Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.[Cu]I.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ccc(Oc2cccc(Br)c2)cc1
Temperature: 90 °C
Yield: 33.6 %

Procedure:
To a solution of 1-bromo-3-iodo-benzene (1.00 g, 3.55 mmol), 4-fluorophenol (462 mg, 3.59 mmol), N,N-dimethylglycine hydrochloride (149 mg, 1.06 mmol), and cesium carbonate (2.28 g, 7.00 mmol) in DMA was added CuI (66.8 mg, 0.351 mmol). The reaction mixture was heated at 90° C. for 48 h, cooled to rt, and then poured into water and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a colorless oil (319 mg, 32%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[I:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[I:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:31][CH:30]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(I)cc3)n2)c1C(F)(F)F
Reaction time: 12 h

Procedure:
To a solution of the title compound from Example 1 Step B (304 mg, 0.81 mmol) in DMF (2.7 mL) were added 4-iodobenzyl bromide (359 mg, 1.21 mmol) and cesium carbonate (788 mg, 2.42 mmol). After 12 h, the reaction mixture was poured into sat. aq. NH4Cl and extracted with EtOAc. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 594.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.94 (dd, J=7.5, 1.5 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 739-7.35 (m, 1H), 7.14-7.12 (m, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 1H), 5.09 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[NH2:2]O.C(O[CH:7]1[CH:16](C)[CH2:15][C:14]2[CH2:13][CH2:12][C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[C:9]=2O1)C>C(#N)C>[N:2]1[C:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH2:12][CH2:13][C:14]=2[CH:15]=[CH:16][CH:7]=1
Reactant: CCOC1OC2=C(CCc3ccccc32)CC1C
Reactant: NO
Agent: Cl
Solvent: CC#N
Product: c1ccc2c(c1)CCc1cccnc1-2
Reaction time: 16 h
Yield: 48.3 %

Procedure:
To a suspension of hydroxylamine hydrochloride (46.1 g, 0.663 mol) in 1070 mL of acetonitrile was added 2-ethoxy-3-methyl-3,4,5,6-tetrahydrobenzo[h]chromene (140 g, 0.265 mol) from step two. The reaction mixture was heated at reflux under nitrogen with stirring for 16 h. Evaporation of the acetonitrile, followed by vacuum distillation of the product yielded 34.5 g of a crude product that was further purified by silica gel chromatography with 5/95 ethyl acetate/hexane as the eluent, yielding 23.2 g (45%) of 5,6-dihydrobenzo[h]quinoline as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCCCN
Solvent: O
Product: CCCCNc1nc(N)nc(N)n1
Yield: 96 %

Procedure:
A mixture of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 100 mL of water, and 29.2 g (0.4 mol) of butylamine was warmed with stirring and allowed to react finally at a reflux temperature for 6 hours. After cooling the reaction mixture, the product was filtered and washed sufficiently with a large amount of water and then washed with toluene. The filtrate was dried at 70° C. for 6 hours in vacuum to obtain 17.5 g (yield 96%) of the titled compound. Melting point: 167° C.
Reaction SMILES: C(NC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[N+:27]([C:30]1[C:31]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:32]([S:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36])([O-])=O>>[NH2:27][C:30]1[C:31]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:32]([S:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]
Reactant: O=C(O)c1cc(SCc2ccccn2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: Nc1cc(C(=O)O)cc(SCc2ccccn2)c1-c1ccccc1

Procedure:
By replacing in Example 1, step E, 3-benzylamino-5-nitro-4-phenylbenzoic acid with 5-nitro-4-phenyl-3-(2-pyridylmethylthio)benzoic acid, and following the procedure described, 5-amino-4-phenyl-3-(2-pyridylmethylthio)-benzoic acid is obtained with a melting point of 210°-211° C.
Reaction SMILES: B.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:16]([CH:20]([CH2:30][CH2:31][CH3:32])[C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:16]([CH:20]([CH:30]2[CH2:32][CH2:31]2)[C:21]2[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=2)[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCC(c1ccc(C(=O)O)cc1)N(CCC)c1nc(-c2ccc(Cl)cc2Cl)c(C)s1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CO)cc1)C1CC1
Reaction time: 8 h

Procedure:
2 ml of 1N borane solution in tetrahydrofuran are added, at -7° C., to 403 mg of the compound of Example 1 in 15 ml of anhydrous tetrahyrofuran, and the mixture is then left stirring overnight. 10 ml of water and 2 ml of methanol are then added in the presence of potassium carbonate. The reaction mixture is evaporated to dryness under vacuum.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH2:12]([N:19]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]([OH:28])=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH2:12]([N:19]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]([O:28][CH2:4][CH3:5])=[N:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(O)nn1Cc1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(C(=O)OC)n(Cc2ccccc2)n1
Temperature: 20 °C

Procedure:
5 mg of sodium iodide, 36 μl of bromoethane and 70 mg of potassium carbonate are added, at a temperature in the region of 20° C., to a solution of 100 mg of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in 1 ml of acetone. The reaction mixture is refluxed for 9 hours, cooled to a temperature in the region of 20° C. and filtered. The filtrate is concentrated under reduced pressure. 76 mg of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[OH-].[Na+].CN(C)C=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22]2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[CH:24][C:23]([C:26]([OH:12])=[O:27])=[CH:22]2)=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: O=Cc1ccn(-c2ccc(F)cc2)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
Potassium permanganate (13 g) and sodium hydroxide (6.6 g) were added to a solution of dimethylformamide (150 ml) and pyridine (130 ml), and 1-(4-fluorophenyl)-3-formylpyrrole (30 g) was added thereto under ice-cooling with stirring. The mixture was warmed to room temperature and stirred further for 3 h. The reaction mixture was filtrated and the filtrate was neutralized with hydrochloric acid. The precipitated crystals were recrystallized from hydrous ethanol to give 1-(4-fluorophenyl)pyrrole-3-carboxylic acid (9.2 g), melting point 204–205° C.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].C(OO)(=[O:22])C>>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])[S:3]([C:6]1[N+:7]([O-:22])=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CN(c1cccc(Cl)c1Cl)S(=O)(=O)c1ccccn1
Reactant: CC(=O)OO
Product: CN(c1cccc(Cl)c1Cl)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
N-methyl-N-(2,3-dichlorophenyl)-2-pyridinesulfonamide (1.7 g, 5.3 mmol) is treated with 40% peracetic acid (approx. 12 ml) at 35°-45° under N2 for 14 hours. The excess peracetic acid is removed under vacuum, and the residue is diluted with methylene chloride, poured into water, neutralized with aq. sodium bicarbonate, washed with brine, dried and evaporated to dryness to give, after purification, the title compound (compound 1, Table A).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[O:14][CH2:13][CH:12]([CH3:15])[NH:11][C:10]=12)=[O:4].ClS([N:22]=[C:23]=[O:24])(=O)=O.C(N(CC)CC)C>ClCCl>[F:17][C:7]1[CH:6]=[C:5]2[C:10]3[N:11]([CH:12]([CH3:15])[CH2:13][O:14][C:9]=3[C:8]=1[F:16])[C:23](=[O:24])[NH:22][C:3]2=[O:4]
Reactant: COC(=O)c1cc(F)c(F)c2c1NC(C)CO2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COc2c(F)c(F)cc3c(=O)[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
A solution of 1.5 g (6.2 mmol) of 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid methyl ester (Example 32a) in 25 mL of dichloromethane is cooled to −20° C. and treated dropwise with 0.92 g (6.5 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at room temperature for 18 hours and the solvent removed in vacuo. The residue is treated with a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer is dried (MgSO4), filtered, and concentrated in vacuo. The residue is dissolved in 50 mL of tetrahydrofuran, and the resulting solution is treated with 5.0 g (5.0 mmol) of triethylamine. After heating at reflux for 4 hours, the solvent is removed in vacuo, and the residue is triturated with 5 mL of dichloromethane/ethyl acetate (80:20). The insoluble material is removed by filtration, washed with the above solvent mixture (2 mL) to give 0.25 g of the title compound, mp 259–261° C. The filtrate is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethyl acetate (80:20) to give 0.38 g of starting material. Continued elution afforded an additional 0.2 g of the title compound. 1H NMR (400 MHz, CDCl3): 11.78 (s, 1H), 7.50 (m, 1H), 4.68 (m, 1H), 4.52 (d, 1H), 4.17 (d, 1H), 1.23 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)([O-:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:23]2[CH2:22][CH2:21][N:20]([C:3]3[C:4]4=[C:13]5[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]4)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]5=[CH:14][C:2]=3[F:1])[CH2:25][CH2:24]2)=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1CCc2c(N3CCNCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCc2c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 10 h
Yield: 60 %

Procedure:
A mixture of 9-fluoro-6,7-dihydro-5-methyl-8-(1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [III]), hydrochloride (1.1 g), p-nitrobenzyl bromide (Compound [IV]) (1.87 g) and triethylamine (1.46 g) in N,N-dimethylformamide (50 ml) was heated with stirring at 80°-90° C. for 10 hr. After evaporation of the solvent, water was added to the residue, and the aqueous mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from a mixture of N,N-dimethylformamide and ethanol (2:1) to give 0.83 g (yield: 60%) of 8-[4-(4-nitrobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [II]) as pale yellow needles, m.p. 230°-233° C. (decompd.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7](O)[CH2:8][CH3:9])[O:4][N:3]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:12][CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH2:8][CH3:9]
Reactant: CCC(O)c1cc(C)no1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Br)c1cc(C)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-methylisoxazol-5-yl)propan-1-ol (0.589 g, 4.17 mmol) in 15 mL of THF was added CBr4 (1.730 g, 5.22 mmol) and triphenylphosphine (1.423 g, 5.42 mmol). The reaction mixture was stirred at room temperature for 3 h. The solid was filtered off, and washed with THF. The filtrate was concentrated and residue was purified by chromatography on silica gel, eluting with 5 to 30% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=204.2 (M+1).
Reaction SMILES: [OH-].[K+].[C:3]([CH:5]([C:10]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C(OC)=O)#[N:4].O>C(O)CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2([CH2:5][C:3]#[N:4])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(C#N)C1(c2ccc(F)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: N#CCC1(c2ccc(F)cc2)CCOCC1
Temperature: 120 °C

Procedure:
To a pre-dissolved solution of KOH (441 mg, 7.87 mmol) in ethylene glycol (20 ml) was added methyl 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate (1.09 g, 3.93 mmol). The mixture was heated to 120° C. for 3 h, and then cooled. H2O was added (50 ml), the product extracted with Et2O (3×50 ml), washed with H2O (50 ml), dried over NA2SO4, filtered and concentrated. Purified by normal phase SiO2 chromatography (5 to 40% EtOAc/hexanes) to give 2-[4-(4-fluorophenyl)oxan-4-yl]acetonitrile as a colorless oil (450 mg, 78%, m/z: 219.1 [M+H]+ observed).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>C(#N)C>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C@H:35]([NH:34][C:14](=[O:16])[C@@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][CH:20]=2)=[O:11])[CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a solution of 1-(4-nitrobenzyloxycarbonyl)-L-proline (3.67 g) in anhydrous acetonitrile (50 ml), N,N-carbonyldiimidazole (1.86 g) was added at room temperature. After stirring for one hour, a solution of (3S)-3-amino-1(tert-butoxycarbonyl)pyrrolidine (1.86 g) in anhydrous acetonitrile (20 ml) was added to the reaction mixture under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure. To the residue, ethyl acetate was added. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate:dichloromethane=1:1), whereby 3.31 g of (3S)-1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)-L-prolylamino]pyrrolidine were obtained as a colorless amorphous substance.
Reaction SMILES: Cl.[CH:2]1([C:6]2[C:15]([C:16]3[NH:25][C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:18]=4[N:17]=3)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:26])[CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:29](C)=O.[Na+].C=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:2]1([C:6]2[C:15]([C:16]3[NH:17][C:18]4[CH2:24][CH2:23][N:22]([CH3:29])[CH2:21][CH2:20][C:19]=4[N:25]=3)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:26])[CH:7]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C2CCC2)cc1C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C)CC3)c(C2CCC2)cc1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of methyl 4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate hydrochloride (compound 82.7, 40 mg, 0.11 mmol), NaBH(OAc)3 (75 mg, 0.35 mmol), and formaldehyde (37 wt %) (26 μL, 0.33 mmol) in tetrahydrofuran (4 mL). The resulting mixture was stirred for 2 h at 40° C., then cooled and the pH of the solution was adjusted to 8-9 with sodium bicarbonate (sat.). The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 20 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29]>CC(C)=O>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([CH3:15])=[CH:14][C:9]=1[C:8](=[O:18])[NH:7][CH2:6][C:5]1[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][C:4]=1[F:21])[CH3:29]
Reactant: Cc1cc(C(=O)NCc2ccc(Br)cc2F)c(O)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 93 %

Procedure:
A stirring solution of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide (1.69 g, 4.76 mmol) in acetone (24 mL, 0.2 M) was treated with an aq K2CO3 solution (3.6 mL, 2 M, 7.12 mmol) and ethylbromoacetate (0.63 mL, 5.69 mmol) in acetone (24 mL, 0.2 M) and heated to 50° C. for 2.5 h. After cooling to room temperature, the solution was concentrated, acidified to pH 1 with 2 N HCl, and diluted with ethyl acetate (100 mL) and washed with 50 mL of saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to provide [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (1.95, 93%) as a white solid: mp 128–129° C.; Rf 0.42 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.79 (bd t, J=4.5 Hz, 1 H), 8.10 (d, J=9.0 Hz, 1 H), 7.34 (t, J=8.3 Hz, 1 H), 7.26–7.23 (m, 1 H), 7.21 (t, J=2.3 Hz, 1 H), 6.53 (d, J=10.5 Hz, 1 H), 4.66 (d, J=3.9 Hz, 1 H), 4.65 (s, 2 H), 4.28 (q, J=7.2 Hz, 2 H), 2.23 (bd d, J=1.5 Hz, 3 H), 1.30 (t, J=7.2 Hz, 3H); Anal. calcd for C19H18BrFNO4: C, 51.60; H, 4.10; N, 3.17. Found C, 51.65; H, 4.19; N, 3.10.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[CH2:9][N:8]([C:15]1[C:20]3[N:21]=[C:22]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)[N:23]=[C:24]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:19]=3[N:18]=[CH:17][N:16]=1)[CH2:7]C2>C(OCC)(=O)C.C1CCCCC1>[CH2:9]([N:8]([C:15]1[C:20]2[N:21]=[C:22]([N:31]3[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH2:36]3)[N:23]=[C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:19]=2[N:18]=[CH:17][N:16]=1)[CH3:7])[C:10]1[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=1
Reactant: COc1cc2c(cc1OC)CN(c1ncnc3c(N4CCOCC4)nc(N4CCC(=O)CC4)nc13)CC2
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCC(=O)CC3)nc12

Procedure:
8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-oxo-piperidin-1-yl) -4-morpholino-pyrimido[5,4-d]-pyrimidine Rf value: 0.09 (silica gel; ethyl acetate/cyclohexane =2:1)
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH2:37]([N:41]1[C:49]([N:50]2[CH2:55][CH2:54][NH:53][C@H:52]([CH3:56])[CH2:51]2)=[N:48][C:47]2[C:42]1=[N:43][C:44]([C:63]1[CH:64]=[N:65][C:66]([NH2:69])=[N:67][CH:68]=1)=[N:45][C:46]=2[N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1)[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl.CO.CN(C)C=O>[NH2:69][C:66]1[N:65]=[CH:64][C:63]([C:44]2[N:43]=[C:42]3[C:47]([N:48]=[C:49]([N:50]4[CH2:55][CH2:54][N:53]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[C@H:52]([CH3:56])[CH2:51]4)[N:41]3[CH2:37][CH:38]([CH3:39])[CH3:40])=[C:46]([N:57]3[CH2:62][CH2:61][O:60][CH2:59][CH2:58]3)[N:45]=2)=[CH:68][N:67]=1
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(N2CCN(C(=O)[C@H](C)O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 48 h
Yield: 49.4 %

Procedure:
L-Lactic acid (25.9 μl, 0.29 mmol), 1-hydroxybenzotriazole monohydrate (37.6 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (70.5 mg, 0.37 mmol), and triethylamine (51.3 μl, 0.37 mmol) were added to an N,N-dimethylformamide solution (2.0 ml) of 5-{9-isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (111.0 mg, 0.25 mmol) at room temperature. The resulting mixture was stirred for 2 days followed by the addition of L-lactic acid (25.9 μl, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (70.5 mg, 0.37 mmol), and triethylamine (51.3 μl, 0.37 mmol). The resulting mixture was stirred for 25 hours and the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride (3.0 ml) followed by the addition of L-lactic acid (25.9 μl, 0.29 mmol), 1-hydroxybenzotriazole monohydrate (37.6 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (70.5 mg, 0.37 mmol), and triethylamine (51.3 μl, 0.37 mmol) at room temperature. The resulting mixture was stirred for 18 hours and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (64.8 mg, 50%) as a pale yellow solid.