Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.025 g (49%). 1H NMR (400 MHz, CD3OD): δ 8.50 (d, J=0.8 Hz, 2H), 8.01-7.96 (m, 2H), 7.92 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.34 (dd, J=1.9, 8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 1.80-1.69 (m, 2H), 1.52-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): 6-113.45 LCMS: (ES+) m/z=565.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2-Methyl-3-nitrobenzylchloride (1.0 g, 5.4 mmol) was dissolved in 30 ml of THF, and to this was added 1-methyl-piperazine (0.65 g, 6.5 mmol) and sodium bicarbonate (2.26 g, 26.9 mmol). The reaction mixture was stirred at 65° C. for 16 hours. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with saturated NH4Cl, H2O, brine and dried over MgSO4. Solvent evaporation afforded 1-(2-methyl-3-nitrobenzyl)-4-methylpiperazine.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[I:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([I:12])[C:5]2=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2ccnc-2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(Cl)c2c(I)cnc-2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.66 mmol) was dissolved in anhydrous DMF (20 mL) and N-iodo succinimide (718 mg, 3.19 mmol) was added. After stirring for 45 minutes at rt, reaction mixture was poured into water (400 mL) and extracted with EtOAc (2×500 mL) Organics were combined and washed with brine (500 mL) and dried over sodium sulfate. Solvents were removed under reduced pressure and purified via column chromatography to afford 2,4-dichloro-5-iodo-1H-pyrrolo[2,3-d]pyrimidine (660 mg, 2.103 mmol) as a yellow solid. ESIMS (M+H)+=315
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:30])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:43][Si:44](Cl)([CH3:46])[CH3:45]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:30])[CH:8]2[Si:44]([Cl:43])([CH3:46])[CH3:45])=[C:12]([C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 99.5 %

Procedure:
To a solution of 15.7 g (38.8 mmol) of 5-tert-butyl-7-(3,5-di-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene in 200 ml of toluene 16.0 ml (40.0 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 10 h, and then 10 ml of THF was added. This mixture was stirred for 2 h at 60° C., then cooled to −20° C., and 25.0 g (194 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was refluxed for 2 h, then evaporated to ca. ¾ of its volume, and filtered through glass frit (G3). The precipitate was additionally washed by 2×30 ml of toluene. The combined filtrate was evaporated to dryness to give 19.2 g (99%) of white solid which was further used without an additional purification.
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].O.Cl.[NH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:22]1[CH2:23][CH2:24][NH:19][CH2:20][C:21]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1csc2ccc(NN)cc12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CNCC4

Procedure:
The compound is formed analogously to that described in Example 15, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 20 g of 4-piperidone hydrochloride monohydrate. Melting point: 224°-225° C.
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.CN(C)C=O.Cl[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[C:41]3[C:36](=[CH:37][C:38]([O:42][CH2:43][O:44][CH3:45])=[CH:39][CH:40]=3)[S:35][CH2:34][C:33]2([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH2:54][O:55][CH3:56])=[CH:49][CH:48]=2)[CH3:46])=[CH:28][CH:27]=1>O>[CH3:45][O:44][CH2:43][O:42][C:38]1[CH:37]=[C:36]2[C:41]([CH:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:9]4[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:16])[C:12]([F:13])([F:14])[F:15])[CH2:11][CH2:10]4)=[CH:31][CH:30]=3)[C:33]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][O:55][CH3:56])=[CH:49][CH:48]=3)([CH3:46])[CH2:34][S:35]2)=[CH:40][CH:39]=1
Reactant: FC(F)(F)C(F)(F)CCCN1CCNCC1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCl)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCN3CCN(CCCC(F)(F)C(F)(F)F)CC3)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
Under argon atmosphere 4-(4,4,5,5,5-pentafluoropentyl)piperazine (70 mg, 0.4 mmol) was added to dimethylformamide solution (0.5 ml) of (3RS,4RS)-4-[4-(2-chloroethyloxy)phenyl]-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-thiochroman (69 mg, 0.13 mmol) and then stirred for 8 hours at 80° C. After adding water, the reaction solution was extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and the crude product thus obtained was then purified using amino silica gel plate (ethyl acetate:hexane=1:2) to obtain 67 mg (yield: 77%) of the title compound.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:7]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
Diphenylmethyl bromide (211 mg, 0.877 mmol) was added to a solution of morpholine (23.9 μL, 0.274 mmol), triethylamine (130 μL, 0.932 mmol) and chloroform (1.4 mL) and was allowed to stir at room temperature. After 48 hr, the reaction mixture was concentrated in vacuo and the resulting crude mixture was purified by column chromatography (10% ethyl acetate/hexanes) to provide the title compound in 14% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting powder was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 221.5 mg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:31][CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:7]2.[BH4-].[Na+].O>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([OH:15])[CH:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:31][CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:7]2
Reactant: CCN(CCCCCC1Cc2cc(OC)c(OC)cc2C1=O)Cc1ccccc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CCCCCC1Cc2cc(OC)c(OC)cc2C1O)Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
To a solution of the 5,6-dimethoxy-2-[5-[N-ethyl-N-[(2-methoxyphenyl)methyl]amino]pentyl]-1-indanone hydrochloride (0.75 g) in methanol (10 ml) was gradually added sodium borohydride (0.3 g) and the mixture was stirred at room temperature for 6 hours. The excess sodium borohydride was then decomposed by addition of water and the solvent was distilled off under reduced pressure. The product was extracted into dichloromethane and washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 0.63 g of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.ClCCl>[Br:10][CH2:8][C:7]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:9]
Reactant: [Br-]
Reactant: CC(=O)c1cc(Br)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1cc(Br)cs1

Procedure:
To 1-(4-bromothiophen-2-yl)ethanone (10 g, 48.8 mmol) in methanol (98 mL) and dichloromethane (163 mL) is added tetra-n-butylammonium tribromide (28.8 g, 58.5 mmol). The reaction mixture is concentrated under reduced pressure at 50° C. to give a residue which is purified by silica gel chromatography, eluting with dichloromethane to give crude 2-bromo-1-(4-bromo-2-thienyl)ethanone. To a solution of the crude 2-bromo-1-(4-bromo-2-thienyl)ethanone in acetonitrile (200 ml) is added potassium carbonate (20.2 g, 146 mmol) and diallylamine (9.48 g, 97.5 mmol). The reaction is stirred at room temperature for 2 hours. Water is added and the solution is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound. ES/MS (m/e): (79Br/81Br) 300/302 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1)C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:22]1C=CC(CC(O[Si](C(C)(C)C)(C)C)C)=CC=1>>[Si:1]([O:8][CH:9]([CH3:22])[CH2:10][C:12]1[CH:13]=[CH:14][C:15]([B:18]([OH:19])[OH:20])=[CH:16][CH:17]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(Cc1ccc(Br)cc1)O[Si](C)(C)C(C)(C)C
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(B(O)O)cc1
Product: CC(Cc1ccc(B(O)O)cc1)O[Si](C)(C)C(C)(C)C
Yield: 54 %

Procedure:
According to the procedure for the preparation of 73D, 77B (2.14 g, 6.50 mmol) afforded 1.04 g (54%) of 77C as a colorless solid. MS (ESI) m/z 295.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:16])=[CH:13][CH:12]=1
Reactant: NCc1ccccc1Cl
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)c1ccc(Br)cc1
Yield: 98 %

Procedure:
To a stirred solution of 2-chlorobenzylamine (2.42 mL, 20 mmol) in THF (80 mL, anhyd) at 0° C. added a solution of 4-bromobenzoyl chloride (4.39 g, 20 mmol) in THF (20 mL, anhyd.) and then triethylamine (2.93 mL, 21 mmol). After 12 h the resulting mixture was filtered and the solids rinsed with EtOAc. The combined filtrates were diluted with EtOAc (100 mL), washed with 1N HCl, satd NaHCO3 and brine, then dried (anhyd Na2SO4) and concentrated to afford the title compound (6.36 g, 98%) as a white solid, which was used in the next step without purification. GC-MS (EI): 322, 324.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: OCCCCC=CCCc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC=CCCc2ccc(OCc3ccccc3)cc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
8-(4-Benzyloxyphenyl)-5-octenol (24 g.) was added in portions over a 15 minute period to a solution of 19.5 g. of p-toluenesulfonyl chloride in 600 ml. of dry pyridine at -10° C. The reaction mixture was stirred for one hour at -10° C., then poured into ice-water and stirred for 20 minutes. The mixture was extracted with chloroform, and the latter washed with aqueous hydrochloric acid, aqueous sodium hydroxide, dried and concentrated. The resulting 8-(4-benzyloxyphenyl)-5-octenyl p-toluenesulfonate was used directly in the next reaction without further purification.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: Cc1cc(NN)nc2ncccc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydrazinyl-4-methyl-1,8-naphthyridine prepared above (84 mg, 0.482 mmol) in CH2Cl2 was added 3,5-dichlorophenyl isocyanate (91 mg, 1.0 eq). The resulting mixture was stirred at room temperature overnight. The resulting precipitate was filtered off and washed with EtOAc to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3 H) 6.78 (s, 1 H) 7.05 (t, J=1.90 Hz, 1 H) 7.23 (dd, J=7.91, 4.40 Hz, 1 H) 7.61 (br. s., 2 H) 8.22 (dd, J=8.06, 1.90 Hz, 1 H) 8.57 (br. s., 1 H) 8.68 (dd, J=4.40, 1.76 Hz, 1 H) 8.98 (s, 1 H) 9.22 (br. s., 1 H).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25]([CH2:27][C@@H:28](O)[CH2:29]C(OCC)=O)#N.Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH2:9][CH2:25][CH2:27][CH2:28][CH3:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diphenylacetamide (211 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -10° C. to -5° C. The mixture is stirred at -0° C. to 20° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared anion. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6 -cyano-5-hydroxy-3-oxo. N,N-diphenylhexanamide which is not isolated. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil. Proton nuclear magnetic resonance spectroscopy (1H-NMR): (Acetone-d6) δ2.02 (m, 2H), 2.73 (m, 2H), 4.1 (m, 2H), 4.52 (m, 1H), 4.74 (s, 1H), 7.2-7.4 (m, 10H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a stirred suspension of 50 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide (XV) (0.17 mmol) in N,N-dimethylformamide (3 mL), 0.09 mL of (3-amino-propyl)-carbamic acid tert-butyl ester (0.51 mmol) and 0.036 mL of triethylamine (0.26 mmol) were added. The reaction mixture was stirred at room temperature overnight, evaporated to dryness and then purified through preparative HPLC on a Waters X Terra RP 18 (19×250 mm, 5 m) column. Mobile phase A was 0.05% ammonia/acetonitrile:95/5 and mobile phase B was acetonitrile/water:95/5. Gradient from 10 to 75% B in 15 min. Fractions containing the desired compound were dried, affording 32 mg (44% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.Cl.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(CCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-hydroxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, tyramine hydrochloride, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:18]([CH:17]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])[CH2:16][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCC(Br)C(=O)OCC
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1ccccc1C)C(=O)OCC
Temperature: 70 °C

Procedure:
A mixture of o-cresol (0.1 mol) and diethyl 2-bromoglutarate (0.1 mol) and K2CO3 (0.11 mol) in 50 mL of DMF are heated at 70° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic solution is washed with water, 0.1N NaOH solution, dried and evaporated to give ethyl 4-carbethoxy-4-(2-methylphenoxy)butyrate which is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Reflux a mixture of (2R,4R)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (198 g, 0.92 mol), 5-bromo-fluoronitrobenzene (224 g, 0.98 mol), triethylamine (273 mL, 1.96 mol) in ethyl acetate (2 L) for 16 h under nitrogen with vigorous stirring. Cool to room temperature and wash with brine. Back-extract the brine layer with ethyl acetate (1 L), combine the organic layers, dry over sodium sulfate, filter and concentrate. Dissolve the resulting solid in warm ethyl acetate (2 L), concentrate to approximately 500 mL and allow crystals to start forming Treat the solution slowly with hexanes (2 L) and allow the mixture to stand at room temperature for 2 h. Collect the yellow solid by filtration, wash with hexanes and dry at 40° C./20 mm Hg to obtain 227 g of desired product. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (2:3:5 ethyl acetate/dichloromethane/heptane gradually increasing to 2:3 ethyl acetate/heptane) to obtain an additional 54 g of desired product. Overall yield: 281 g (70%). [α]D20−81 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.90 (m, 1H), 2.48 (br s, 1H), 3.14 (m, 1H), 3.45 (m, 1H), 3.63 (m, 1H), 3.81 (m, 2H), 4.29 (m, 1H), 5.12 (m, 1H), 7.08 (d, 1H), 7.65 (dd, 1H), 8.15 (d, 1H), 8.57 (br d, 1H, NH).