Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc2cccnc2c2ncccc12
Yield: 62 %

Procedure:
A magnetically stirred solution of 5nitro-1, 10-phenanthroline (2,.01 g, 8.93 mmol) and tin(II) chloride dihydrate (6.05 g, 26.81 mmol) was heated to reflux for 3 h in ethanol (100 mL) and then concentrated in vacuo to give a viscous residue. The residue was treated with concentrated NaOH and then extracted with CHCl3 (3×50 mL). The organic layer was separated, washed with water (2×50 mL) and brine (1×50 mL), dried over anhydrous sodium sulfate, and then concentrated in vacuo to afford 1.08 g (62%) of the amine as a tan solid: m.p. 255-258 C; MS(fab):m/e 196 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:16](Cl)[O:17][CH3:18].CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:16][O:17][CH3:18])[CH:5]=[O:6]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)cc(Br)c1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
A solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.0 g, 4.1 mmol) in DMF (10 mL) was cooled at 0° C., NaH (180 mg, 4.5 mmol) was added, and the mixture was stirred for 15 minutes. MOM-Cl (360 mg, 4.5 mmol) was added, and the mixture was warmed to room temperature in two hours. TLC (PE:EtOAc=5:1) indicated that the starting material was consumed. Ice water was added to quench the reaction, and aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (0.7 g, yield: 59.3%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][OH:23])=[N:11][CH:10]=1.O[C:36]1[CH:37]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[F:31][C:29]([F:32])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][O:23][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(COc2cccc(C(F)(F)F)c2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58.2 %

Procedure:
A solution of 80 mg (0.17 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7), 0.027 ml (0.22 mmol) 3-hydroxybenzotrifluoride, 47 mg (0.17 mmol) triphenylphosphine and 32 mg (0.17 mmol) diethyl azodicarboxylate in 2 ml tetrahydrofuran was stirred at room temperature over night. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 62 mg (60%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: [OH:1][C:2]([CH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])([CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO>[OH:1][C:2]([CH2:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH2:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)(CS(=O)(=O)c1ccc(OC)cc1)CS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)propionic acid, ethyl ester (0.70 g, 1.3 mmol) in 25 mL of methanol is added sodium hydroxide (25 mmol in 10 mL of water). The reaction mixture is stirred at ambient temperature for 1 hour, and then quenched by the addition of 25 mL of 1N HCl. Methanol is removed under reduced pressure, and the product is extracted with several portions of ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a white solid.
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:20]([C:19](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)#[N:21]
Reactant: COc1ccc(CC#N)cc1
Reactant: CCOC1(OCC)CCCN1C
Solvent: c1ccccc1
Product: COc1ccc(C(C#N)=C2CCCN2C)cc1

Procedure:
Boil 30.0 g of 2,2-diethoxy-1-methylpyrrolidine, 25 g of 4-methoxybenzylcyanide and 150 ml of benzene under reflux for 4 hours. Concentrate the refluxed reaction product and distil the residue twice under a vacuum to obtain 30.6 g (79% of theory) of the title compound (b.p. 158° at 0.005 mm of Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:35]C([O-])=O)([O:27][CH:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:29])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:29][CH:28]([O:27][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:27][CH:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:29])=[O:35])[C:10]2=[O:24])[C:14]1=[O:16])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Reactant: CCCCCC(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(C)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(C)CCCCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
4.28 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione, 7.26 g of 2-heptyl dicarbonate from Example B3, 0.20 g of 4-dimethylaminopyridine and 300 ml of dry tetrahydrofuran are mixed and the mixture is stirred at 55° C. for 4 hours. The suspension is filtered off with suction on a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure, and the residue is admixed with 100 ml of isopropanol. After 30 minutes the precipitate is filtered off with suction, washed with isopropanol and dried under reduced pressure to leave 3.46 g (45% of theory) of 2,5-di-2-heptyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as orange crystals. NMR (CDCl3) [ppm]: δ=7.67 (d, 4H), 7.45 (d, 2H), 4.67 (q, 2H), 1.53 (m, 2H), 1.48 (m, 2H), 1.28 (m, 16H), 0.88 (t, 6H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:19](=[O:22])[CH:20]=[CH2:21])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(F)ccc1N
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCc1cc(F)ccc1NC(=O)C=C
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A round-bottom flask containing the product from Step 1 (10.6 g, 70.1 mmol) was fitted with a stirbar and septa. Tetrahydrofuran (200 mL) and triethylamine (15.0 mL, 108 mmol) were added, giving a solution that was cooled to −10° C. Acryloyl chloride (6.0 mL, 73.6 mmol) was then added, and the resulting mixture was allowed to gradually warm to room temperature. After 16 hours, the reaction was concentrated to remove most of the tetrahydrofuran, then diluted with ethyl acetate (200 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give an oil which was purified via flash chromatography on silica gel (15% to 40% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][O:16][CH2:32][CH3:33])=[NH:14])=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCONC(=N)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
P1.2) A solution of 790 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine in 20 ml of dimethylformamide is added dropwise in the course of 15 minutes at 0-5° C. to 80 mg of sodium hydride 55% in 10 ml of dimethylformamide. After 3 hours' stirring at 0-5° C., 256 mg of ethyl iodide are added. After being stirred for 16 hours at room temperature the reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-ethoxy-benzamidine is obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14]([O:16]C)=O.[F:23][C:24]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:26]C(O)=O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14](=[O:16])[CH2:26][CH2:25][C:24]([F:34])([F:23])[C:30]([F:33])([F:32])[F:31]
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsilyl)amide (1.0M, 10 mL, 10 mmol) was added dropwise to a −78° C. THF (20 mL) solution containing methyl 2-bromo-5-chlorobenzoate (0.836 g, 3.35 mmol) and 3,3,4,4,4-pentafluoropentanoic acid (0.644 g, 3.35 mmol, intermediate from Step A). After stirring for 15 minutes at −78° C. the solution was warmed to 0° C. and stirred for an additional 2 hours. The reaction was quenched with an excess of aqueous 1N HCl(ca 20 mL) and stirred overnight at room temperature. The solution was concentrated to remove the majority of the THF. The solution was then diluted with EtOAc and washed with 1N NaHCO3 (twice) and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (liquid). 1H NMR (500 MHz, CH3 CN-d3): δ 7.64 (d, J=8.6 Hz, 1H); 7.56 (d, J=2.6 Hz, 1H); 7.40 (dd, J=8.5, 2.7 Hz, 1H); 3.23 (t, J=7.3 Hz, 2H); 2.61-2.50 (m, 2H). m/z=365.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 3-methoxyphenylboronic acid according to the general procedure B. Obtained as an orange solid (818 mg).
Reaction SMILES: [CH3:1][C@@:2]1([NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=3)[CH2:8]2)[CH2:4][CH2:3]1>O1CCCC1>[CH2:21]([NH:20][C@:2]1([CH3:1])[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]=3)[CH2:8]2)[CH2:4][CH2:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Solvent: C1CCOC1
Product: C[C@]1(NCc2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of N-{(3aR,4S,6aS)-4-methyl-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}benzamide (180 mg, 0.462 mmol) from Example 15 in tetrahydrofuran (1 mL) was added dropwise borane tetrahydrofuran complex solution (1.387 mL, 1.387 mmol). The reaction was heated at 80° C. for 3 hours, quenched with 2 N HCl (0.5 mL) and then stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic washes were purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.69 (d, J=8.0, 1H), 8.65 (d, J=7.4, 2H), 8.57-8.48 (m, 2H), 8.44 (t, J=7.3, 1H), 8.14 (d, J=7.2, 1H), 7.69 (d, J=8.6, 1H), 4.92-4.83 (m, 2H), 4.76-4.65 (m, 2H), 4.52-4.46 (m, 1H), 4.46-4.39 (m, 1H), 4.13-4.05 (m, 1H), 3.72 (dd, J=15.8, 7.9, 1H), 3.26 (dq, J=13.2, 8.3, 1H), 2.87-2.73 (m, 2H), 2.71-2.58 (m, 1H), 2.49 (dq, J=9.4, 5.0, 1H), 2.29 (s, 3H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH:21]([NH:25]C(OC(C)(C)C)=O)[CH2:20]2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[S:48][C:49]([C:53]([OH:55])=O)=[C:50]([CH3:52])[N:51]=2)=[CH:43][CH:42]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:53]([C:49]3[S:48][C:47]([C:44]4[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=4)=[N:51][C:50]=3[CH3:52])=[O:55])[CH2:20]2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(N2CCCC(NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 0 °C
Yield: 75.8 %

Procedure:
Methyl 3-benzyloxy-5-(3-tert-butoxycarbonylaminopiperidin-1-yl)benzoate (23.0 mg, 0.0522 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). While this solution is chilled in an ice bath and stirred, trifluoroacetic acid (80 μL, 6.82 mmol) was added and the reaction mixture was stirred for 2 hours. Subsequently, the mixture was concentrated and a 10% hydrochloric acid/methanol solution (1.5 mL) was added to the residue. The mixture was then stirred at room temperature for 1 hour and was concentrated. The same process was repeated 3 times and the resulting solid were washed with ethyl acetate. This gave 20.9 mg of a blown powder. This product (19.8 mg) was dissolved in N,N-dimethylformamide (1 mL). While the solution was chilled to 0° C. and stirred, 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid (15.5 mg, 0.0611 mmol), 1-hydroxybenzotriazole monohydrate (8.8 mg, 0.0575 mmol), N-methylmorpholine (17 μL, 0.155 mmol) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (11.7 mg, 0.0610 mmol) were added and the mixture was stirred for 20 min. The reaction mixture was further stirred at room temperature for the subsequent 6 hours. Subsequently, the mixture was diluted with ethyl acetate and the organic layer washed sequentially with 5% aqueous citric acid, a saturated aqueous sodium bicarbonate solution, water and brine. The washed product was then dried over anhydrous sodium sulfate and was concentrated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=4:1) gave 22.8 mg (75%) of the desired compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[CH3:9][NH:10][CH3:11]>C1COCC1>[CH3:9][N:10]([CH3:11])[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: CNC
Reactant: O=Cc1csc(Cl)n1
Solvent: C1CCOC1
Product: CN(C)c1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminothiazole (30 g, 0.3 mmol) in conc. hydrochloric acid (150 mL) at 0° C. was added dropwise a saturated solution of sodium nitrite (20.7 g) in water. After 75 minutes at 0° C., cuprous chloride (29.7 g) was added portionwise and the mixture stirred at 0° C. for a further 150 minutes. The mixture was neutralised with conc. sodium hydroxide solution and partitioned between diethyl ether and water. The organic phase was washed with brine, dried over sodium sulphate and evaporated in vacuo to afford 2-chlorothiazole as an oil. To a solution of 2-chlorothiazole (15.9 g, 133 mmol) in THF (200 mL) at −74° C. was added n-BuLi (1.6M in hexane, 90 mL). After 10 minutes, a solution of DMF (14 mL) in THF (90 mL) was added and the mixture allowed to attain room temperature over 2 hours. The mixture was then poured slowly into hydrochloric acid (2M, 400 mL), basified with ammonium hydroxide and extracted with dichloromethane (2×300 mL). The combined organic fractions were dried over sodium sulphate and evaporated in vacuo to afford 2chloro-thiazol4-carboxaldehyde as a solid. A mixture of 2chloro-thiazole-4-carboxaldehyde (20 g) in 2.5% aqueous THF (400 mL) and dimethylamine (13 g, 2.5 equiv.) in THF (150 mL) were combined and stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, the residue partitioned between water and dichloromethane and the organic layer dried over sodium sulphate. Evaporation of the solvent afforded the title compound as a solid
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1)=[N:4]OS(C1C=CC(C)=CC=1)(=O)=O.[NH3:34]>C(Cl)Cl.CO.O>[F:33][C:2]([F:32])([F:1])[C:3]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH3:23])=[CH:18][CH:17]=2)[N:4]=[N:34]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)ON=C(c2ccc(C(C)NC(=O)OC(C)(C)C)cc2)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C2(C(F)(F)F)N=N2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 46 %

Procedure:
tert-Butyl 1-(4-(2,2,2-trifluoro-1-(tosyloxyimino)ethyl)phenyl)ethylcarbamate (400 mg, 0.82 mmol) was dissolved in CH2Cl2 (5 ml). Ammonia in MeOH (7 ml, 7M) was added and the resulting mixture was stirred at room temperature for 7 days. The reaction was then diluted with water (50 ml) and extracted with CH2Cl2 (2*25 ml). Combined organics were dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography using Pet. Ether/EtOAc (3:1) as eluent to give 125 mg (46%) of the title compound as white solids.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a mixture of Boc-Leu-OH.H2O (2.5 g), H-DTrp-OBzl (2.9 g) and HOBT.H2O (1.6 g) in dichloromethane (50 ml) was added EDCI.HCl (2.0 g) under ice cooling. After being stirred at room temperature for 16 h, the mixture was washed with water, 10% aq. citric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexane to give Boc-Leu-DTrp-OBzl (4.79 g). To a solution of the dipeptide (753 mg) in dichloromethane (7 ml) were added methyl chloroformate (1 ml), pulverized NaOH (89 mg) and TBAHS (20 mg) under ice cooling. After being stirred of the mixture at room temperature for 30 min, pulverized NaOH (89 mg) was added. This procedure was repeated twice more. The reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3, 10% aq. citric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from dichloromethane and petroleum ether to give Boc-Leu-DTrp(COOMe)-OBzl (721 mg) as colorless crystals. The dipeptide (708 mg) was dissolved in methanol (7 ml) - THF (5 ml) and 10% Pd/C (70 mg) was added. The mixture was vigorously stirred at room temperature under an atmospheric pressure of hydrogen for 1 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give Boc-Leu-DTrp(COOMe)-OH (580 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:7])[CH2:6][CH2:5][CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][C:3]1([NH:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(N)CCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(NS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a stirred solution of 1-methyl-cyclobutylamine hydrochloride (0.100 g, 0.8 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.090 g, 67%). 1H NMR (300 MHz, CDCl3) δ 4.49 (br s, 1H), 3.03 (s, 3H), 2.40-2.25 (m, 2H), 2.12-2.00 (m, 2H), 1.95-1.75 (m, 2H), 1.58 (s, 3H).