Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N-:4][N:3]=1.[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH2:27]Br)[C:20]([O:22][CH3:23])=[O:21]>CO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:27][C:26]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:16][CH3:15])[N:3]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[n-]c2c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(Cl)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 70 %

Procedure:
A mixture of 2.19 g. of sodium 3-chloro-6-nitroindazolide in 50 ml. methanol was stirred with 2.85 g methyl 3-methoxy-4-bromomethylbenzoate for 2 hours. After addition of 150 ml. water the resultant precipitate was collected and recrystallised from ethyl acetate to give methyl 4-[3-chloro-6-nitroindazol-1-yl-methyl]-3-methoxybenzoate in 70% yield as a solid, m.p. 167°-168° C. A mixture of 1.25 g. of this solid was hydrogenated in the presence of 385 mg. 5% w/w palladium on calcium carbonate in 20 ml. ethyl acetate and 20 ml. methanol for 3 hours at a pressure of 1.1 bar. The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated to low volume in vacuo and the residue (ca 3 ml.) was diluted with ether and petroleum ether (b.p. 40°-60° C.) and cooled to -20° C. The precipitated solid was collected and dried at 80° C. to give the ester L in 90% yield, m.p. 131°-131.5° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:18][C:17]([F:19])([F:20])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:12]=1)([OH:25])[C:21]([F:22])([F:24])[F:23]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 30.1 %

Procedure:
(R)-2-Methylpiperazine (37.9 mmol, 3.8 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (37.9 mmol, 12.79 g) and potassium carbonate (76 mmol, 10.49 g) were stirred at room temperature in acetonitrile (50 mL) overnight. The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 85/15/1.5 dichloromethane/methanol/ammonia) to afford the title compound (4.06 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[CH2:18]([C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:17]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31]3)[C:5]=2[CH:4]=1
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 67.9 %

Procedure:
Heat a suspension of 2-methyl-4H-3-thia4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (466 mg, 1.75 mmol) and 2-(S)-phenethyl-piperazine (1.0 g, 5.3 mmol) in DMSO (2.5 mL) and toluene (10 mL) at reflux for 48 hours. Evaporate the toluene under vacuo and pour the resulting solution into water (10 mL). Purify the resulting brown solid by flash chromatography eluting with methylene chloride/methanol (95:5) to give 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene as a yellow solid (478 mg, 65%): mp 75–84° C.; 1H NMR(CDCl3): δ1.76 (m, 2H), 2.31 (s, 3H), 2.60 (dd, 1H), 2.71 (m, 2H), 2.80 (m, 1H), 2.92 (m, 2H), 3.04 (m, 1H), 3.96 (m, 1H), 4.12 (m, 1H), 4.91 (s, 1H), 6.29 (s, 1H), 6.60 (d, 1H), 6.89 (t, 1H), 6.96 (t, 1H), 7.03 (d, 1H), 7.15–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 403 (100).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:15][C:3]=12.[Cl:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[N:26]([CH3:41])[C:27]([C:30]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]3)=[N:28][N:29]=1>>[ClH:20].[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][S:24][C:25]3[N:26]([CH3:41])[C:27]([C:30]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:31]=4[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]5)=[N:28][N:29]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[O:15][C:3]=12
Reactant: FC(F)(F)c1nc2cc3c(c(Br)c2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C(F)(F)F)oc6c(Br)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-bromo-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (58 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a colourless slightly hygroscopic solid (20 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][N:64]1[CH2:69][CH2:68][CH2:67][C:66]([CH2:78][OH:79])([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=2[F:77])[CH2:65]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:77][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=1[CH2:70][C:66]1([CH2:78][OH:79])[CH2:67][CH2:68][CH2:69][N:64]([NH:63][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:65]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NN1CCCC(CO)(Cc2ccccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN4CCCC(CO)(Cc5ccccc5F)C4)cc23)ccn1
Reaction time: 1 h

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (605 mg, 1.22 mmol), HATU (572 mg, 1.50 mmol) and (1-amino-3-(2-fluorobenzyl)piperidin-3-yl)methanol (258 mg, 0.94 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (0.819 mL, 4.7 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 h. Upon completion, the reaction was quenched with water (10 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:21]=[C:22]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]3[CH2:29][NH:28][CH2:27][CH2:26][C:24]=3[N:25]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.OCC=O.C([BH3-])#N.[Na+]>CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:21]=[C:22]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]3[CH2:29][N:28]([CH2:2][CH2:1][OH:4])[CH2:27][CH2:26][C:24]=3[N:25]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1
Reactant: COc1cc(Nc2nc3c(c(Nc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: CC(=O)O
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(c(Nc4ccccc4)n2)CN(CCO)CC3)ccc1-n1cnc(C)c1
Reaction time: 0.17 h
Yield: 381.7 %

Procedure:
Acetic acid (0.803 μL, 0.01 mmol) was added to a solution of N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (Example 7, 0.03 g, 0.07 mmol) and 2-hydroxyacetaldehyde (4.21 mg, 0.07 mmol) in MeOH (5 mL). The reaction mixture was stirred for 10 min and sodium cyanoborohydride (4.41 mg, 0.07 mmol) added. The reaction was stirred for an additional 15 min and solvent evaporated under reduced pressure. The crude product was dissolved in MeOH/DMSO and purified by preparative HPLC to give 2-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (0.018 g, 53.5%). MS (ESI+)/(ESI−) m/z 472/470
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH3:30])[C:4]=2[N:3]=1.[CH3:31][O-:32].[Na+]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:10]3[C:9]4[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH3:30])[C:4]=4[N:3]=[C:2]3[O:32][CH3:31])=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 8-chloro-7-[4-(4-chlorobenzoyl)-benzyl]-1,3-dimethylxanthine (866 mg) in DMF (40 ml) was added sodium methoxide (10 ml, 28% in methanol) and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as colorless powder (470 mg, 54%). 1H-NMR (CDCl3) δ: 3.40(3H,s), 3.54(3H,s), 4.17(3H,s), 5.36(2H,s), 7.38-7.78(8H,m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
To a solution of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone (15.3 g, 94.3 mmol) in N,N-dimethylformamide (150 mL) were serially added ethyl bromoacetate (16.5 g, 99.0 mmol) and potassium carbonate (13.7 g, 99.0 mmol) and the mixture was stirred at 60° C. for 6 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to provide 19.5 g of the title compound. Yield 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:21][C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[C:26]2[CH:31]=[C:30]([NH:32][C:33]3[NH:34][CH2:35][CH:36]([OH:39])[CH2:37][N:38]=3)[CH:29]=[C:28]([OH:40])[CH:27]=2)[CH2:15][C:16]([O:18]CC)=[O:17])[CH:5]=[C:6]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:21][C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[C:26]2[CH:31]=[C:30]([NH:32][C:33]3[NH:38][CH2:37][CH:36]([OH:39])[CH2:35][N:34]=3)[CH:29]=[C:28]([OH:40])[CH:27]=2)[CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: N#CC1(c2cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c3cc(O)cc(NC4=NCC(O)CN4)c3)c2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (1.006 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (212 mg, 5.052 mmol) and the reaction mixture was stirred at room temperature overnight (16 h). The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The DCM layer was removed and discarded after analyzed by LC-MS, shows the DIPU, byproducts and baseline impurities only. The aqueous layer was acidified with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA. The pure fractions were mixed together and evaporated in vacuo to give the desired product, after lyophilization, as a colorless lyophilized powder (305 mg). LC-MS analysis of the solid shows the desired product: (3S)-3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 569 (35ClM+H) and m/z 571 (37ClM+H); Calcd for C27H29ClN6O6: 569.01
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C@H:32]([C:39]([NH:41][C@H:42]([CH:47]=[N:48][NH:49][C:50]([NH2:52])=[O:51])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1.CN1CCOCC1>CN(C)C=O.ClCCl>[CH2:12]([CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:31][C@H:32]([C:39]([NH:41][C@H:42]([CH:47]=[N:48][NH:49][C:50]([NH2:52])=[O:51])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A mixture of 240 mg of 2-benzyl-3-phenylpropionic acid and 170 mg of 1,1'-carbonyldiimidazole was added to 10 ml of dry dichloromethane, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was added to a solution of 650 mg of L-histidyl-L-leucinal semicarbazone.2p-toluenesulfonic acid salt and 200 mg of N-methylmorpholine in 10 ml of dry N,N-dimethylformamide, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol=10/1 by volume) to obtain 162 mg of N-(2-benzyl-3-phenylpropionyl)-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=1>CN(C=O)C>[CH3:29][C:22]1[CH:21]=[C:20]([CH:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[C:3]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 175.6 %

Procedure:
Sodium Hydride (19.09 g, 477 mmol) was added portionwise over 30 minutes to an ice cooled solution of ethyl phenylmethyl propanedioate (115 ml, 477 mmol) in DMF (500 ml). Upon complete addition, the reaction was allowed to warm to room temperature. After stirring for 30 minutes, a solution of 4-fluoro-2-methyl-1-nitrobenzene (30 ml, 239 mmol) in DMF (250 ml) was added, the reaction heated to 100° C. and stirred at this temperature for 16 hours under an atmosphere of argon. The reaction was then left to stand at room temperature for 72 hours. The reaction was quenched with concentrated HCl (˜100 ml) with stirring and cooling (ice bath), diluted with ethyl acetate (2 L), washed with water (3×2 L), brine (1 L), dried over sodium sulfate, filtered and concentrated to give a dark yellow oil (˜150 g). Purification was by silica chromatography, 1500 g cartridge, sample loaded as a toluene solution to the pre-conditioned column). A gradient of 0 to 5% acetone in pentane eluted the higher running component, this was followed by a gradient of 5 to 15% acetone in isohexane to elute the excess benzyl ethyl malonate and required product. Product-containing fractions were concentrated to give the title compound as a pale yellow oil (71.21 g). MS (ES−) [C19H19NO6—H]− 356. 1H-NMR (400 MHz, d6-DMSO) δ 1.14 (3H, t, J 7), 2.50 (3H, s), 4.01-4.21 (2H, m), 5.14-5.25 (2H, m), 5.27 (1H, s), 7.28-7.49 (7H, m), 8.00 (1H, d, J 8)
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Br[Mg]C1CCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCC1
Temperature: 25 °C

Procedure:
A solution of cyclopentyl magnesium bromide in ether (2.0 M, 12.5 mL, 25 mmol) (Aldrich) was added dropwise to a suspension of 6-chloroisatin (1.82 g, 10 mmol) (prepared according to the procedure of Kraynack, E. A. et al., supra) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 1 hour, 15% aqueous ammonium chloride solution (50 mL) was added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 30 minutes and filtered to give crude rac-6-chloro-3-cyclopentyl-3-hydroxy-1,3-dihydro-indol-2-one as a white powder. (Yield 0.62 g, 24.6%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([CH3:28])[O:27][CH2:26][CH2:25][NH:24][CH2:23]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:24]3[CH2:25][CH2:26][O:27][C:22]([CH3:28])([CH3:21])[CH2:23]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1c(CCN2CCOC(C)(C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (116 mg, 0.39 mmol) in DCE (10 mL) was added 2,2-dimethylmorpholine (68 mg, 0.59 mmol), trimethyl orthoformate (0.22 mL, 1.96 mmol) and acetic acid (0.02 mL, 0.39 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (125 mg, 0.59 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give the title compound as a pale yellow solid (100 mg, 65%). LCMS (Method H): RT=2.51 min, [M+H]+ 395.4
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.O[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][O:11][C:23]2[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(/c1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 0 °C

Procedure:
The above allyl alcohol (0.77 g, 2.16 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.47 g, 2.37 mmol) and triphenylphosphine (0.68 g, 2.59 mmol) were dissolved in a mixture of anhydrous toluene (10 mL) and tetrahydrofuran (3 mL). The mixture was degassed, cooled to 0° C. and a degassed solution of diisopropyl azodicarboxylate (0.525 g, 2.60 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise under nitrogen. The reaction mixture was stirred at ambient temperature over night. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95: 5-90:10) affording methyl (E)-[4-[3-(4-bromophenyl)-3-[4-trifluoromethylphenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[N:19]1([CH2:24][CH2:25][N:26]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[N:19]1([CH2:24][CH2:25][N:26]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:27]([CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:33])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(CCCCCl)N(CCN1CCCC1)CC1CCCCC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCOc1ccc2[nH]c(=O)ccc2c1)N(CCN1CCCC1)CC1CCCCC1
Yield: 10.3 %

Procedure:
To 50 ml of dimethylformamide are added 1.73 g of 6-hydroxycarbostyril, 1.8 g of K2CO3 and 0.5 g of KI. To this mixture being stirred at 60°-70° C. is dropwise added 4.2 g of N-[2-(1-pyrrolidinyl)ethyl]-N-(5-chloropentanoyl)-cyclohexylmethylamine. Then, the mixture is stirred for 4 hours at the same temperature. The solvent is removed by evaporation. The residue is dissolved in 200 ml of chloroform and the solution is washed with diluted hydrochloric acid, a 1% aqueous sodium hydroxide solution and water in this order, and dried with anhydrous magnesium sulfate. The desiccant is removed by filtration and the filtrate is concentrated. The residue is purified by means of a silica gel column chromatography (eluent; chloroform:methanol=20:1) and recrystallized from diethyl ether to obtain 0.5 g of 6-[4-{N-[2-(1-pyrrolidinyl)ethyl]-N-cyclohexylmethylaminocarbonyl}-butoxy]carbostyril.