Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[CH:31]([Mg]Cl)([CH3:33])[CH3:32]>C1COCC1>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:24][CH2:25][C:26]([OH:29])([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:28]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCC(=O)CC3)nncc2c1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCC(O)(C(C)C)CC3)nncc2c1
Temperature: -78 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-(4-oxopiperidin-1-yl)phthalazin-6-yl)benzamide (100 mg, 250 μmol) (Method A, followed by deprotection of the ketal) in 5 mL THF was stirred at −78° C. and treated with isopropylmagnesium chloride (250 μl, 499 μmol). The mixture was stirred at −78° C. warming to RT over 4 h. The mixture was quenched with 5 mL sat NH4Cl and extracted with dichloromethane (3×50 mL). The combined organics were dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel chromatography eluting with 1-5% 2M ammonia methanol/dichloromethane to give the title compound. Found MS (ES+): 445(M+H)+.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)=[CH:28][CH:27]=2)[CH3:25])C(=O)OC(C)(C)C)[N:11]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)=[CH:28][CH:27]=2)[CH3:25])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(-c3cnn(C)c3)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(-c3cnn(C)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl 4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (45 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then was concentrated and diluted with DCM (10 mL). The solution was washed with saturated NaHCO3 solution and brine. After separation, the aqueous phase was extracted with DCM (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give (S)-4-isopropyl-3-(2-(((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid (35 mg, 97% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18](Br)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>CCO.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Temperature: 80 °C

Procedure:
3-benzyl-2-(1-bromopropyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-3, 0.080 g, 0.23 mmol) was dissolved in EtOH (2.0 mL) and treated with N,N-dimethyl ethylenediamine (0.05 mL, 0.46 mmol). The reaction was heated to 80° C. for 24 hours. The reaction was diluted with EtOAc (10 mL), washed with 5% NH4Cl, and dried over MgSO4. The organics were concentrated under reduced pressure to provide 3-benzyl-2-(1-{[2-(dimethylamino)-ethyl]amino}propyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-4). MS 355.1 found 354.5 required.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:37]=[C:38]([C:42](=[O:44])[CH3:43])[CH:39]=[CH:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[C:42]([C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27])(=[O:44])[CH3:43]
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-[3-(bromomethyl)phenyl]ethanone (0.73 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (1.02 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:26]1C(C)=NC=CC=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[C:19]([CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Reactant: Cc1ncccc1Br
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2C)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=334.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:18][CH:17]=2)[OH:15])=[CH:7][CH:8]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1
Solvent: CO
Product: CCN(CC)CCOc1ccc(C(O)c2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1
Yield: 75 %

Procedure:
1.420 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzofuran-3-yl][4-[2-diethylaminoethoxy]phenyl] methanone was reduced to the carbinol by the method described in Example 1. This yielded 1.07 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9](=O)[NH:10][C@@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]=2[O:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:23][C:9]1[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:10]=1
Reactant: COC(=O)C[C@@H]1NC(=O)c2ccccc2-c2c(C)noc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C[C@@H]1N=C(Cl)c2ccccc2-c2c(C)noc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of methyl 2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.4754 g, 1.661 mmol) in CH2Cl2 (4 mL) was added phosphorus pentachloride (0.432 g, 2.075 mmol). The reaction mixture was stirred at room temperature for 1 h. To the mixture was added aqueous 10% Na2CO3 and stirred vigorously for 15 min. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated to give yellow foam after drying. The foam was filtered over a plug of silica and eluted with 20% EtOAc:80% Hexanes. The product methyl 2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.4701 g, 1.543 mmol, 93% yield) was obtained as a white foam. LC/MS m/z 305 [M+H]+.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12].C(N(CC)CC)C>C(O)C>[C:4]1([CH2:3][CH2:2][C:1](=[O:10])[CH2:12][CH2:11][C:13](=[O:14])[CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: C=CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)CCc1ccccc1

Procedure:
67.1 g (0.5 mol) of hydrocinnamaldehyde, 35.1 g (0.5 mol) of methyl vinyl ketone, 13.5 g (0.05 mol) of Cat. 1, 20.2 g (0.2 mol) of triethylamine and 500 ml of ethanol are brought together, in the manner described in Example 1. The product is worked up as described in Example 21. Fractional distillation gives 1-phenyl-heptane-3,6-dione.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:9]=1[O:10][CH2:11][C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:13]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)COc1cc(Cl)c(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(COc1cc(Cl)c(Cl)cc1Cl)Nc1ccccn1

Procedure:
After filling in a dry 250 ml flask respectively 150 ml of anhydrous benzene and 32.5 g (0.118 mol) of 2,4,5-trichlorophenoxyacetyl chloride synthesized in Example 14, 11 g (0.118 mol) of 2-aminopyridine was added with vigorous stirring, and then 8.1 ml of triethylamine was slowly dropped to be heated and refluxed for 2-3 hours, while the external temperature was maintained at 80°-90° C.
Reaction SMILES: [CH3:1][C:2]1([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:20][CH2:19]2)=O)[O:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[CH3:1][C:2]1([CH2:16][N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:22][CH2:23]2)[O:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12
Reactant: CC1(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)OCc2ccccc2-n2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)OCc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3.0 g of 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl}-2H-benzimidazol-2-one in 120 ml of tetrahydrofuran is added 700 mg of lithium aluminum hydride. The reaction mixture is then heated at reflux temperature for 6 hours followed by stirring at room temperature for 18 hours. The reaction mixture is diluted with 150 ml of ether and the excess lithium aluminum hydride destroyed in the usual manner described below. The resulting granular precipitate is removed by filtration. The organic phase is washed with 150 ml of dilute sodium hydroxide and then 150 ml of brine. The organic extracts are then dried over magnesium sulfate, filtered and solvent evaporated under reduced pressure to yield 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-benzimidazol-2-one, m.p. 199°-201°, the compound of formula II wherein R1 and R5 =H, and R2 =CH3 and n=1.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:31][CH:30]=1>C(Cl)Cl.CO>[CH3:41][N:40]([CH3:42])[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:43])=[O:39]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)nc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(=O)N(C)C)cn3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide (Step 119.1), stirring the reaction mixture for 72 h at rt. The title compound: ESI-MS: 583.0 [M+H]+; tR=4.02 min (System 1); TLC: Rf=0.36 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](OS(C)(=O)=O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 13a, 6.1 g, 21.2 mmol) and triethylamine (8.9 mL, 63.5 mmol) in methylene chloride (75 mL) at 0° C. was added methanesulfonyl chloride (2.4 mL, 31.8 mmol). The resulting solution was warmed to room temperature and stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with 1N HCl (150 mL) and diluted with water (100 mL). The layers were cut and the organic layer was washed with 1N HCl (2×100 mL), a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford 7.8 g (99%) of (S)-5-(3-methanesulfonyloxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as an orange foam. This material was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=2.0 Hz), 5.15-5.17 (m, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.43-3.60 (m, 3H), 3.30-3.37 (m, 1H), 2.94 (s, 3H), 2.17-2.23 (m, 1H), 2.09-2.16 (m, 1H). mp 79-81° C. Anal. Calcd. for C12H18N2O7S2: C, 39.34; H, 4.95; N, 7.65; S, 17.50. Found: C, 39.20; H, 5.00; N, 7.56; S, 17.66.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([Cl:26])[C:16]=2[N:15]=[CH:14]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([Cl:26])[C:16]=2[N:15]=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c(Cl)nc3ccccc3c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCn1cnc2c(Cl)nc3ccccc3c21
Yield: 61.4 %

Procedure:
0.10 g (0.267 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-4-chloro-1H-imidazo-[4,5-c]quinoline was dissolved in 6 ml of methylene chloride. 0.21 ml (2.67 mmol) of trifluoroacetic acid was added thereto and the mixture was concentrated under reduced pressure. 2 ml of a 1N sodium hydroxide aqueous solution and brine were added to the residue and the mixture was extracted five times with chloroform. The extract was dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with diethyl ether (containing a small amount of methylene chloride) and the precipitate thus formed was collected by filtration to obtain 45 mg (0.164 mmol) of 1-(4-aminobutyl)-4-chloro-1H-imidazo[4,5-c]quinoline (shown below) as pale orange powder. ##STR44## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3400, 2950, 1670, 1520, 1360.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10](=[O:69])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](=[O:68])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:67]=[CH:66][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][C:59]([O:61]C(C)(C)C)=[O:60])=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10](=[O:69])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](=[O:68])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])=[CH:40][CH:39]=2)=[O:37])=[CH:66][CH:67]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Reaction time: 1 h
Yield: 116 %

Procedure:
tert-butyl 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (7.36 g, 7.85 mmol) was dissolved in a solution of DCM:TFA (2:1, 50 ml) and left to stir for ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on oil pump overnight to yield 8.35 g of crude 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid as yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH2:30][C@H:31]([OH:36])[C@@H:32]([OH:35])[CH2:33][NH2:34]>>[NH2:29][CH2:30][CH:31]([OH:36])[CH:32]([OH:35])[CH2:33][NH:34][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][CH3:27])[C:14](=[O:28])[N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[CH2:22][C:21]2=[CH:20][N:19]=1
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: NC[C@H](O)[C@@H](O)CN
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NCC(O)C(O)CN)nc21
Yield: 42.7 %

Procedure:
7-(4-Amino-2,3-dihydroxy-butylamino)-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.5 g (1.2 mmol) 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.433 g (3.6 mmol) (S,S)-1,4-diamino-butane-2,3-diol. The final product was purified by column chromatography (40:6:1 dichloromethane/methanol/sat. aqueous ammonium hydroxide solution) which gave 0.24 g (43%) of the final product as a white solid: mp 115° C. (dec.); MS (APCI) m/z 469.1, 470.2.
Reaction SMILES: C([C:3]1[N:7]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30]N)[CH3:26]>O>[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][NH:11][C:9](=[O:10])[CH:8]([CH3:12])[N:7]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6]1)[CH3:26]
Reactant: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1C(C)C(N)=O
Reactant: CCN(CC)CCCN
Solvent: O
Product: CCN(CC)CCCNC(=O)C(C)n1cc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A mixture of 27.3 g (0.085 mol) of ethyl 3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide of example 9 and 120 mL of 3-(diethylamino)propanamine was heated 5 hr on a steambath. The reaction was poured into water and extracted into ethyl acetate. The ethyl acetate layer was dried and stripped to an oil in which a solid slowly crystallized. The crystals were removed and recrystallized from cyclohexane to yield 6.2 g of N-[3-(diethylamino)propyl]-3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide, mp 87°-89° C.
Reaction SMILES: CON(C)[C:4](=[O:23])[CH2:5][CH:6]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[H-].[CH2:28]1COC[CH2:29]1>>[O:23]=[C:4]([CH2:28][CH3:29])[CH2:5][CH:6]([P:15]([O:20][CH2:21][CH3:22])(=[O:16])[O:17][CH2:18][CH3:19])[P:7]([O:9][CH2:10][CH3:11])(=[O:8])[O:12][CH2:13][CH3:14]
Reactant: CCOP(=O)(OCC)C(CC(=O)N(C)OC)P(=O)(OCC)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOP(=O)(OCC)C(CC(=O)CC)P(=O)(OCC)OCC
Temperature: -78 °C
Yield: 54 %

Procedure:
A solution of N-methoxy-N-methyl-3,3-bis(diethoxyphosphinyl)propionamide (1.00 g, 2.6 mmol) in THF (5 ml) was slowly added to a slurry of 80% sodium hydride (80 mg, 2.7 mmol) in THF (10 ml) at 0° C. Stirring was continued until all of the hydride was consumed (~20 minutes). The solution was cooled to -78° C. and ethylmagnesium bromide (1.0 ml of a 3.0M solution in diethyl ether, 3.0 mmol) was added. After the addition, the reaction mixture was warmed to 0° C. and stirred for one hour. The reaction was quenched by pouring slowly into a well-stirred ice-cold mixture of ethanol (40 ml) and concentrated HCl (5 ml). The solvents were removed in vacuo, the residue was taken up in brine (20 ml) and extracted with dichloromethane (4×20 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo, and the resulting oil was purified by flash chromatography on silica gel eluting with 10% i-propanol in ethyl acetate to give the title compound (0.50 g, 54%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1.[NH3:18]>CO>[Br:1][C:2]1[C:7]([C:8]([NH2:18])=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1
Reactant: CCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Reactant: N
Solvent: CO
Product: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of methyl 5-bromo-2-(3-ethylureido)isonicotinate (Intermediate 1, 56.22 g, 186.0 mmol) in 7N ammonia in methanol (1 L) was allowed to stir at room temperature in a sealed flask for 1½ d. The precipitate that formed was collected by filtration, rinsed with acetonitrile (500 mL), and then dried on the high vacuum pump overnight, yielding 50.8 g of a solid (95.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:18]1([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: NCC1(c2cccnc2)CCCC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3cccnc3)CCCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=329.0, tR (minutes, Method A)=1.14