Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([CH:8]1[CH2:10][N@@:9]1[S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1ccc(C[C@H]2CN2)cc1
Agent: CN(C)S(=O)(=O)[N@@]1CC1Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)[N@]1CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a cooled (−10° C.) solution of (S)-2-benzylaziridine (100 g, 0.751 mol) and N,N-dimethylsulfamoyl chloride (84.5 mL, 0.787 mol) dichloromethane (100 mL) was added N,N-diisopropylethylamine (131 mL, 0.751 mol). The resulting yellow solution was stirred at −10° C. for a minimum of 16 hours. After this period, a 0.5M solution of citric acid (500 mL) was added and the phases were separated. The organic phase was then washed with 1.0 M sodium bicarbonate solution (500 mL). The organic phase was then solvent exchanged into tert-butyl methyl ether (500 mL). The solution was then cooled to 0° C., and heptane (100 mL) was added dropwise over a period of 2 hours. The mixture was then aged for an additional 2 hours at 0° C., and then cooled (−10° C.), to allowed compound IIa to precipitate out as a white, crystalline solid (27.8 g, 77%). Tlc assay: Rf 0.53 (SiO2; 1:1 heptane:ethyl acetate. KMnO4). 1H NMR (400 MHz, CDCl1): δ 7.20-7.29 (m, 5H), 2.94 (dd, J=14, 5 Hz, 1H), 2.80-2.88 (m, 1H), 2.70 (dd, J=14, 7 Hz, 1H), 2.66 (s, 6H), 2.56 (d, J=7 Hz, 1H), 2.14 (d, J=4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.4, 129.3, 128.9, 127.2, 40.6, 38.3, 38.1, 33.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][O:22][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][OH:22])[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CO[C@H](CO)COCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of diethyl (S)-[2-benzyloxy-1-(t-butyldiphenylsilyloxymethyl)ethoxy]methylphosphonate (3.09 g, 5.4 mmol) in trifluoroacetic acid/water 2:1 (12 ml) was stirred at ambient temperature for 1 hour. The solution obtained was extracted with hexane (2×10 ml) and the aqueous containing phase evaporated to dryness. The residue obtained was treated with ethanolic ammonia (5 ml) for 5 minutes at ambient temperature, the solvent evaporated and the residue chromatographed on silica gel using dichloromethane/methanol 95:5 as eluant. The title compound was obtained as a colourless oil (1.35 g, 75%). IR: νmax (film) 3380, 3060, 3030, 2980, 2910, 2860, 1495, 1480, 1450, 1390, 1370, 1250, 1160, 1100, 1075, 975, 910, 890, 820, 780, 740, 700 cm-1. 1H NMR: δH [(CD3)2SO]1.21, 1.22 (2×3H, 2×t, J=7 Hz, (OCH2CH3)2, 3.4-3.65 (5H, m, CH2, CH,CH2), 3.94 (2H, d, J=8.5 Hz, OCH2P), 3.97-4.1 (4H, m, (OCH2CH3)2), 4.5 (2H, s, CH2Ph), 4.67 (1H, t, J=5.5 Hz, D2O exchangeable OH), 7.20-7.40 (5H, m, Ph). Found: C, 53.20; H, 7.72%. C15H25O6P 0.33 H2O requires: C, 53.25; H, 7.64%. m/z: observed 332.1383. C15H25O6P requires 332.1387. [α]D25 (CHCl3) +16.7° (c=1.06).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1([CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCCO)C.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:22]1[CH2:23][CH2:24][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Solvent: CCOCCO
Solvent: O
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(Cl)ccc2n1

Procedure:
4,6-Dichloro-2-methylquinoline (0.1 g) and 3-phenylpyrrolidine (0.15 g) in 2-ethoxy-ethanol (1.5 mL) was heated in a microwave at 240° C. for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane. Evaporation of the desired fractions gave the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:21][CH2:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][CH2:28]3)[C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(=O)CO2

Procedure:
6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (310 mg, 1.73 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) (2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) afforded the product as a solid (58%).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=O)=O)(C)(C)C.[C:19]1(S(CP(OCC)(=O)OCC)(=O)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].[CH:40]([S:42]([CH:45]=[CH2:46])(=[O:44])=[O:43])=C.[ClH:47]>CCOC(C)=O>[ClH:47].[C:19]1([CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:9]([NH2:8])[CH:10]=[CH:40][S:42]([CH:45]=[CH:46][C@@H:9]([NH2:8])[CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:44])=[O:43])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)(C)OC(=O)NC(C=O)Cc1ccccc1
Reactant: CCOP(=O)(CS(=O)(=O)c1ccccc1)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Boc-Phe-VS-Ph was prepared by reaction of Boc-Phe-H with diethyl phenylsulfonylmethanephosphonate in the presence of 2 N sodium methoxide, yield 85%. 1H-NMR (CDCl3) δ 1.3-1.4 (s, 9H, Boc), 2.9 (d, 2H, CH2-Phe), 4.4-4.5 (b, 1H, α-H), 4.6-4.7 (b, 1H, NH), 6.3 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.3 (m, 5H, Ph), 7.5-7.8 (m, 5H, SO2-Ph). MS (FAB+) m/z 388 (M+1, 15%), 288 (M−Boc+1, 100%). Boc-Phe-VS-Ph was deblocked with 6.7 N HCl in EtOAc to give Phe-VS-Ph.HCl, yield 88%. 1H-NMR (DMSO-d6) δ 2.9-3.0 (m, 1H, CH2-Phe), 3.1-3.2 (m, 1H, CH2-Phe), 4.2 (b, 1H, α-H), 6.7-6.8 (m, 2H, CH═), 7.1-7.3 (m, 6H, CH═ and Ph), 7.6-7.8 (m, 5H, SO2-Ph), 8.6-8.8 (b, 2H, NH2). MS (FAB+) m/z 288 (M−Cl, 100%).
Reaction SMILES: [F:1][C@@H:2]1[C:25]2[C@:20](C)([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C:19]2[C@H:4]([C@H:5]3[C@:16]([CH3:28])([CH2:17]C=2)[C@@:8]([O:29][C:30](=[O:32])[CH3:31])([C:9](=[O:15])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:33])[CH2:6]3)[CH2:3]1.Br[C:35]1([Br:42])NC(=O)N[C:36]1=[O:41].C(OCC)(=O)C>O1CCOCC1.O>[F:1][C@@H:2]1[C:25]2[C@:20]([CH3:19])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C@:35]2([Br:42])[C@H:4]([C@H:5]3[C@:16]([CH3:17])([CH2:28][C@@H:36]2[OH:41])[C@@:8]([O:29][C:30](=[O:32])[CH3:31])([C:9](=[O:15])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:33])[CH2:6]3)[CH2:3]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reactant: O=C1NC(=O)C(Br)(Br)N1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Reaction time: 0.17 h

Procedure:
Ten (10) g of 6α-fluoro-16β-methyl-17α,21-diacetoxypregna-1,4,9(11)-triene-3,20-dione in 110 ml of dioxane (A.R.) plus 2.2 mls of a solution of 4.4 ml 70% HClO4 in 200 mls of water, is treated with 4 g of dibromohydantoin in the dark at R.T. for a period of one hour or when TLC using 50% ethyl acetate/50% hexane shows the reaction to be complete. The reaction mixture is precipitated in 2 l of water, stirred for 10 minutes and the crystalline precipitate collected by filtration, washed with water, and air dried to give 11.4 g of 6α-fluoro-9α-bromo-11β-hydroxy-16β-methyl-17α,21-diacetoxypregna-1,4-diene-3,20-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][NH:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[N:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:29]([NH:28][CH3:27])[S:30][CH:31]=2)=[CH:41][CH:40]=1
Reactant: CNc1nc(-c2ccc(CN)cc2)cs1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CNc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)cs1
Yield: 21.3 %

Procedure:
Use a method similar to the General Procedure 1-3, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.48 g, 1.14 mmol) and 4-(2-methylamino-thiazol-4-yl)-benzylamine (0.4 g, 1.8 mmol), to obtain 7-chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (0.12 g, 21%). MS (ES+) m/z: 495 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:10].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>>[Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-:10]
Reactant: O=S(=O)(O)O
Reactant: Clc1nccnc1Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Product: [O-][n+]1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 750 g. (5 mol) of 2,3-dichloropyrazine* in 5 l. of sulfuric acid at 10° C, is gradually added 1,500 g. (5.5 mol) of potassium persulfate. The reaction mixture is stirred at room temperature for 24 hours and carefully poured into 19 l. of ice water. The aqueous solution is extracted with chloroform and the extract is washed with sat. NaHCO3 and sat. NaCl solutions and dried over MgSO4. Evaporation of the solvent provides 698 g. (85%) of white solid. MP 101-103° C. (lit. MP 104°-106° C). This material is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18](=O)[NH2:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:26][CH2:27]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Reaction time: 1 h

Procedure:
295 mg of 2-trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino-3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate were dissolved in 20 ml of THF. 166 μl of triethylamine and 91 μl of trifluoroacetic anhydride were successively added dropwise. The mixture was stirred for 1 h and then the same amounts of triethylamine and trifluoroacetic anhydride were again added. After stirring for a further hour, the mixture was partitioned between 150 ml of ethyl acetate and 150 ml of water. The organic phase was dried with MgSO4. The solvent was removed in vacuo and the residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[NH2:5][C:6]1[C:15]([CH3:17])([CH3:16])[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(=O)(O)[O-].[Na+]>C(O)C.O.C1(C)C(C)=CC=CC=1>[CH3:16][C:15]1([CH3:17])[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[CH:2]=[CH:3][N:5]=[C:6]12.[ClH:1]
Reactant: CC1(C)C(N)=Nc2ccccc2C1(O)c1ccccc1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CC1(C)c2nccn2-c2ccccc2C1(O)c1ccccc1
Product: Cl
Yield: 263.3 %

Procedure:
To a solution of freshly prepared chloroacetaldehyde (2.30 g., 0.03 mole) in absolute ethanol (50 ml.) and water (12.5 ml.) was added a solution of 2-amino-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (6.66 g., 0.025 mole) in absolute alcohol (62.5 ml). Sodium bicarbonate (2.5 g) was added and the mixture refluxed for 6 hours. After cooling, a small precipitate was filtered off, and the filtrate concentrated in vacuo, taken up in water, extracted with ether, dried and evaporated. The residue was crystallised from isopropyl alcohol to give an intermediate (3.77 g., m.p. 188°-190° C). A solution of this intermediate in dried xylene (200 ml.) was refluxed under a Dean and Stark head for 21 hours, cooled and the xylene evaporated. The hydrochloride of the residue was recrystallised from isopropyl alcohol to give the title compound as its hydrochloride (2.4 g., 258°-260° C).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]([CH3:4])[CH3:3].CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][NH:35][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16]
Reactant: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C
Yield: 38.9 %

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (40.0 mg) was prepared by following General Procedure F starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.72 (1H, m), 7.54 (1H, m), 7.35 (1H, m), 4.00-3.99 (2H, m), 2.81-2.80 (3H, d), 1.23 (1H, m), 0.95-0.92 (6H, m), 2 —NH proton signals were not observed.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](CC2CCC(F)(F)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCC(F)(F)CC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
Trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (300 mg, 0.77 mmol) (from example 89, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.227 mL, 0.77 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.047 mL, 0.77 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (267 mg, 97%) as a slightly yellow solid. MS m/z 357 (M−H)−
Reaction SMILES: ClCCl.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[N:12][C:13]=1[NH:14][NH:15]C(OC(C)(C)C)=O)=[O:8])[CH3:5].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[N:12][C:13]=1[NH:14][NH2:15])=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(NNC(=O)OC(C)(C)C)ncn1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(NN)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To 50 ml of a dichloromethane solution containing 3.7 g of 3-benzyl-5-(N′-t-butoxycarbonylhydrazino)-3H-imidazole-4-carboxylic acid ethyl ester, 20 ml of trifluoroacetic acid was added. The resulting mixture was stirred at room temperature for 4 hours, and 100 ml of toluene was added thereto. The mixture was concentrated under reduced pressure. The residue was dissolved in 400 ml of ethyl acetate, and the solution was washed with 200 ml of a 2 N sodium hydroxide solution. The aqueous layer was extracted with 200 ml of ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (1.65 g) as a light yellow solid.
Reaction SMILES: [NH:1]([C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35](OCC)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.[OH2:50].[NH2:51][NH2:52]>C(O)C.CN(C=O)C>[NH:1]([C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:51][NH2:52])=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:50])=[CH:8][CH:9]=1
Reactant: O
Reactant: NN
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 48 h

Procedure:
6.0 g of Z-Tyr-(D)-Met(O)-Gly-Phe-OEt is dissolved in a mixed solvent of 20ml of ethyl alcohol-20 ml of DMF, and 2 ml of hydrazine hydrate is added tothe solution, which is then allowed to stand at room temperature for 2 days. The ethyl alcohol is distilled off, followed by adding diethyl ether, and the precipitated crystals are collected by filtration. The crystals are boiled with acetonitrile for washing. The yield of the product is 5.0 g, m.p. 182°-184° C., Rf1 =0.10, [α]D21 -13.4° (c=0.44, DMF),
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=O.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:17]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[CH:19]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1cc[nH]n1
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1cc(Cl)ccc1O)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 5-chloro-2-hydroxybenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[CH:20]1([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:23][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:25])[CH2:22][CH2:21]1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: O=C(NC1CC1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 1168.8 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 150 mg of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring for 5 minutes, the mixture was cooled to 0° C., 124 mg of phenyl N-cyclopropylcarbamate was added and the mixture was further stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, the organic layer was washed 3 times with water and once with aqueous ammonium chloride solution, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), to obtain 2.4 g of a colorless powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:6]=[CH:7][CH:8]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].NCCC(O)=O>C(O)(=O)C>[S:22]=[C:21]1[NH:23][C:24](=[O:25])/[C:26](=[CH:12]/[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=2)/[S:20]1
Reactant: O=Cc1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CSC(=S)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: O=C1NC(=S)S/C1=C\c1ccccc1Nc1cccc(C(F)(F)F)c1
Yield: 66.4 %

Procedure:
To a room temperature solution of 2-[[3-(trifluoromethyl)phenyl]amino]benzaldehyde (749 mg, 2.83 mmols) and rhodanine (398 mg, 2.99 mmols) in 20 mL of acetic acid is added β-alanine (382 mg, 4.29 mmols). The solution is heated at reflux for 45 min. During this time a thick precipitate forms. The mixture is filtered hot, washing with an additional 10 mL of acetic acid, to provide 715 mg (66%) of (Z)-2-thioxo-5-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylene]-4-thiazolidinone as a bright red-orange solid; mp=234°-236° C. Calc'd for C17H11F3N2OS2: