Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24](=[CH2:27])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32].Br[CH2:38][C:39]([NH2:41])=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:41][C:39]([CH2:38][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:28])[CH:11]1[C:24](=[CH2:27])[CH2:25][CH3:26])=[O:40].[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32]
Reactant: NC(=O)CBr
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(CC)C1N(CC(N)=O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reaction time: 8 h
Yield: 36.2 %

Procedure:
Racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2 g, 3.4 mmol) prepared in Example 161b, 2-bromo-acetamide (1.4 g, 10.2 mmol) and cesium carbonate (6.6 g, 20.4 mmol) were mixed in DMF (10 mL). The mixture was stirred overnight. Then the solution was concentrated and the residue was purified by Prep-TLC to give product (800 mg).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.C(O)(C)(C)C>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in toluene (960 ml), and 35% conc. hydrochloric acid (30.0 g) was added. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in t-butanol (130 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (50.6 g, yield: 25.0%) and 2-keto-L-gulonic acid (146.8 g, residual ratio: 65.7%).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[CH:8][CH:7]=1>CS(C)=O.CN(C=O)C>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=2)=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanide (0.75 g) was added to a solution of the crude product from step (vi) in DMSO (10 ml) and DMF (10 ml). The mixture was stirred at rt for 18 h, then partitioned between EtOAc/water. The organics were separated, washed with aq NaHCO3 solution, dried and evaporated under reduced pressure to afford the subtitle compound, 1.2 g.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[I:27]I.[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc(-c2ccccc2)c1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCn1cc(-c2ccccc2)nc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 1-butyl-4-phenylimidazole (4.0 g, 20 mmol) in 60 ml of anhydrous THF at −78° C. under nitrogen is added a solution of n-butyllithium in hexane (1.6M, 13.13 ml, 21 mmol, 1.05 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 h followed by dropwise addition of a solution of iodine (5.33 g, 21 mmol, 1.05 eq.) in 40 ml of THF. The resulting solution is stirred at −78° C. for 30 min. and then warmed to room temperature. Saturated ammonium chloride (30 mL) is added to quench the reaction. The resulting mixture is evaporated a reduced pressure to remove THF, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) affords 5.73 g of 1-butyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.73 (2H, dd, J=1.2, 8.4 Hz), 7.36 (2H, m), 7.30 (1H, s), 7.24 (1H, m), 3.92 (2H, t, J=7.2 Hz), 1.79 (2H, m), 1.41 (2H, m), 0.98 (3H, t, J=7.2 Hz); MS (+VE) m/z 327 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2C3C(CCC)=[CH:12][C:11](=[O:17])[O:10][C:9]=3[C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[C:19]([OH:20])[C:5]=2[CH:4]=[CH:3]1.[CH3:26][C:27]1C=CC(S([O-])(=O)=O)=CC=1.[CH:37]1[CH:42]=[CH:41][NH+]=[CH:39][CH:38]=1.CC1OC(C)OC(C)O1.C(C(O)=O)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:39][CH2:38][CH2:37][C:42]1[C:41]2[C:6]3[O:7][C:2]([CH3:25])([CH3:1])[CH:3]=[CH:4][C:5]=3[C:19]3[O:20][C@H:26]([CH3:27])[C@@H:22]([CH3:23])[C:21](=[O:24])[C:18]=3[C:9]=2[O:10][C:11](=[O:17])[CH:12]=1
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: c1cc[nH+]cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC1OC(C)OC(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)C3=O
Yield: 27.1 %

Procedure:
To a stirring solution of chromene 4 (350 mg, 1.0 mmol) and PPTS (250 mg, 1.0 mmol) in 1,2-dichloroethane (2 mL) at ambient temperature under N2 was added 3 mL paraldehyde (22.5 mmol). The resulting mixture was refluxed for 7 h. Then, CF3CO2H (1 mL), an additional equivalent of PPTS and 1 mL of paraldehyde were added; the mixture was refluxed overnight. The reaction mixture was neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate (50 mL×3). The crude product obtained by evaporation under reduced pressure was washed with hexane. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:2) to afford 100 mg (27% yield) of chromanone 7 and 30 mg (8% yield) of 7a. Chromanone 7 (10,11-trans-dihydro-6,6,10,11-tetramethyl-4-propyl-2H,6H,12H-benzo[1,2-b:3,4-b':5,6-b"] tripyran-2,12-dione) obtained by this method was identical with an authentic sample by comparison of TLC, HPLC and spectroscopic data.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.C(O)(C)C.[Br:36][C:37]1[CH:38]=[C:39]([OH:44])[C:40]([Cl:43])=[CH:41][CH:42]=1>C(Cl)Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([O:44][CH:1]([CH3:6])[CH3:2])[CH:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cc(Br)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Oc1cc(Br)ccc1Cl
Reaction time: 0.17 h

Procedure:
To 1.70 g (6.5 mmol) of triphenylphosphine in 25 mL of CH2Cl2 at 0° C. was added 1.14 g (6.5 mmol) of diethylazodicarboxylate. After 10 minutes, 390 mg (6.5 mmol) of isopropanol was added, followed rapidly by 1.03 g (5.0 mmol) of 3-Bromo-6-chlorophenol. The reaction was complete within three hours, and was partitioned between ether and water. The phases were separated, and the ether phase was diluted with hexanes and washed twice with 10% aqueous methanol and once with brine. The ether/hexanes phase was dried over Na2SO4, filtered, and concentrated in vacuo to yield product as a clear oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:12]=[C:13]([NH:16][C:17]([NH2:19])=[S:18])[S:14][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:20][I:21]>CO>[IH:21].[C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:12]=[C:13]([NH:16][C:17](=[NH:19])[S:18][CH3:20])[S:14][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(-c2csc(NC(N)=S)n2)o1
Reactant: CI
Solvent: CO
Product: CSC(=N)Nc1nc(-c2ccc(CNC(C)=O)o2)cs1
Product: I
Yield: 84.3 %

Procedure:
A suspension of 4-(5-acetylaminomethylfuran-2-yl)-2-thioureidothiazole (12.6 g) and methyl iodide (7.2 g) in methanol (200 ml) was refluxed for 5.5 hours. The solvent was removed under reduced pressure. The residue was washed with ethyl acetate to afford 4-(5-acetylaminomethylfuran-2-yl)-2-(2-methylisothioureido)thiazole hydriodide (15.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]([OH:23])(=O)[CH3:21]>O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:20](=[O:23])[C:21]3[CH2:2][CH2:3][CH2:4][CH2:5][C:7]=3[C:8]2=[O:9])=[C:4]([F:19])[CH:3]=1
Reactant: CC(=O)O
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 175.4 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetarhydrophthalic anhydride (7.56 g) and acetic acid (50 g) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and water (75 g) was added thereto. The precipitated crystals were collected by filtration to give the compound (I) (15.4 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:25])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and methyl iodide in acetonitrile there is obtained 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 79° C.;
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=O)C.C(OC(=O)C(CC)CCN1C(=S)N2C3C=C(C4C=CC([N+]([O-])=O)=CC=4)OC=3C=C2C1=O)C.[N:55]([CH2:58][CH2:59][CH2:60][C:61]#[N:62])=[C:56]=[S:57].C([O-])([O-])=O.[K+].[K+]>C(O)C>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[O:13][C:8]3[CH:7]=[C:6]4[C:4](=[O:3])[N:55]([CH2:58][CH2:59][CH2:60][C:61]#[N:62])[C:56](=[S:57])[N:10]4[C:9]=3[CH:11]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Reactant: N#CCCCN=C=S
Agent: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#CCCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 110 °C

Procedure:
2-(4-nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (60.97 mg, 0.21 mmol), prepared as described hereinabove (see, preparation of Compound 1), 4-isothiocyanato-butyronitrile (664 mg, 2.1 mmol) and a fine powder of anhydrous K2CO3 (27.6 mg, 0.2 mmol) are mixed together in a sealed tube, provided with a magnetic stirrer, and the mixture is heated at 110° C. for 2 hours. The mixture is cooled to room temperature, ethanol is added (2 ml), and the formed precipitate is filtered. The crude product is recrystallized from ethanol to give Compound 35.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=O)#N.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.[F:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1>>[C:31]([CH:15]1[CH2:14][O:13][CH:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[CH:11][CH:10]=3)[C:6]([C:18]3[CH:19]=[C:20]([C:21]([NH:54][CH2:53][C:52]4[CH:55]=[CH:56][C:49]([F:48])=[CH:50][CH:51]=4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[N:7]2)[CH2:17][CH2:16]1)#[N:33]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(C(=O)O)c1)nn2C1CCCCO1
Reactant: NCc1ccc(F)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Product: N#CC1CCC(n2nc(-c3cccc(C(=O)NCc4ccc(F)cc4)c3)c3ccccc32)OC1
Yield: 92 %

Procedure:
The reaction of 3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)benzoic acid (1.0 g, 2.87 mmol), HOBT (1.16 g, 8.62 mmol), EDCI (1.64 g, 8.62 mmol) and 4-fluorobenzylamine (0.98 mL, 1.07 g, 8.62 mmol) furnished 1.2 g (90% yield) of the title compound. ES-MS (m/z) 455 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([NH:34][C:35]2[C:36]([NH2:41])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:41][C:36]1[C:35]([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:43][CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)O)c(OCC(C)(C)CNC(=O)OC(C)(C)C)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OCC(C)(C)CNC(=O)OC(C)(C)C)cc1
Yield: 73.4 %

Procedure:
In a manner substantially equivalent to Example 101-D, 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-methoxybenzoic acid (2.92 g, 8.25 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.00 g, 8.25 mmol) were coupled. The crude material was dissolved in dichloromethane, and aminomethylated polystyrene was added to remove the unreacted acid chloride. The resin was filtered, the solution added directly to a SCX column (Varian, 60 cc/10 g, prewashed with MeOH), and the product washed through the column with 9:1 CHCl3:MeOH. Concentration of the wash in vacuo gave 3.50 g (73.4%) of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Fc1cc(F)c2cc[nH]c2c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(F)c2c(c1)NCC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a suspension of 4,6-difluoro-1H-indole (5 g, 32.9 mmol) in dry dichloromethane (100 mL) was added triethylsilane (10 g, 85.5 mmol) at room temperature. The reaction was then cooled to 0° C. and trifluoroacetic acid (50 mL) was added dropwise. The reaction was stirred at room temperature for 4 hours. The mixture was poured into cold saturated aqueous sodium bicarbonate solution and diluted with dichloromethane (200 mL). The layers were separated and the organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica chromatography to give the title compound (4.5 g, 90% yield) as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](OC)=[O:11].CN(C)C=O.C(O)(=O)C>[OH-].[K+]>[CH3:1][N:2]1[C:10](=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[NH:4][C:3]1=[O:14]
Reactant: CNC(=O)Nc1ccsc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2ccsc2c1=O
Reaction time: 0.5 h

Procedure:
Methyl 3-(N'-methylureido)thiophene-2-carboxylate (4,2 g, 20 mmol) was suspended with stirring in 5% aqueous potassium hydroxide (50 ml). Dimethylformamide was added until a clear solution was obtained. Stirring was continued for 30 min, whereafter the solution was neutralized with acetic acid. This afforded a crystalline precipitate of the title compound, which was separated by filtration and washed with water. M.p.>300° C.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].O>C(O)(C)C>[C:1]([S:14]([N:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCN(CC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 56 °C
Yield: 65.9 %

Procedure:
A one-liter flask fitted with a thermocouple, addition tunnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2NH(C3H7) (120.0 g; 0.352 mole), and sodium carbonate (39.0 g). The mixture was heated to 93° C. and ethyl bromoacetate (62.0 g; 0.371 mole) was slowly added over a period of 4 hours, and then the ensuing mixture was allowed to stir overnight at 93° C. To this mixture was added water (120.0 mL) and the temperature was 56° C., at which point sulfuric acid (23.8 g; concentrated) at a rate to keep the temperature below 100° C. Two phases formed and the bottom layer was recovered and washed with water (150 mL). This crude material was distilled (95-121° C.; 4.0 mm Hg) to yield C4F9SO2N(C3H7)CH2CO2C2H5 (132.0 g). A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2N(C3H7)CH2CO2C2H5 (116.0 g; 0.27 mole) KOH (20.0 g; 0.303 mole) water (60 mL) and isopropanol (60.0 g). The mixture was heated at reflux for 2 hours, and a Dean-Stark trap was added. As isopropanol was removed from the trap, an equivalent amount of water was added to the reaction mixture. When the reaction mixture reached 101° C. water (25 mL) was added and the mixture was cooled to 56° C.; upon addition of sulfuric acid (31.0 g; concentrated) the temperature increased to 78° C. and two phases appeared. The bottom phase was separated and distilled (136-142° C.; 4.0-5.4 mm Hg) to yield a white solid, C4F9SO2N(C3H7)CH2CO2H (71.0 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:30][C:29](=[O:31])[N:28](CC3C=CC(OC)=CC=3)[S:27]2(=[O:42])=[O:41])[CH:20]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:11])=[O:7])(=[O:3])[CH3:2].C([SiH](C)C)(C)(C)C>C(O)(C(F)(F)F)=O>[C:1]([NH:4][C@@H:5]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:6]([NH:8][C@H:9]([C:10](=[O:11])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:30][C:29](=[O:31])[NH:28][S:27]2(=[O:42])=[O:41])[CH:20]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCNC(=O)[C@H](Cc1cccc(CN2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: C[SiH](C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNC(=O)[C@H](Cc1cccc(CN2CC(=O)NS2(=O)=O)c1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
The title H compound, (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamide (77 mg, 0.111 mmol) is dissolved in TFA (2.2 mL) containing t-butyl-dimethylsilane (0.055 mL, 0.33 mmol) and heated at 80° C. for 3.75 h. The reaction is concentrated under nitrogen stream and the resulting tan solid is taken up in 60% MeCN in water. Water (1 mL) is added, and the mixture is filtered through a 0.1 micron Acrodisc filter. The filtrate is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in 7 aliquots and eluted at 30 mL/min with a gradient of 90:10 (water containing 0.1% TFA: MeCN) to 10:90 over 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac to yield the product still containing an unknown impurity by HPLC. This is chromatographed again, using the same column, but a different elution gradient, 90:10 (0.1% TFA in water: MeCN) to 40:60 over 14 min. Fractions containing product are combined and concentrated to yield (S)-2-acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-ethyl}-3-phenyl-propionamide as a white film: [M+1]+=572.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:37])[C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[C:15]([CH2:25][OH:26])[C:14]([CH2:27][NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:13][N:12]=1)C1C=CC=CC=1.[CH3:38]O>[Pd]>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][CH2:27][C:14]2[C:15]([CH2:25][O:26][CH3:38])=[C:16]([OH:17])[C:11]([C:10]([NH:9][OH:8])=[O:37])=[N:12][CH:13]=2)=[CH:31][CH:32]=1
Reactant: CO
Reactant: O=C(NOCc1ccccc1)c1ncc(CNCc2ccc(F)cc2)c(CO)c1OCc1ccccc1
Agent: [Pd]
Product: COCc1c(CNCc2ccc(F)cc2)cnc(C(=O)NO)c1O
Yield: 75 %

Procedure:
Compound 9a (0.013 g, 0.019 mmol, 1 eq) and 10% Pd/C catalyst (5 mg) were stirred in 4 mL of methanol under an atmosphere of hydrogen for 12 hrs. The catalyst was filtered and reaction mixture was concentrated under vacuum yielding 0.006 g of 5-((4-fluorobenzylamino)methyl)-N,3-dihydroxy-4-(methoxymethyl)picolinamide) (75% yield) as a white solid; MS-ESI m/z 322 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=O)[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: Cc1onc(-c2ccccc2)c1COc1cc(OCc2ccccc2)ccn1
Yield: 28 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (95 mg, 0.50 mmol) was converted using 4-benzyloxy-2(1H)-pyridone instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 52 mg, 28%) which was obtained as a colourless oil. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[O:12]1[CH:14]([CH2:15][CH3:16])[CH2:13]1.[OH-].[K+]>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH:14]([OH:12])[CH2:15][CH3:16]
Reactant: CCC1CO1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(O)COc1cccc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
A mixture of 3-trifluoromethylphenol (75 ml, 0.617 moles), 1,2-epoxybutane (58 ml, 0.617 moles), potassium hydroxide pellets (86%, 0.062 moles), and water (10 ml) were heated with stirring at 65° C. for four hours. At this point more 1,2-epoxybutane (58 ml, 0.617 moles) was added and stirring at 65° C. continued overnight. The reaction was allowed to cool to room temperature and the lower phase taken off and the upper phase extracted with methylene chloride (2×100 ml). The organic phases were combined and washed with 5% sodium hydroxide solution (150 ml) and water (3×150 ml). This reaction solution was dried over anhydrous magnesium sulfate and stripped under vacuo to yield 138 g of the desired alcohol, as determined by infra-red spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy.