Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC(C(OCC)=O)C1.[F:31]C1C=CC(C(Cl)=O)=CC=1>>[F:31][C:5]1[CH:4]=[CH:3][C:2]([C:1]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl nipecotate (230.9 mg; 1.47 mmol) and commercially available 4-fluorobenzoyl chloride (173 μl; 1.47 mmol). The crude product was distilled at 220° C./0.1 torr, giving ethyl 1-(4-fluorobenzoyl)-3-piperidinecarboxylate (283.4 mg) as a light yellow oil. MS m/z (positive ion) 581 (dimer+Na+; 50), 302 (M+Na+; 100), 280 (MH+; 95), 234 (45), 229 (25), 158 (50), 122.5 (60).
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[OH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][CH:2]([F:6])[C:3]([F:5])([F:4])[O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12][CH:13]=1
Reactant: FC(F)=C(F)Cl
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(OC(F)(F)C(F)Cl)cn2)cc1

Procedure:
26 liters of chlorotrifluoroethene were introduced from a gas burette into a gas-tight stirred apparatus containing a mixture of 244 g (1.0 mol) of 5-hydroxy-2-(4-nitrophenylazo)pyridine, 138 g (1.0 mol) of potassium carbonate and 2 liters of dry DMF. The mixture was filtered through Celite, and the solid was washed with 1 liter of acetone. The solvent was removed from the filtrate by evaporation on a rotary evaporator. The residue was taken up in 2.5 liters of ethyl acetate and washed four times with 500 ml of saturated sodium chloride solution in each case.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].CN(C=O)C.CCN=C=NCCCN(C)C.Cl>O>[C:21]([CH2:23][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:6][CH:7]=1)=[O:25])#[N:22]
Reactant: COC(=O)c1ccc(CCCc2ccc(N)cc2)cc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a mixture of 16.0 g of methyl 4-[3-(4-aminophenyl)propyl]benzoate, 7.70 g of cyanoacetic acid, and 50 mL of DMF was added 17.1 g of EDCI/hydrochloride under ice-cooling. After stirring at room temperature for 18 hours, to the reaction mixture was added 200 mL of water at room temperature. After vigorous stirring at room temperature for 30 minutes, the precipitate was collected by filtration to obtain 19.3 g of methyl 4-(3-{4-[(cyanoacetyl)amino]phenyl}propyl)benzoate as a beige solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=1)[CH3:2].[CH3:17][O:18][C:19](=[O:36])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([S:30][CH2:31][CH2:32][CH:33]=O)=[CH:24][C:23]=1[CH3:35]>>[CH3:17][O:18][C:19](=[O:36])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([S:30][CH2:31][CH2:32][CH2:33][N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:6][N:5]=2)=[CH:24][C:23]=1[CH3:35]
Reactant: CCNc1ccc(-c2ccc(F)cc2)cn1
Reactant: COC(=O)COc1cc(OC)c(SCCC=O)cc1C
Product: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccc(F)cc2)cn1

Procedure:
Compound 70B and Compound 64A were reacted in a manner analogous to Compound 63C to give the title product. MS m/z 499 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C-:35]#[N:36].[Na+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:35]#[N:36])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1ccc(CN(CCCCCCC#N)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 86.8 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1[6-[(methylsulfonyl)oxy]hexyl]urea, 0.5 g of sodium cyanide, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-70° C. for 16 hours. The mixture was poured into water and extracted with dichloromethane. The procedure of Example 518 was continued and gave 1.5 g (88% yield) of the desired product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.ClC1C=CC2C(N3CCNCC3)C3=NC=CC=C3CCC=2C=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:47]=1.N1C=CC(CC(O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:53](=[O:54])[CH2:52][C:48]4[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12
Reactant: Clc1ccc2c(c1)CCc1c(Cl)ccnc1C2N1CCNCC1
Reactant: O=C(O)Cc1cccnc1
Agent: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: O=C(O)Cc1ccncc1
Product: O=C(Cc1cccnc1)N1CCN(C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Yield: 88.8 %

Procedure:
By substituting in Example 75, 4,8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (0.3 g, 0.86 mmoles) (Preparative Example 41) for 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 3-pyridylacetic acid (0.1181 g, 0.86 mmoles) for 4-pyridylacetic acid and using the method described in Example 75, one obtains the title compound (0.357 g, 88%, MH+ 467).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].I[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl carbamate 155 (300 mg, 1.10 mmol) in THF (5 mL) at 0° C. is added sodium hydride (53 mg, 1.32 mmol, 60% dispersion in mineral oil) in one portion. After stirring 15 minutes, iodomethane is added (82 μL, 1.32 mmol) and the reaction mixture warmed to RT and stirred 16 h. The reaction is then quenched with 5% citric acid (10 mL) and extracted into EtOAc (2×10 mL). The combined organic phases are dried over Na2SO4 and purified by column chromatography (70% EtOAc in heptane) to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)OC2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1OCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A solution of 6-methoxy-3H-isobenzofuran-1-one (50 g, 0.3 moles), prepared as described in example 34, in CH2Cl2 (250 ml) under N2 at −5° C., was dropwise added with BBr3 (360 ml 0.36 moles). At the end of the addition the solution was stirred at room temperature overnight, then cooled and added with further BBr3 (60 ml, 60 mmoles). The stirring was kept on for 4 hours at room temperature. The mixture was cooled and added with CH3OH (250 ml), then dried under vacuum to give a solid which was triturated in ethyl ether and washed with ethyl ether and ethyl acetate. After drying under vacuum at 40° C. a solid was obtained which was joined to the solid yielded by drying the mother liquors, discolouring and triturating in ethyl ether. There were obtained 33.51 g of the title compound (yield: 73%).
Reaction SMILES: [OH:1][CH:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4](=O)[O:3]1.S(Cl)([Cl:12])=O>>[Cl:12][CH:4]1[C:5]([CH3:8])=[C:6]([CH3:7])[C:2](=[O:1])[O:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1=C(C)C(O)OC1=O
Product: CC1=C(C)C(Cl)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.6g of 2-hydroxy-3,4-dimethyl-5-oxo-2,5-dihydrofuran and 10 ml of thionyl chloride was stirred for 2 hours at room temperature. By concentrating the reaction mixture under reduced pressure, 7.5g of light-yellowish oily 2-chloro-3,4-dimethyl-5-oxo-2,5-dihydrofuran was obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.[CH3:28][CH2:29][CH2:30]C1C2C3OC(C)(C)C=CC=3C3OC(C)C(C)C(O)C=3C=2OC(=O)C=1>CO.O=[Pt]=O>[CH3:20][C@@H:16]1[C@H:15]([OH:21])[C:14]2[C:9]3[O:8][C:6]([CH:5]=[C:4]([C:3]4[CH:28]=[CH:29][CH:30]=[CH:1][CH:2]=4)[C:10]=3[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]=2[O:18][C@H:17]1[CH3:19])=[O:7]
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)CC4)O[C@@H](C)[C@H](C)[C@@H]3O
Agent: O=[Pt]=O
Solvent: CO
Product: C[C@H]1[C@H](C)Oc2c3c(c4c(-c5ccccc5)cc(=O)oc4c2[C@H]1O)OC(C)(C)C=C3

Procedure:
This example illustrates the preparation of antiviral 7,8-dihydro compounds (FIG. 6) of series 2, specifically 7,8-dihydrocalanolide A, 7,8-dihydrocalanolide B, 7,8-dihydro-costatolide, and 7,8-dihydrosoulattrolide from the corresponding 7,8-unsaturated compounds of series 1. Of these six compounds, only one structure (7,8-dihydrocostatolide; Stout, G. H., et al., J. Org. Chem., 29, 3604-3609 (1964)) had been previously reported, however none of the six were known heretofore to have antiviral activity. The 7,8-dihydro compounds were made by catalytic hydrogenation of the selected appropriate 7,8-unsaturated precursors. In a typical procedure, 10 mg of calanolide A was stirred with 2.5 mg PtO2 (Aldrich) in 4 ml MeOH under an atmosphere of H2 (a balloon filled with H2 was attached to the reaction vessel to provide a slightly positive pressure of H2) for 30 min. The mixture was filtered, and the solvent removed in vacuo to provide a light yellow oil which was purified by SiO2HPLC (21.1×300 mm, Dynamax column) eluted with 25 ml/min hexane/EtOAc (7:3) to give 9.0 mg of 7,8-dihydrocalanolide A (EIMS m/z 372, appropriate for C22H28O5 ; 1H NMR, see Table 5). In an exactly analogous fashion, 6 mg of calanolide B with 3 mg PtO2 in 4 ml MeOH was converted to 3.6 mg of 7,8-dihydrocalanolide B (EIMS m/z 372, appropriate for C22H28O5 ; 1H NMR, see Table 5); 100 mg of costatolide with 15 mg PtO2 in 20 ml MeOH was converted to 89.9 mg 7,8-dihydrocostatolide (EIMS m/z 372, appropriate for C22H28O5 ; 1H NMR, see Table 5); and 12 mg of soulattrolide with 3 mg PtO2 in 4 ml MeOH was converted to 8.9 mg 7,8-dihydrosoulattrolide (EIMS m/z 406, appropriate for C25H26O5 ; 1H NMR, see Table 5).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[O:39]1CCCC1>>[C:1]1([C@H:7]([OH:39])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: C1CCOC1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Product: O[C@H](CCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1,3-diphenylpropanone (1.07 g; 5.09 mmol) in tetrahydrofuran (10 mL) was cooled to −23° C. and treated with an asymmetric reducing agent, (+)-B-chlorodiisopinocampheyl-borane (1.80 g; 5.60 mmol) in 20 mL THF, and the resulting solution was allowed to stand overnight at −23° C. After evaporating to dryness, the residue was treated with ether (65 mL) and diethanolamine (1.0 g) and stirred for 3 hrs. The mixture was then filtered to remove solids and concentrated, and the residue was purified using gradient elution (5% ethyl acetate/hexane to 10% ethyl acetate) on a silica gel column to obtain 660 mg (61%) of (1R)1,3-diphenyl-1-propanol as a crystalline white solid, 1HNMR (360 MHz, CDCl3): d 1.95-2.15 (m, 3H); 2.59-2.78 (m, 2H); 4.65 (dd, 1H, J=5.4, 7.8); 7.14-7.35 (m, 10H).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1)[CH3:13]
Reactant: O=C1CCC2CCC(=O)N12
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCC1CCC(=O)N1

Procedure:
Twenty-eight grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 100 g of ethyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at reflux for 104 hours. The mixture is cooled and excess ethyl alcohol is distilled at reduced pressure. The oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from carbon tetrachloride-petroleum ether yields 5-oxo-2-pyrrolidinepropanoic acid ethyl ester with a melting point of 60°-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:15])[CH3:14])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:14])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CC(C)N(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)N(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isopropyl-pyrrolidin-3-yl-amine (0.68 mmol, 1.7 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol, 2 eq) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.4 mmol, 1.0 eq) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.85 (6H, d), 1.50–1.90 (10H, m), 2.10–2.60 (8H, m), 3.50 (3H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.10–7.40 (8H, m), 7.50 (1H, d), 8.50 (1H, dd). ESI-MS m/z: 546 (M+1), UV retention time: 1.40 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC(C)CN
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC(C)C

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with isobutylamine following general procedure B to afford 4-isobutylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (280 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.6 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-1-isobutyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (22 mg). LCMS: m/z 328 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:17])[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1

Procedure:
The product from Example 59B (1.37 g, 6 mmol) was suspended in CH2Cl2 (100 mL), treated with TsCl (2.28 g, 12 mmol), treated with 4-dimethylaminopyridine (100 mg, 0.82 mmol), treated with triethylamine (2.2 mL. 16 mmol), and heated at reflux for 4 hours. The mixture was washed with H2O, dried (MgSO4), concentrated under reduced pressure and chromatographed on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound. 1H NMR (DMSO-d6) δ 1.99 (t, J=6.95 Hz, 2H), 2.23 (t, J=6.95 Hz, 2H), 2.45 (s, 3H), 2.47 (m, 2H), 6.91 (bs, 2H), 7.31 (m, 1H), 7.4 (m, 2H), 7.55 (dd, J=7.29, 1.87 Hz, 1H), 7.5 (d, J=8.48 Hz, 2H), 8.03 (d, J=8.14 Hz, 2H). MS (M+H)+ m/z 382.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[C:34]([CH3:40])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)([C:27]3[N:31]([CH3:32])[N:30]=[N:29][CH:28]=3)[OH:26])[CH:8]=2)[N:3]=1.[NH:41]1[CH2:44][CH2:43][CH2:42]1.CN(C=O)C>CCOC(C)=O>[N:41]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([Cl:24])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]4[C:34]([CH3:40])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=4)([C:27]4[N:31]([CH3:32])[N:30]=[N:29][CH:28]=4)[OH:26])[CH:8]=3)[N:3]=2)[CH2:44][CH2:43][CH2:42]1
Reactant: C1CNC1
Reactant: Cc1ccc(C(O)(c2ccc3nc(Cl)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccc3nc(N4CCC4)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (198 mg, 0.347 mmol, Example 151), azetidine (70 μL, 1.04 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The residue was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C33H31ClN8O, 590.2. m/z found, 591.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.07-8.02 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.38-7.31 (m, 1H), 7.08-6.99 (m, 4H), 6.98 (s, 1H), 6.88-6.77 (m, 2H), 5.89 (d, J=1.9 Hz, 1H), 4.29 (s, 2H), 4.12 (t, J=7.5 Hz, 4H), 3.93 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 2.31-2.18 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH:11]1([C:15]2[N:23]3[C:18](C(=O)NC=N3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[CH:11]1([C:15]2[N:23]3[C:18]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: c1nc[nH]n1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncnn2c(C3CCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrous pyridine (10 mL) was added phosphorus oxychloride (POCl3) (0.578 mL, 6.20 mmol) and stirred at rt for 15 min. This mixture was dropwise charged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3H imidazo[5,1-f][1,2,4]triazin-4-one (0.653 mg 2.07 mmol) in anhydrous pyridine (14 ml) and stirred for 1.5 h. The reaction mixture was cooled to 0° C. quenched with 2M NH3 in isopropanol (IPA) until basic then allowed to reach rt and stirred for an additional 2 h. The reaction mixture was filtered through a fritted Buchner funnel and washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography on silica gel [eluting with 30% EtOAc in DCM] resulting in the title compound as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m, 2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4](Cl)=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][C:3]1[C:4]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: Clc1ncncc1Br
Reactant: NC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(c2ncncc2Br)CC1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-4-chloropyrimidine hydrochloride 21 (0.10 g, 0.36 mmol) in DMF (2 mL) was added triethylamine (0.51 mL, 3.6 mmol). After stirring for 30 min, a solution of isonipecotamide (0.14 g, 1.1 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (60 mg, 58%), m.p. 188-190° C.; umax (CHCl3)/cm−1 3012, 2853, 1682, 1566, 1447, 1359, 1144, 1017, 950; m/z (ESI) C10H14BrN4O requires 285.0346, found [M+H]+ 285.0344.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(O[C:25]([CH3:28])([CH3:27])[CH3:26])(=O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O.C(OCC)(=O)C>[C:1]([NH:11][C@H:12]([C:18]([O:20][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 25 g of Nα-CBZ-L-lysine from Sigma, where CBZ is benzyloxycarbonyl, 250 mL of t-butyl acetate and 14 mL of 70% perchloric acid was vigorously mixed until all solids were dissolved. After stirring overnight, 375 mL of ethyl acetate was added followed by 250 mL of water. The pH of the aqueous layer was raised to 5.5 with 20% NaOH whereupon the organic phase was separated. The aqueous phase was extracted with the ethyl acetate solution and the pH again raised to 10.5 whereupon it was again extracted with 200 mL of fresh ethyl acetate. The organic extracts were combined, washed with saturated brine, dried over Na2SO4 and concentrated. The residue was dried overnight under high vacuum to yield 23.2 g of a colorless, viscous material.