Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CCO.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=1
Reactant: COC(=O)C1CCN(c2ncc([N+](=O)[O-])cc2C)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CCN(c2ncc(N)cc2C)CC1
Yield: 100.8 %

Procedure:
Methyl 1-(3-methyl-5-nitropyridin-2-yl)piperidine-4-carboxylate (2.40 g) was dissolved in EtOH (86 mL), treated with 10% Pd/C (860 mg) and placed under an atmosphere of hydrogen (balloon). LCMS indicated complete reaction at ˜100 mins. The catalyst was filtered off and solvent removed under vacuum to leave a colourless oil (2.16 g). This was used in the next step without further purification. 1H NMR δ 1.58-1.75 (m, 2H), 1.81-1.91 (m, 2H), 2.10 (s, 3H), 2.37-2.50 (m, 1H), 2.55-2.75 (m, 2H), 2.99-3.09 (m, 2H), 3.61 (s, 3H), 6.76 (d, 1H), 7.48 (d, 1H). MS m/e MH+ 250.27.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[C:5]1(=[O:11])O[C:8](=[O:9])[CH:7]=[CH:6]1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:5]1(=[O:11])[NH:4][C:8](=[O:9])[CH:7]=[CH:6]1.[CH2:1]([NH2:4])[C:2]#[CH:3]
Reactant: O=C1C=CC(=O)O1
Agent: C#CCN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1C=CC(=O)N1

Procedure:
After the reaction of propargylamine and maleic anhydride in the presence of TEA, the intermediate acid was cyclized in the presence of acetic anhydride and sodium acetate at 70° C., to afford the desired propargylamine maleimide.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>ClCCl>[C:1]1([N:11]=[C:19]=[S:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2ccccc12
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: S=C=Nc1cccc2ccccc12
Temperature: 25 °C

Procedure:
To the mixture of 1-naphthylamine (21.48 g), triethylamine (33.39 g), and dichloromethane (250 mL) was added a dicholomethane (50 mL) solution of thiophosgen (18.97 g) at bleow 20° C. over 30 minutes, and the mixture was stirred at room temperature. The reaction mixture was added into ice-water (1000 mL), extracted with diethyl ether (1000 mL). The extract was washed two times with brine (1000 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to obtain crude (1-naphthyl)isothiocyanate.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:44]=1[C:55]([NH2:57])=[O:56]>C(Cl)Cl>[C:1]([C:3]1([C:6]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:44]=2[C:55]([NH2:57])=[O:56])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C(=O)O)CC1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 1-cyanocyclopropanecarboxylic acid (0.75 g, 7 mmol) in DCM (40 mL) was added HATU (3.5 g, 10 mmol) and DIPEA (3.4 mL, 20 mmol). After stirring at room temperature for 1 h, 3-aminobiphenyl-2-carboxamide (from example 218: 1 g, 5 mmol) was added and the reaction mixture stirred for an additional 16 h. The reaction mixture was washed with water and the organic phase dried, filtered, concentrated under reduced pressure and purified by silica gel chromatography (60% ethyl acetate in hexanes) to provide 3-(1-cyanocyclopropanecarboxamido)biphenyl-2-carboxamide (0.75 g, 74% yield) as a white solid. LCMS Method T: retention time 1.53 min; [M+1]=306.2.
Reaction SMILES: [NH:1]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@@H:2]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.Cl.Cl.CC(O)=O>CO>[NH:1]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[C@@H:2]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)O
Yield: 74.6 %

Procedure:
2.7 Grams (3.5 mM) of Z-D-Lys(BOC)-Gly-Arg-CHA.HCl was dissolved in a small amount of MeOH, followed by addition of 7 ml of 2N-HCl/AcOH and the mixture was reacted at room temperature for 1 hour. The reaction mixture was reprecipitated from dry diethyl ether and the crystals precipitated were collected by filtration and dried to obtain crude Z-D-Lys-Gly-Arg-CHA.2HCl. This crude product was purified by means of a column chromatography by using "TOYOPEARL HW 40F" column using MeOH as a developing solvent to obtain 1.8 g (74.6%) of Z-D-Lys-Gly-Arg-CHA.2HCl. Rf2 =0.31. Melting point: 220.0° C. (decomposed). [α]D20 -16.0 (C=1, 50% AcOH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1C=CC2N(O)N=NC=2[CH:39]=1.CCN=C=NCCCN(C)C.Cl>C(O)C>[CH2:34]([O:14][C:13](=[O:15])[C@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
In ethanol (60 ml), 5-t-butoxycarbonylamino-(2R)-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanoic acid (1.9914 g) was dissolved. The solution was added with HOBt (770.2 mg) and WSCI hydrochloride (1.0927 g) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and a saturated saline solution, followed by drying with magnesium sulfate. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.9846 g) as a white solid.
Reaction SMILES: Cl.CN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O[N:36]1[C:40]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:36][CH3:40])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: On1nnc2ccccc21
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (48 mg) and triethylamine (0.10 mL) in N,N-dimethylformamide (10 mL) were added (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.16 g), 1-hydroxybenzotriazole (94 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg). After stirring at 4° C. to room temperature for 7 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow oil, which was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give a colorless oil. The oil was crystallized from ethyl acetate-hexane to give the title compound (144 mg, 88%) as colorless needles. MS 474 (MH+). mp 125-126° C.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:19]=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
2-Methyl-2-({4-[2-({6-[4-(trifluoromethoxy)phenyl]pyridazin-3-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (520 mg) obtained in Example 213-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (233 mg) as a white amorphous.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[CH2:14][CH2:15]Cl)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:7]=[C:8]([N:12]2[CH2:15][CH2:14][C:13]2=[O:17])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCN1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3-nitrophenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3-nitrophenyl)-2-azetidinone as the residue.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8]>ClCCl>[OH:2][CH2:1][CH2:3][NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11]
Reactant: CCCCN=C=O
Reactant: NCCO
Solvent: ClCCl
Product: CCCCNC(=O)NCCO
Temperature: 30 °C
Yield: 113 %

Procedure:
61.7 grams (1 mole at 99% purity) of ethanolamine and 170 grams of dichloromethane were charged to a flask eguipped with stirrer, thermometer, feed tank, distillation head and condenser. 101 grams (1 mole at 98% purity) of butyl isocyanate were fed to the flask dropwise with stirring and cooling (utilizing a dry ice bath) over a period of 1.5 hours such that the temperature of the reaction mixture was maintained at about 30° C. At this time some solid had been formed and it was redissolved by heating to 46° C. The flask contents were stirred at 46° C. for an additional two hours and then freed of volatile materials by stripping at 90° C. and 2 mm Hg, leaving 181 g of solid product. This material was recrystallized from 2-butanone giving tiny white crystals melting at 67° C. The HLB value of N-(2-hydroxyethyl)-N'-1-butyl urea is 12.9.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]([CH2:15]Cl)=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]2[O:1][C:13]([CH3:15])=[CH:14][C:11]=2[CH:10]=1)=[O:7]
Reactant: C=C(Cl)CCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2oc(C)cc2c1
Temperature: 200 °C
Reaction time: 89 h
Yield: 10.3 %

Procedure:
Methyl 4-hydroxybenzoate (25.51 g), 2,3-dichloropropene (22.33 g) and potassium carbonate (27.65 g) were heated in 2-butanone (150 ml) at 70° C. for 20 hr. The reaction mixture was concentrated, and water was added, which was followed by extraction with toluene. The extract was washed with saturated brine and concentrated. To the concentrate (34.5 g) was added diethyl aniline (100 ml) and the mixture was stirred at 200° C. for 89 hr. After cooing, toluene and concentrated hydrochloric acid were added and the toluene layer was washed with saturated brine, and dried over sodium sulfate. After concentration, formic acid (80 ml) was added to the residue (34.5 g) and the mixture was refluxed for 25 hr. After concentration, ethyl acetate and water were added. The separated toluene layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the objective compound (3.30 g).
Reaction SMILES: [CH3:1][C:2](P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C([CH:24]([CH2:37][CH2:38][CH3:39])[C:25]#[C:26][P:27](=[O:36])([O-:35])[O:28][C:29]([CH2:31][CH2:32][CH2:33][Cl:34])=[CH2:30])C>[Au].ClC(Cl)C>[CH2:1]([O:35][P:27]1(=[O:36])[CH:26]=[C:25]([CH2:24][CH2:37][CH2:38][CH3:39])[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][Cl:34])[O:28]1)[CH3:2]
Reactant: C=C(CCCCl)OP(=O)([O-])C#CC(CC)CCC
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(CCCCl)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Method 1—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, 5-chloropent-1-en-2yl ethylhex-1-ynylphosphonate (Example 17, 87.6 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-3-chlorpropyl-1,2-oxaphosphorin 2-oxide (82.3 mg, 94%) which is a title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:7]([C:22](O)=[O:23])[CH2:6]1)=[O:4].Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[C@@H:7]([C:22](=[O:23])[NH:34][O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Reaction time: 24 h

Procedure:
To a stirred solution of (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 4-methyl ester (4.4 g, 12.3 mmol), O-benzylhydroxylamine hydrochloride (2.15 g, 13.5 mmol), and triethylamine (5.15 mL, 36.9 mmol) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (6.0 g, 12.3 mmol) at ambient temperature. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate, and brine. The organic mixture was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (elution with 5% methanol in methylene chloride) to provide (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester as a colorless solid.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH:16]([C:19]([CH3:26])([NH2:25])[C:20]#[C:21][C:22]([OH:24])=O)([CH3:18])[CH3:17].[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>O1CCCC1.N1C=CC=CC=1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:22](=[O:24])[C:21]#[C:20][C:19]([CH:16]([CH3:17])[CH3:18])([CH3:26])[NH2:25])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)C(C)(N)C#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CC(C)C(C)(N)C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2mmol) and N-methylmorpholine (1.0 g, 9.9 mmol) were added to an ice cold solution of 1.5 g (9.67 mmol) of isopropyl-methyl-amino-but-2-ynoic acid in 70 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.870 g of isopropyl-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 452.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:52]([C:55]1[CH:56]=[C:57]([C:61]2[N:62]=[C:63]([NH2:66])[S:64][CH:65]=2)[CH:58]=[CH:59][CH:60]=1)([O-:54])=[O:53]>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:66][C:63]1[S:64][CH:65]=[C:61]([C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([N+:52]([O-:54])=[O:53])[CH:56]=2)[N:62]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-Pro-OH (1.5 g, 6.15 mmol) and HATU (2.3 g, 6.15 mmol) were combined in 30 mL of dry DMF. To this solution was added DIEA (1.5 mL, 8.8 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 4-(3-nitro-phenyl)-thiazol-2-ylamine (0.9, 4.1 mmol). Reaction mixture was stirred at room temperature overnight. The crude material was purified using reverse phase HPLC to yield 2-[4-(3-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester. MS: 453.1 (M+H+).
Reaction SMILES: [CH:1](N1CCCC1=O)=[CH2:2].[C:9]1([N:15]=[N+:16]=[N-:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([N:15]2[CH:2]=[CH:1][N:17]=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CN1CCCC1=O
Reactant: [N-]=[N+]=Nc1ccccc1
Solvent: CCO
Product: c1ccc(-n2ccnn2)cc1

Procedure:
In the method of preparation, the reaction between the N-vinylpyrrolidinone and the phenyl azide is carried out at room temperature in ethanol as solvent, and allowed to stand in the dark for several weeks, depending on the reactivity of the phenyl azides. Refluxing the reaction mixture eliminates the 5-(2-oxo-1-pyrrolidino) group and yields the 1-phenyl triazole.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:11]=2[CH:10]=[C:9]([C:19]([OH:21])=[O:20])[CH:8]=1.[CH3:22]O>>[CH3:22][O:20][C:19]([C:9]1[CH:8]=[C:7]([CH3:6])[C:12]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:11]=2[CH:10]=1)=[O:21]
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1
Yield: 92.1 %

Procedure:
Sulfuric acid (12 mL, 0.22 mol) was added to 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (30 g, 136 mmol) dissolved in MeOH (670 mL, 16 mol). The mixture was refluxed for 36 hours and concentrated in vacuo. The recovered material was dissolved in 500 mL EtOAc and washed with a saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated to provide Intermediate (7a) as a brown solid (29.1 g). MS m/z: [M+H+] calcd for C13H16N2O2, 233.1. found 233.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[CH3:20]O>Cl>[CH3:20][C:12]1[N:13]=[C:14]([NH2:16])[S:15][C:11]=1[S:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:10])=[O:9]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)N2CCN(C)CC2)s1
Reactant: CO
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1

Procedure:
A solution of N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide (1 g, 3.1 mmol) in methanol (5 mL) and 6 N hydrochloric acid (5 mL) was heated in a microwave oven (4×5 min at 80° C.). The reaction mixture was partly evaporated to remove most of the methanol, and the residue was washed with DCM (10 mL). The water phase was isolated, and the pH adjusted to 8-9. Extraction with DCM (3×25 mL), drying over anhydrous magnesium sulphate, and evaporation in vacuo gave white crystals of 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine. Yield: 0.53 g (61%). 1H-NMR (CDCl3): δ 5.46 (m, 2H); 3.18 (m, 4H); 2.51 (m, 4H); 2.45 (s, 3H); 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: COC(=O)c1ccc(OCC(=O)NN)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added methyl 4(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 86 mg of the title compound (80%) as a orange powder in 94% purity by HPLC (Rt: 4.17, gradient of 8 min, MaxPlot detection between 230 and 400 nm).