Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH3:16])[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:20][CH:19]=1)[C:7]2=[O:37])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH3:16])[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([OH:32])=[O:31])=[CH:20][CH:19]=1)[C:7]2=[O:37])([CH3:2])[CH3:3]
Reactant: CCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-isopropyl-2-n-propyl-3-[(2'-(t-butoxycarbonyl)biphen-4-yl)-methyl]-quinazolin-4(3H)-one (0.198 g, 0.44 mmol) in a mixture of methylene chloride (3 ml) and anhydrous trifluoro acetic acid (3 ml) containing anisole (0.05 ml) was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure and the residue was triturated with dry ether to give the solid product, which was then collected by filteration and dried in vacuo over NaOH and P2O5 to give the desired product as the mono trifluoroacetate salt. 1H-NMR(CDCl3): 0.91 (t, 3H, J=7.35 Hz), 1.32 (d, 6H, J=6.9 Hz), 1.47 (m, 2H), 1.72 (m, 2H), 3.12 (m, 3H), 5.48 (s, 2H), 7.14-7.96 (m, 11H), 8.16 (d, 1H, J=1.9 Hz). FAB-MS m/e 399 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([CH3:49])=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:43][C:44]1[S:45][C:46]([CH3:49])=[CH:47][N:48]=1)=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cnc(N)s1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ncc(C)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-methylthiazole (58 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 18 mg of the title compound.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].O=S(Cl)Cl.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:23]2)=[C:17]([CH2:24][CH3:25])[CH:16]=1)#[N:14]
Reactant: CCc1cc(C#N)ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Solvent: O=S(Cl)Cl
Product: CCc1cc(C#N)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was reacted with SOCl2 followed by 4-cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.S(Cl)([Cl:18])=O>CN(C=O)C>[ClH:18].[Cl:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nncc(O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2nncc(Cl)c2cc1OC
Product: Cl

Procedure:
The starting material, 4-chloro-6,7-dimethoxycinnoline hydrochloride was obtained by heating a solution of 4-hydroxy-6,7-dimethoxycinnoline (1 g, 4.8 mmol) in thionyl chloride (20 ml) containing DMF (2 drops) at reflux for 3 hours. After cooling and evaporating the excess thionyl chloride, the solid was triturated with ether and filtered to give 4-chloro-6,7-dimethoxycinnoline hydrochloride (1.2 g, quantitative).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:22]([C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[C:33]([CH:34]=O)=[CH:32][N:31]=[CH:30]2)=[CH:26][CH:25]=1)#[N:23].CCOC(C)=O>ClCCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([CH2:34][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:32][N:31]=[CH:30]2)=[CH:36][CH:37]=1)#[N:23]
Reactant: COC(=O)CN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of glycine methyl ester hydrochloride (595 mg, 4.74 mmol) in 1,2-dichloroethane at 0° C. was added 4 Å powdered molecular sieves (3 g), followed by sodium triacetoxyborohydride (1.51 g, 7.1 mmol). The 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde from Step E of Example 1 (1.00 g, 4.74 mmol) was added, and the reaction was stirred overnight, allowing it to warm to room temperature. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in CH2Cl2, and propylamine (20 vol %) was added. The reaction was stirred for one hour, then concentrated in vacuo, and purified by silica gel chromatography (95:5; CHCl3:MeOH) to provide the titled amine product.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[N:11][C:10]([Cl:13])=[CH:9][N:8]=2)[N:6]=1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][NH:33][CH2:32][C@@H:31]1[CH3:36])=[O:28].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[CH2:34][CH2:35][C@@H:30]([NH:29][C:27]([C:21]4[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=4[Cl:19])=[O:28])[C@@H:31]([CH3:36])[CH2:32]3)[S:3][C:4]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1cnc(Cl)cn1
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)c(Cl)c1Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](C)C2)nc1-c1cnc(Cl)cn1
Temperature: 50 °C
Yield: 76.7 %

Procedure:
To a stirred solution of ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate (Intermediate 47, 1.8 g, 5.142 mmol), and 3,4-dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide (Intermediate 39, 1.47 g, 5.142 mmol) in N-methyl 2-pyrrolidinone (1 mL) was added N,N-Diisopropylethylamine (1.7 mL, 10.284 mmol) at room temperature. The reaction mixture was heated to 50° C. for 5 h. The reaction mixture was cooled to room temperature, water (60 mL) was added, the precipitated product was collected by filtration, washed with water and dried to afford 2.2 g (78%) of ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH3:16])=[N:8]1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]2=[N:12][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[N:15][C:13](=[O:14])[C:10]2=[C:9]([CH3:16])[NH:8]1
Reactant: O=Cc1ccncc1
Reactant: Cc1nn(C2CCCC2C)c(N)c1C(N)=O
Product: Cc1[nH]n(C2CCCC2C)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 120 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carboxamide (2.3 g, 10.4 mmol) in xylenes (8.0 ml) under argon was added 4-pyridinecarboxaldehyde (1.5 ml, 15.5 mmol). The reaction mixture was warmed to 120° C. and stirred for 1 hour at which time the mixture became homogeneous. The reaction mixture was then heated to 160° C. for 24 hours and then cooled to room temperature. A solid precipitated which was collected by filtration through a glass frit. The solid was washed with ether, saturated NaHCO3 then water and was recrystallized from DMF. The solid was collected on a glass frit and was washed with methanol, then ether and dried at 110° C. for 72 hours in high vacuum to afford 1.05 g (33%) of 1-(2-methylcyclopentyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as white crystals m.p. 290°-291° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-:24].[K+].[K+]>CN(C)C=O>[F:11][C:10]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:6]([NH2:7])=[O:24])[CH:8]=[CH:9][C:2]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 150 °C
Yield: 58.2 %

Procedure:
The reaction was split into 4, using a quarter of the reagents in each: to a mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (4 g, 16.00 mmol), phenylboronic acid (3.90 g, 32.0 mmol) and potassium carbonate (6.63 g, 48.0 mmol) in N,N-dimethylformamide (DMF) (64 ml) was added palladium tetrakistriphenylphosphine(0) (1.849 g, 1.600 mmol). Each reaction was heated in the microwave at 150° C. for 30 min. The combined reaction mixtures were filtered through celite, washed with ethyl acetate and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the organic phase washed with sodium bicarbonate solution (100 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The brown oil was triturated with dichloromethane and filtered to give a pale yellow solid, 2-(trifluoromethyl)-4-biphenylcarboxamide (2.47 g) which was used without further purification. To 2-(trifluoromethyl)-4-biphenylcarboxamide (2 g, 7.54 mmol) in ethanol (80 ml) was added potassium hydroxide (4.23 g, 75 mmol) and water and the mixture heated to 90° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and 2M HCl (100 mL). The organic phase was isolated and dried (phase separator) and the solvent removed in vacuo to give the crude product. Purification using the Biotage Horizon, reverse phase cartridge, eluting 5-100% MeCN in water to give an off-white solid the title compound (960 mg) (N2123-46-A5). MS (ES): C14H6F3O2 requires 266; found 265 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[F:21][CH:22]([F:24])Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:22]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[F:24]
Reactant: FC(F)Cl
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(c2nc(C)nc3ccccc23)C(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100 mg, 0.35 mmol) in 3 mL of dimethylformamide in a 15 mL high pressure reaction vessel was cooled to −78° C. Diflurochloromethane (about 0.8 mL) was condensed into the solution, then cesium carbonate (160 mg, 0.49 mmol) was added. The reaction vessel was capped and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and cooled to −78° C. and the seal tube was uncapped, warm to room temperature and allowed to stand for 2 h. The reaction mixture was diluted with 50 mL of ethyl acetate and the organic layer was washed with water (50 mL×3), followed by saturated aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexane, 6 drops triethylamine/500 mL of solvent) to give the title compound (35 mg, 0.111 mmol, 32%). 1H NMR (CDCl3): 8.35 (dd, J=1.8, 8.1, 1H), 7.35−(m, 3H), 7.25 (t, J=72.1, 1H), 7.21-7.25 (m, 2H), 6.86-6.91 (m, 2H), 3.82 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[OH:12][CH2:13][CH:14]1[CH2:20][O:19][CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]1.CC[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH:32]1([CH2:33][O:12][CH2:13][C:14]2([OH:9])[CH2:20][O:19][CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[CH2:30][CH2:31]1
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)N1CCOCC(CO)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
70-75% m-Chlorobenzenecarboperoxoic acid (145 g, 0.59 mol, 1.2 eq) was added in portions to a stirred solution of tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (Preparation 79, 107 g, 0.5 mol, 1 eq) in DCM (1.0 L) that caused heating of the mixture. The reaction mixture was stirred for 24 h at room temperature, then diluted with hexane (500 mL) and filtered. The separated precipitate was washed on a filter with DCM/hexane mixture, and the combined filtrate was washed with aqueous potassium carbonate, dried over sodium sulfate, and evaporated. The residue was vacuum-dried to give title compound (117 g, 0.51 mol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:21])[CH3:20]>CO>[CH3:20][C:11]1([CH3:21])[CH:10]([CH2:9][CH2:8][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1
Reactant: C=CC(=O)OC
Reactant: CC1(C)Oc2ccccc2CC1CCN
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1Cc2ccccc2OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.74 g (55 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 5.13 g (25 mmol) of 3-(2-aminoethyl)-2,2-dimethylchroman in 50 ml of methanol. The mixture is stirred for 16 hours at room temperature and then concentrated by evaporation in vacuo, yielding 9.43 g (100% of the theorectical yield) of N-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil which is further used in that form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=O.[OH-:21].[Na+].Cl>>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:12]2[C:11]([OH:21])=[CH:8][C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[N:1]=2)=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ncccc1C=O
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2nc3ncccc3cc2O)cc1
Reaction time: 72 h
Yield: 1 %

Procedure:
2-Amino-pyridine-3-carbaldehyde (100 mg) and 2-bromo-1-p-tolyl-ethanone (174 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml), and the suspension was hermetically sealed and, in this state, was allowed to stand for 3 days. The reaction solution was neutralized with 10% hydrochloric acid, and the resultant precipitate was then collected by filtration and was washed with water and chloroform. The powder as the residue was dried under the reduced pressure to give 2-p-toluyl-[1,8]naphthyridin-3-ol (2 mg, yield 1%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].C(N(CC)CC)C.O1CCCC1>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:16](=[O:17])[O:15][CH2:14][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCC2CN(Cc3ccccc3)CCN12
Yield: 64.6 %

Procedure:
A mixture of (4-benzylpiperazin-2-yl)methanol (2.8 g, 10 mmol) prepared according to J. Med. Chem. 1993, 36, 2075-2083 and 1,1′-carbonylbis(1H-imidazole) (3.2 g), triethylamine (2.8 ml) and tetrahydrofuran (30 ml) was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.5 g, yield 65%) as a colorless oil from a fraction eluted with ethyl acetate. MS 233 (M+1).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([C:26]([C@@:28]1(C)CO1)=O)[CH2:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1.[CH:32]([S:34](C=C)(=[O:36])=[O:35])=C.CON(C)C(=O)[C@@H](NC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC1C=CC(CNC(=O)OC(C)(C)C)=CC=1>>[CH3:32][S:34](/[CH:28]=[CH:26]/[C@@H:9]([NH2:8])[CH2:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)C(=O)[C@@]2(C)CO2)cc1
Reactant: C=CS(=O)(=O)C=C
Agent: CON(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)/C=C/S(C)(=O)=O)cc1

Procedure:
Retro-synthetically, the modified oligopeptides can be prepared from tripeptide hydrazide N3Phe-Leu-Leu-NHNH2 and the properly protected warhead amines in an (epimerization free) azide coupling. The synthesis of P1-benzyl amine containing vinyl sulfone and epoxyketone warheads leading to inhibitors 4a and 4b is shown in Scheme 3. The synthetic scheme commenced with the introduction of the aminomethylene substituent on L-phenylalanine 8, by performing an electrophilic aromatic substitution with N-(hydroxymethyl) trichloroacetamide under acidic conditions. In this reaction both the ortho and the para substituted isomers were formed, which could be separated by column chromatography. The desired para substituted isomer was obtained in 35% yield. After Cbz-protection of the α-amine, compound 9 was obtained. Basic removal of the trichloroacetamide group followed by Boc protection of the formed amine gave 10, which was coupled to N,O-dimethylhydroxylamine to give Weinreb-amide 11. Upon a reaction with 2-lithiumpropene the α′,β′-unsaturated ketone 12 was obtained. Stereoselective reduction to the allylic alcohol 13 and subsequent asymmetric epoxidation and Dess-Martin oxidation resulted in epoxyketone 14. This compound was α-amine deprotected by hydrogenation, which finalized the synthesis of compound 15. The vinylsulfone analogue was created by α-amine deprotection of compound II, followed by tritylation (16). Reduction of the Weinreb-amide, followed by a Horner-Wadworth-Emmons reaction and de-tritylation finally resulted in compound 18.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[Cl:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 67.7 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 88 mg (0.560 mmol) of 2-chlorobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (179 mg, 68%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.42, FD-MS: M+ =565, 567.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[H-].[Na+].[CH2:22]([SH:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[ClH:1].[CH2:22]([S:27][C:2]1[C:3]([C:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=2)=[N:4][CH:5]=[CH:6][N:7]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN1CCCC(O)(c2nccnc2Cl)C1
Reactant: CCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCSc1nccnc1C1=CCCN(C)C1
Product: Cl
Reaction time: 1 h
Yield: 19 %

Procedure:
A mixture of 1 g (0.0044 mol) of (1) and 7 ml of thionyl chloride was stirred 1 h, the excess thionyl chloride was evaporated, and the residue was treated with ice-water. The solution was made basic with 5 N NaOH and the mixture extracted 3× with 25 ml of CH2Cl2. The solvent was evaporated from the dried extracts, the residue was dissolved in 10 ml of THF, and the solution was added to a suspension of sodium hexylthiolate in THF prepared from 0.18 g (0.0078 mol) NaH, 2 ml (0.016 mol) pentanethiol, and 30 ml of THF. The reaction was heated to reflux for 20 min followed by distillation of most of the THF from the reaction mixture. The solvents were evaporated, the residue treated with water, and the mixture extracted 3× with 25 ml of CH2Cl2. The solvent was evaporated from the dried extracts and the residue purified by radial chromatography eluting with 5% ethanol/0.5% NH4OH/CHCl3. The hydrochloride salt (36), 0.26 g, 19% yield crystallized from ethyl acetate as colorless crystals, mp 123°-124° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.38 (4H, m), 1.7 (2H, m), 2.58-2.7 (1H, m), 3.0 (3H, d), 3 05-3.2 (4H, m), 3.5-3.6 (1H, m), 3.7-3.82 (1H, m), 4.4-4.47 (1H, d), 6.8 (1H, m), 8.15 (1H, d), 8.28 (1H, d). Anal. C15H23N3S-HCl requires C: 57.40; H: 7.71; N: 13.37%. Found C: 57.43; H: 7.63; N: 13.45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Cl[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: ClCCc1ccncc1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccncc2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 4-(2-chloro-ethyl)-pyridine by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (CD3OD) δ 8.68 (d, J=6.4 Hz, 2H), 8.27 (s, 1H), 7.84 (d, J=6.4 Hz, 2H), 7.06-6.98 (m, 3H), 4.75 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.53 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 409.1.