04 (2H, m); 13C NMR (75 MHz, CDCl3) δ 40.38, 36.37, 34.35, 33.12, 32.99, 29.33, 28.87, 28.49, 25.46.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)([OH:3])=O.ClC(OCC(C)C)=O.[OH:27][CH2:28][CH2:29][NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[OH:27][CH2:28][CH2:29][N:30]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)=[O:3]
Reactant: O=C(O)CCCOc1ccc2c(c1)CCC(=O)N2
Reactant: OCCNC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(OCCCC(=O)N(CCO)C3CCCCC3)ccc2N1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Into 100 ml of chloroform were added 2.5 g of 6-(3-carboxypropoxy)-3,4-dihydrocarbostyril and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 1.5 ml of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation, stirring was continued for 30 minutes and 2.0 g of N-(2-hydroxyethyl)cyclohexylamine was added to the reaction mixture and further stirred at a room temperature for 2 hours. After the reaction was completed, the chloroform solution of the reaction product was washed with a diluted NaHCO3 aqueous solution, a diluted hydrochloric acid and water in this order. The chloroform solution was dried with anhydrous Na2SO4, then the chloroform was removed by distillation and the residue thus obtained was recrystallized from chloroform-petroleum ether to obtain 2.1 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 139°-141.5° C.
Reaction SMILES: [C:1]([C:3]1(C(OCC)=O)[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1([CH3:13])[CH3:12])#[N:2].C(=O)(O)[O-].[Na+].O>C(O)CCO>[CH3:12][C:4]1([CH3:13])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[C:1]#[N:2]
Reactant: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: OCCCO
Product: CC1(C)C(C#N)C1c1ccccc1
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
A mixture of 234 mg (0.96 mmole) of cyclopropanoid cyanoester 10 (produced in accordance with Example VIII), 174 mg (2.1 mmoles) of sodium bicarbonate, and 35 mg of water in 2.0 mL of 1,3-propanediol was heated at reflux, protected from atmospheric moisture, for 45 minutes. The product was isolated by diluting the cooled mixture with 25 mL of saturated brine and extraction with ether. The ether extracts were washed in successive order with 20 mL of 1:1 (v/v) 1M aqueous NaOH:saturated brine and 20 mL of 10% aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Removal of the ether by evaporation at reduced pressure afforded 157 mg (95% yield) of nitrile 17 as a mixture of cis and trans stereoisomers, subsequently shown by NMR analysis (vinyl H absorption at approximately 5.0δ) to be accompanied by a minor amount (~10-15%) of ring-opened by-product.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.42 min.; [M+H]+: 403.73 g/mol.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:48][CH:49]=[CH:50][N:51]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:42]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:51][CH:50]=[CH:49][N:48]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55][C:24]2[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=2)[N:42]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
1-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-3-pyridyl}ethan-1-one was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-yl]ethylamine and 1-(6-chloro-3-pyridyl)-ethanone (prepared as described in Tetrahedron 48:9233 (1992)) in accordance to the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1>CCCCO>[C:14]1([C:4]2[N:3]=[C:2]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: CCCCO
Product: CNS(=O)(=O)c1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: 30 °C
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-2,6-diphenyl-pyrimidine (0.2 g, 0.75 mmol) in n-BuOH (7 mL) was added 4-amino-N-methyl-benzenesulfonamide (0.146 g, 0.78 mmol) and the mixture was stirred at reflux temperature for 72 hours under nitrogen. The mixture was then cooled to temperature in the range of 20-40° C., the solid precipitated was filtered off and dried to give the title compound (0.13 g, 43% yield).