Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:16][CH2:17][CH2:18]Br.Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[C:10]2[N:11]([C:7]3[C:8]([N:9]=2)=[CH:13][CH:14]=[C:5]([CH2:3][OH:4])[CH:6]=3)[CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCc1ccc2nc3n(c2c1)CCCS3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a round bottomed flask was added 4.06 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 4.04 grams of 1,3-dibromopropane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and concentrate yielded 3 grams (68%) product. NMR (DMSO): δ 7.91 (m, 3H), 4.13 (m, 2H), 3.93 (s, 1H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2). MS: 221.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH2:21]([S:28][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
Under nitrogen atmosphere, to a mixture of methyl 2-chloro-3-nitrobenzoate (20.8 g, 96.5 mmol) and potassium carbonate (40.0 g, 289 mmol) in N,N-dimethylformamide (300 mL) was added benzyl mercaptan (11.5 mL, 98.0 mmol) at 0° C., and the mixture was stirred at 90° C. for 6 hr, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1→1/2) to give the title compound (28.5 g, yield 97%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=3)=[CH:9][CH:8]=[C:7]([F:31])[C:3]=1[C:4]([NH2:6])=[O:5].[C:32]1(OS(C(F)(F)F)(=O)=O)[CH2:36][CH2:35][CH2:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH:36]1([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13]([CH2:12][O:11][C:10]2[C:2]([F:1])=[C:3]([C:7]([F:31])=[CH:8][CH:9]=2)[C:4]([NH2:6])=[O:5])=[CH:21]3)[CH2:35][CH2:34][CH:33]=[CH:32]1
Reactant: CC1(C)OB(c2ccc3c(c2)C=C(COc2ccc(F)c(C(N)=O)c2F)C3)OC1(C)C
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4C=CCC4)ccc3C2)c1F
Temperature: 80 °C
Yield: 68 %

Procedure:
To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.25 g, 0.56 mmol) in 7 ml of anhydrous DMF and water (3.5 ml) was added trifluoromethanesulfonic acid cyclopent-1-enyl ester (0.37 g, 1.70 mmol) and potassium phosphate (0.14 g, 0.60 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.05 g, 0.08 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.14 g, 65%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.22 (m, 2H), 2.01 (m, 2H), 2.88 (m, 2H), 5.68 (s, 2H), 6.43 (s, 1H), 7.01 (t, J=9.20 Hz, 1H), 7.37 (m, 1H), 7.67 (d, J=8.40 Hz, 1H), 7.89 (br s, 1H), 7.94 (s, 1H), 8.07 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (387.15), HPLC (method II) Rt=13.74 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1.Cl>CN(C)C=O>[C:17]([C:15]1[CH:16]=[C:11]([CH2:10][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH:12]=[CH:13][C:14]=1[OH:20])(=[O:19])[CH3:18]
Reactant: O=C1CCCN1
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CN2CCCC2=O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20.0 mmol) in 15 mL dry dimethylformamide under argon, cooled in an ice-bath was added dropwise a solution of 2-pyrrolidinone (1.70 g, 20.0 mmol) in 5 mL dimethylformamide. The ice-bath was removed, the mixture was stirred 30 minutes, and a solution of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol) in 5 mL dimethylformamide was added dropwise. The mixture was stirred four hours, poured into 75 mL ice water, acidified with 7 mL 3N hydrochloric acid, and extracted with methylene chloride (3×75 mL). The extract was washed with water (25 mL) and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude product which was purified by flash chromatography on silica gel slutlug with 2:98 methanol:chloroform to give 1.92 g (82%) product as a viscous oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23][C:42]([C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@:26]2([C:27]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:33][C:25]2=[O:24])[CH2:41]3)=[O:43])[CH2:10]1
Reactant: N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.42 h
Yield: 76.9 %

Procedure:
To a solution of (6S,8S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine (7.0 mg, 0.023 mmol) in N,N-dimethylforinamide (105 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (6.5 mg, 0.023 mmol), 1-hydroxy-7-azabenzotriazole (0.3 mg, 2.1 μmol), N-methylmorpholine (2.56 μL, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 mg, 0.023 mmol). The mixture was stirred 25 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (10.5 mg). HRMS 594.1931 (M+1). 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H); 8.84 (d, J=8.6 Hz, 1H); 8.07 (dd, J=5.3, 1.6 Hz, 1H); 7.83 (s, 1H); 7.79 (d, J=8.0 Hz, 1H); 7.40-7.36 (m, 2H); 7.32-7.28 (m, 2H); 7.22 (dd, J=7.3, 1.6 Hz, 1H); 6.92 (s, 1H); 6.88 (dd, J=7.3, 5.3 Hz, 1H); 4.34 (d, J=7.9 Hz, 1H); 3.80 (t, J=10.3 Hz, 4H); 3.40 (d, J=16.3 Hz, 2H); 3.19 (dd, J=16.4, 3.5 Hz, 2H); 2.33-2.29 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH2:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])[CH:7]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[Br:18][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[O:15]1
Reactant: C=CCCC(O)CCc1cc(F)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(F)cc1CCC1CCC(CBr)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8 (3.24 g, 18.0 mmol) in dry CH2Cl2 (50 mL) at 0° C. was added N-bromosuccinimide (3.56 g, 20.0 mmol) portion-wise and the reaction was warmed to room temperature and stirred for 12 h. Solvent was then removed in vacuo and the product was purified by flash column chromatography (EtOAc/hexane, 5:95, v:v, Rf=0.1) and resulted in a colorless oil as a 2:1 mixture of trans:cis diastereomers; 1H NMR (CDCl3, 500 MHz): δ 6.86-6.81 (m, 2 H), 6.72 (dd, J=4.6, 8.6 Hz, 1 H), 4.22 (m, 1 H), 4.03 (m, 1 H), 3.78 (s, 3H), 3.44 (dd, J=4.3, 9.7 Hz, 1 H), 3.34 (dd, J=6.4, 9.7 Hz, 1 H), 2.6 (t, J=7.3 Hz, 2 H), 2.13 (m, 1 H), 2.05 (m, 1 H), 1.75 (m, 1 H), 1.67-1.46 (m, 5 H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CN(C=O)C.ClCCl>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C=O)c2cccnc12
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (170 mg, 0.98 mmol) in DMF (5 ml) were added anhydrous potassium carbonate (150 mg) and 2-bromoacetic acid ethyl ester (0.12 ml, 180 mg, 1.08 mmol) at room temperature and the stirring was continued for 1 h. Then the reaction mixture was diluted with dichloromethane, the organic layer was washed several times with water, dried over sodium sulfate and then evaporated under vacuum. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (9:1) as eluant; to give 190 mg (74.8% yield) of pure 2-(5-formylquinol-8-yloxy)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(F)c1
Yield: 88.4 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 3-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.72 g (88%) of 1-benzyl-piperidin-4-yl 3-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>O1CCOCC1.CCOC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: NCC(O)CO
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(NCC(O)CO)nc1
Temperature: 80 °C

Procedure:
A mixture of 3-amino-1,2-propanediol (4.93 g, 54.1 mmol) and 6-chloronicotinonitrile (1.50 g, 10.8 mmol) was prepared in anhydrous dioxane (20 mL), and then stirred at RT for hours and 80° C. for additional hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with a half saturated solution of brine (2×50 mL) and brine (50 mL). The aqueous layers were extracted with EtOAc (2×50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by trituration in hot MTBE (10 mL) and filtration, the title compound was obtained as a white powder (970 mg, 46%). UPLC/MS, M+(ESI): 193.9, M−(ESI): 192.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].Br.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:18]=[N:17][N:16]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21]
Reactant: CCCc1c(OCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Reactant: BrCCCCc1cccnc1
Agent: Br
Product: CCCc1c(OCCCc2nnnn2CCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
1-[2-Hydroxy-3-propyl-4-[3-(1H-tetrazol-5-yl)propoxy]phenyl]ethanone was allowed to react with 3-(4-bromobutyl)pyridine hydrobromide according to procedure B and the product was purified by high pressure liquid chromatography to give 1-[2-hydroxy-3-propyl-4-[3-[1-[4-(3-pyridinyl)butyl]-1H-tetrazol-5-yl]propoxy]phenyl]ethanone, which is the N-1 isomer, and 1-[2-hydroxy-3-propyl-4-[3-[2-[4-(3-pyridinyl)butyl]-2H-tetrazol-5-yl]propoxy]phenyl]ethanone, which is the N-2 isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-nitrophenol (1.57 g, 10.0 mmol) in 20 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K2CO3 powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (100 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 4-ethoxy-2-fluoro-1-nitrobenzene as a pale yellow oil: MS (ESI) 186 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9](=[O:23])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]([CH:12]([CH3:14])[CH3:13])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:3][CH:4]=2)[N:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:9](=[O:23])[N:10]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:13])[CH3:14]
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C(C)C)cc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C(C)C)cc1
Temperature: 100 °C

Procedure:
(±)-7-Chloro-4-isopropyl-3-(4-methoxy-phenyl)-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (22.0 mg; 0.054 mmol) (from Example 11d supra) and aniline (50 μL; 0.55 mmol) (Aldrich) were combined and heated in an oil bath at 100° C. for 1 hour. Upon cooling, the residue was triturated with hexanes and the supernatant was decanted off. The residue was dissolved in ethyl acetate and washed with water and then brine. The organic phase was mixed with silica gel, concentrated and subsequently purification by flash chromatography (Biotage 12M; 40:60 ethyl acetate-hexanes) and crystallization from dichloromethane-ether-petroleum ether gave (±)-4-isopropyl-3-(4-methoxy-phenyl)-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 14.8 mg; 59.1%). Melting Point: 229–235° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23]C1C=C2C(CCC2N)=CC=1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:22])[CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: COc1ccc2c(c1)C(N)CC2
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCc3ccc(OC)cc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-methoxyindan-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.31, 1.87, 2.59, 2.67, 2.75, 2.87, 2.95, 3.79, 4.55, 5.75, 6.83, 7.19, 7.70; HRMS (FAB) calcd for C18H23N3O+H 298.1919, found 298.1909. Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.19; H, 7.76; N, 13.84.
Reaction SMILES: C(S([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])(=O)=O)C1C=CC=CC=1.CC(OC(N[C@H](C(O)=O)CCCCNC(OCC1C(Cl)=CC=CC=1)=O)=O)(C)C.C(N)(C)(C)C.F.C1(OC)C=CC=CC=1>>[NH2:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: N[C@@H](CCCCNS(=O)(=O)Cc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: F
Solvent: COc1ccccc1
Solvent: CC(C)(C)N
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Boc-Lys(Xys)-OH (124.4 mg, 0.3 m.mol), Nε -benzylsulfonyllysine (90 mg., 0.3 m.mol) and Boc-Lys-(2-Cl-Z)-OH.t-butylamine salt (146.4 mg, 0.3 m.mol) are each treated with hydrogen fluoride (2 ml) in the presence of anisole (0.1 ml) at -20° C. for one hour. After the hydrogen fluoride is distilled off, the residue is dissolved in water (50 ml). An aliquot of the solution is taken and the lysine content of the sample is determined by an amino acid analyzer. The % yields of lysine are calculated.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:17](=O)[CH3:18].S(=O)(=O)(O)O>>[CH:17](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)[CH3:18]
Reactant: CC=O
Reactant: COc1cc2c(cc1OC)C(NN)=NCC2
Agent: O=S(=O)(O)O
Product: CC=NNC1=NCCc2cc(OC)c(OC)cc21

Procedure:
In a manner similar to that of Step C of Example 1, condensation of 1-hydrazino-6,7-dimethoxy-3,4-dihydroisoquinoline (7.2 g.) with acetaldehyde (4.3 g.) and treatment of the resulting product with sulfuric acid afforded 1-(2-ethylidenehydrazino)-6,7-dimethoxy-3,4-dihydroisoquinoline (I: X=CH3, X' =Y=Y' =H, Z=Z' =CH3O) sulfate monohydrate (5.3 g., m.p. 165°-168° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[O:17][CH2:18][C:19](O)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1>O1CCCC1>[NH:39]1[C:38]([NH:37][C:19](=[O:20])[CH2:18][O:17][C:16]2[CH:22]=[CH:23][CH:24]=[C:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:15]=2)=[N:42][N:41]=[N:40]1
Reactant: O=C(O)COc1cccc(CCNC(=O)OCc2ccccc2)c1
Reactant: Nc1nnn[nH]1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(COc1cccc(CCNC(=O)OCc2ccccc2)c1)Nc1nnn[nH]1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution at 40° C. of 13.1 g. (39.8 mMol) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenoxyacetic acid and 130 ml. anhydrous tetrahydrofuran are added 6.48 g. (39.9 mMol) carbonyl-bis-imidazole, followed by stirring for 30 minutes at 40° C. 3.39 g. (39.9 mMol) anhydrous 5-aminotetrazole are then added thereto and allowed to react for 18 hours at 60° C. After distilling off the tetrahydrofuran, there is obtained a colourless oil which is stirred with 130 ml. 2N hydrochloric acid, crystallisation thereby taking place. The crystals are filtered off with suction, triturated with dilute hydrochloric acid, again filtered off with suction and washed with water. After drying in a vacuum at 80° C. over potassium hydroxide and recrystallising from nitromethane, there are obtained 12.7 g. (50.5% of theory) of the desired product; m.p. 164°-167° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc2ccccc2n1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1ccc2ccccc2n1)NO
Reaction time: 48 h
Yield: 76 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (90 mg, 0.24 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 48 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4) to furnish IV as a colourless oil (66.43 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([O-:14])=[O:13])C([O-])=O)[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Na+].CS(C)=O.[C:28](OCC)(=O)[CH3:29]>O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:15])[C:12]([O:14][CH2:28][CH3:29])=[O:13])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)[O-])(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A mixture of 100 millimoles diethyl 2-(2-fluoro-4-biphenylyl)-methylmalonate VI, 110 millimoles sodium chloride, 200 millimoles water and 50 milliliters dimethyl sulfoxide is heated under nitrogen at about 130° to 180° C. for about 6 hours. On cooling the mixture is diluted with 100 milliliters water and 100 milliliters ethyl acetate. The layers are separated and the organic layer is washed two times with 25 milliliters of water. After drying over disodium sulfate the organic layer is concentrated in vacuo to give the desired ethyl 2-(2-fluoro-4-biphenylyl)propionate.
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])(=[O:30])[CH3:29]>>[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38]([O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:22][CH:23]=1)=[O:39])=[O:34])(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(O)cc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(OC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O)cc1
Yield: 45.3 %

Procedure:
4-Oleoylaminophenol (372 mg) and 259 mg of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 255 mg of the title compound (yield: 39%).