Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[NH2:18])=[O:30])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: Nc1c(C(=O)O)ccc2ccccc12
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2N)CN1CC1CCCCC1

Procedure:
(2S,4S)-4-[(1-Amino-naphthalene-2-carbonyl)-amino]-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester and 1-amino-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C24H32N3O3[(M+H)+] 410, obsd. 410.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](O)([CH2:14][CH:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:26][C:24]1[CH:25]=[C:20]([CH:15]([C:16]([F:17])([F:19])[F:18])/[CH:14]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:7][CH:8]=2)\[CH3:13])[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CC(O)(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C/C(=C\C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a solution of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p-toluenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to ambient temperature and dissolved in ethyl acetate. The solution was washed with sat aq NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCOCC1>[N:9]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: O=C1NOCC(=S)N1
Solvent: C1COCCO1
Product: O=C1N=C(n2ccnc2)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 56.2 %

Procedure:
To a solution of 1.0 g (0.0075 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 50 ml of freshly distilled dry dioxane is added 0.52 g (0.0077 mole) of imidazole. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 0.7 g (56 percent) of 5-(1H-imidazol-1-yl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3ccncc3)cc21
Product: CC1c2cc(-c3ccncc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-ethyl-N-acetyl-aniline [3 g, Reference Example 33(a)] in acetic anhydride (8 mL) and acetic acid (4 mL), at −5° C., was treated dropwise with a mixture of acetic acid (1.75 mL) and concentrated nitric acid (1.22 mL). The mixture was warmed to 0° C., then stirred at 0° C. for 2 hours and then poured onto water. This mixture was evaporated and the resulting oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residual oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (2:5) to give 4-ethyl-2-nitro-N-acetyl-aniline (1.4 g) as an orange solid. LC-MS (METHOD B): RT=2.95 minutes; 209.2 (M+H)+. (b) 4-Ethyl-5-methyl-2-nitro-N-acetyl-aniline
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[CH3:6][N:7]1[C@H:11]2[C:12]([C:15](OC)=O)=[CH:13][CH2:14][C@@H:8]1[CH2:9][CH2:10]2>C1COCC1>[CH3:2][C:1]1[N:3]=[C:15]([C:12]2[CH:11]3[N:7]([CH3:6])[CH:8]([CH2:14][CH:13]=2)[CH2:9][CH2:10]3)[O:5][N:4]=1
Reactant: CC(N)=NO
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Solvent: C1CCOC1
Product: Cc1noc(C2=CCC3CCC2N3C)n1
Temperature: 60 °C

Procedure:
Acetamide oxime (500 mg, 6.75 mmol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with Nail (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 mmol) and 4 A· molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h, After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:20][C:19]([CH:30]=O)=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:20][C:19]([CH2:30][NH:13][CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH3:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Reactant: CC(N)c1ccnc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The 1-quinolin-4-yl-ethylamine (510 mg, 3 mmol) and 6,4′-dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) were stirred with acetic acid (300 mg, J. T. Baker) in methyl alcohol (15 mL0 at room temperature for 4 h. To the reaction solution was added sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich) at 0° C. The mixture was stirred under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with saturated aqueous sodium bicarbonate (30 mL). The methyl alcohol was removed from the mixture via vacuo. The residue was extracted by ethyl acetate (30 mL×4). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated via vacuo. The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 72% yield (287 mg, 0.72 mmol).
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:16][C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[CH2:23]([C:17]1([OH:16])[CH2:22][CH2:21][N:20]([CH:2]([CH3:15])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(Cl)C(=O)c1ccc2c(c1)CC(=O)N2
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccc2c(c1)CC(=O)N2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
5-(2-Chloropropionyl)-2(1H,3H)-indolone (2.5 g, 11.2 mmol), 4-hydroxy-4-benzylpiperadine (2.1 g, 11.2 mmol), and triethylamine (1.56 ml, 11.2 mmol) were combined in ethanol and refluxed overnight. The mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over calcium sulfate, and concentrated. The crude product was flash chromatographed on silica gel eluting first unreacted 5-(2-chloropropionyl)-2(1H,3H)-indolone with 1:1 ethyl acetate:hexane. Continued elution with ethyl acetate gave 3.6 g of product as a light brown foam. Recrystallization from ethyl acetate/hexane gave 1.23 g of purified title product. Less pure fractions from the column and mother liquors from the recrystallization were rechromatographed as above with 1:1 and then 3:1 ethyl acetate:hexane. Product fractions were triturated with ether/hexane to give 0.2 g more product for a total yield of 1.43 g, 34%; m.p. 188°-192° C.; NMR 8.22 (s, 1H), 8.08 (d, J=8 Hz, 2H), 7.99 (s, 1H), 7.31-7.13 (m, 5H), 6.89 (d, J=8 Hz, 1H), 4.03 (q, J=6.8 Hz, 1H), 3.57 (s, 2H), 2.72 (s, 2H), 2.72-2.58 (m, 3H), 2.46 (distorted t, 1H), 1.75-1.40 m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.23-1.19 (m, 1H).
Reaction SMILES: C[N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:30])[NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:30])[N:25]2[C:16](=[O:18])[CH2:15][C:3]1[NH:2][C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1Cc2c(F)cccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 29.2 %

Procedure:
The product is prepared by following the procedure described in example 29c using 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c), 0.11 g of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c], and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 120 μl of pyridine and 3.0 ml of N,N-dimethylformamide. 79 mg of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCCC1.CO>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:4](=[S:3])[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:6]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)n(C(=O)OC(C)(C)C)c(=S)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in oil) (5.55 g; 138 mmol) is added in small portions at 10° C., with stirring, to a solution of 2-mercapto-5-methoxybenzimidazole (10 g; 55.5 mmol) in solution in 400 ml of tetrahydrofuran under argon. The reaction mixture is then stirred for 30 minutes at 0° C., and then BOC2O (26.64 g; 122 mmol) is added in one go. Stirring of the reaction mixture is then carried out for 18 hours at ambient temperature. The reaction mixture is diluted with methanol, filtered over Celite and then concentrated to dryness. The residue obtained is subsequently taken up in a 1/1 mixture of petroleum ether/isopropyl ether. The solid which precipitates is then suction-filtered off to yield the title product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[NH:19][CH:18]=[N:17][N:16]=2)=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[N:19]=[CH:18][N:17]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[N:16]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: O=C(c1ccc(Cl)cc1)c1ccsc1-c1nnc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccsc1-c1ncn(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 500 mL, round bottomed flask, (4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone (16.89 g, 58.29 mmol) was dissolved in tetrahydrofuran (500.0 mL, 6164 mmol). To the solution were added dihydropyran (31.9 mL, 3.50E2 mmol) and p-toluenesulfonic acid monohydrate (16.6 g, 87.4 mmol). The mixture was stirred for 3 h at rt. The reaction was quenched by the addition of saturated aqueous solution of sodium bicarbonate (200 mL). The aqueous phase was separated and then extracted with EtOAc (300 mL). The combined organic phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to afford (4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)methanone as an oil which was dried under high vacuum overnight (19.4, 89.1%). LCMS: (FA) ES+ 374.2, 376.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(#N)C>[CH:11]([N:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(N2CCN(C)CC2)nc2c1cnn2C(C)C
Yield: 100.2 %

Procedure:
To a stirred solution of ethyl 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.3 g, 0.964 mmol) in acetonitrile (10 mL), K2CO3 (0.26 g, 1.93 mmol) and 1-methylpiperazine (0.289 g, 2.892 mmol) was added. The reaction mixture was refluxed for 3 h. On completion of reaction, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to obtain the desired intermediate (0.32 g, 94.9%).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][C:6]3=[N:11]O)[CH:3]=[CH:2]1>CO.[Ni].O>[CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH2:11])[CH2:3][CH2:2]1
Reactant: ON=C1CC2CC1C1C=CCC21
Agent: [Ni]
Solvent: CO
Solvent: O
Product: NC1CC2CC1C1CCCC21
Reaction time: 20 h

Procedure:
2.2 g of 1,3a,4,6,7,7a-hexahydro-4,7-methanoinden-5-one oxime were dissolved in 50 ml of methanol, and about 10% Raney nickel, dissolved in 50% water, was added. The mixture was hydrogenated at 100 bar and 100° C. for 20 hours, the catalyst was then filtered off, and the solvent was evaporated under reduced pressure. The residue was taken up in ether and 6 N aqueous sodium hydroxide solution, the phases were separated, the aqueous phase was extracted three times with ether, the combined organic phases were dried with magnesium sulfate and filtered, and the filtrate was concentrated. This gave 1.8 g of a colorless oil which was purified by kugelrohr distillation. This gave 0.96 g of the desired amine as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:9][CH2:10][CH2:11][NH2:12].[CH3:13][N:14]=[C:15]=[S:16].C(OCC)(=O)C.C(O)C>C(O)C>[CH3:13][NH:14][C:15]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[N:4]=1)=[S:16]
Reactant: Cc1cn(C)c(CSCCN)n1
Reactant: CN=C=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=S)NCCSCc1nc(C)cn1C

Procedure:
The reaction of 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole (derived from the 6.2 g. dihydrobromide) with methyl isothiocyanate (1.34 g.) in ethanol (50 ml.) followed by chromatography on a column of silica gel with ethyl acetate-ethanol (9:1) as eluant gave N-methyl-N'-[2-((1,4-dimethyl-2-imidazolyl)methylthio)ethyl]thiourea (2.1 g.). (Found: C, 46.8; H, 6.9; N, 21.5; S, 24.9. C10H18N4S2 requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][N:31]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH:15]=[C:14]1[CH:16]([CH3:17])[CH3:18])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 36, 1.2 g, 3.11 mmol) following the procedure described for Intermediate 10, using 2.4 equivalents each of triphenylphosphine and diisopropylazodicarboxylate. The desired product was obtained as yellow foam (1.22 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:22][OH:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:14][CH:15]=1.O[C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:14][CH:15]=1)[CH2:22][O:23][C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1
Reactant: COc1cc(CO)ccc1OCc1csc(N2CCOCC2)n1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCOCC2)n1
Reaction time: 15 h
Yield: 59.3 %

Procedure:
To a mixture of {3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (0.93 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.85 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.06 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as crystals (0.83 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (2:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: C([NH:11][CH2:12][C:13]([N:15]=[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[S:17]1)=[O:14])(OCC1C=CC=CC=1)=O.[BrH:26].C(OCC)C>C(O)(=O)C>[BrH:26].[NH2:11][CH2:12][C:13]([N:15]=[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([S:22]([NH2:25])(=[O:23])=[O:24])[S:17]1)=[O:14]
Reactant: Cn1nc(S(N)(=O)=O)sc1=NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cn1nc(S(N)(=O)=O)sc1=NC(=O)CN
Reaction time: 3 h

Procedure:
The desired compound is prepared by subjecting 2-(N-carbobenzyloxy-glycylimino)-3-methyl-1,3,4-thiadiazoline-5-sulphonamide (0.5 gm) suspended in glacial acetic acid (5ml) to a solution of hydrogen bromide in glacial acetic acid (32% w/w. 8.0 ml) at room temperature for about 1 hour with stirring. Diethyl ether (50 ml) is then added and the mixture set aside for three hours at 0° C. The solid precipitate is collected, washed with diethyl ether, and dried to give the desired product, 2-(glycylimino)-3-methyl-1,3,4-thiadiazoline-5-sulphonamide hydrobromide, m.p. 209°-210° C. (0.4 gm).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[K+]>C1(C)C=CC=CC=1>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 95 °C
Reaction time: 51 h
Yield: 90 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (5 g, 23 mmol) was mixed with a 73% aqueous potassium hydroxide solution (5.7 g) and toluene (10 ml), and the mixture was heated to 95° C. and stirred for 51 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 90%.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13]([C@H:15]1[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[C:17]([C:33]([O:35][CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[O:16]1)=O.[CH3:49][NH:50][CH2:51][CH2:52][CH3:53]>>[CH:36]([O:35][C:33]([C:17]1[O:16][C@@H:15]([C:13](=[O:12])[N:50]([CH3:49])[CH2:51][CH2:52][CH3:53])[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH:18]=1)=[O:34])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(=O)N[C@@H]1[C@@H](NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCNC
Product: CCCN(C)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To (2R,3R,4S)-3-acetylamino-4-(tert-butoxycarbonylamino)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid 6-benzhydryl ester 2-(2,3,4,5,6-pentafluoro-phenyl) ester (1.18 g) in dry tetrahydroduran (13 ml) was added N-methyl-propylamine (0.152 g) and the reaction was stirred at 23° C. for 4 hours. The solvent was removed in vacuo and the residue was chromatographed over silica (Merck 9385, 150 g) using medium pressure (~4 psi) and ethyl acetate as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam. (0.85 g); 1H NMR (250 MHz, D6 -DMSO) 8.10-7.98 (1H, m), 7.48-7.26 (10H, m), 6.91 (1H, s), 6.58 (1H, m), 6.03 (1H, m), 5.13 (1H, m), 4.34 (1H, m), 4.03 (1H, m), 3.37 (2H, m), 3.07+2.81 (3H, s), 1.77 (3H, s), 1.64-1.22 (2H, m), 1.37 (9H, s), 0.81 (3H, m): Mass spec (Low resolution): MH+ =566, MH+ -BOC=466; Mass analysis: