Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O[CH2:10][CH:11]([CH2:13]O)O>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:13][CH:11]=[CH:10]2
Reactant: OCC(O)CO
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc2ncccc2c1

Procedure:
4-Fluoroaniline (ex Aldrich) and anhydrous glycerol (ex Fluka) were reacted together in a Skraup reaction according to Sveinbjornsson et al, J. Org. Chem., 16, 1450 (1951) to give 6-fluoroquinoline. The latter (3.82 g) in glacial acetic acid (22 ml) was treated with 30% hydrogen peroxide (7 ml) for 4 hours at 70°-80° C. Additional 30% hydrogen peroxide (7 ml) was added and the mixture kept for 16 hours at 70°-80° C. The solvents were removed at reduced pressure and the residue neutralized with solid sodium carbonate and extracted with chloroform. The organic phase was washed with hexane and dried to give 6-fluoroquinoline-N-oxide (3.13 g). The latter (1 g) was heated under reflux with acetic anhydride (6 ml) in the absence of moisture for 1 hour, the hot mixture treated with water (6 ml), boiled for 1 hour and poured onto fresh ice. After neutralisation with aqueous sodium carbonate the solid product, 2-hydroxy-6-fluoroquinoline, was collected by filtration and dried (0.39 g). 2-chloro-6-fluoroquinoline was obtained by analogy with Example IV and used in Stage a.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[Cl:30][CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33]>O1CCCC1>[Cl:30][CH2:31][C:32]([NH:34][C:35]([O:1][CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:36])=[O:33]
Reactant: O=C=NC(=O)CCl
Reactant: C[C@@]1(/C=C/CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@]1(/C=C/COC(=O)NC(=O)CCl)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
300 mg (0.73 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(3-hydroxy-propenyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2carboxylate were dissolved in 10 ml of tetrahydrofuran under argon and treated with 90 μl (1.05 mmol) of chloroacetyl isocyanate. The mixture was stirred for 3 hours, evaporated and chromatography was carried out over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:n-hexane (9:16) as the eluent.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:38]([CH3:39])=[CH:37][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH4+].[Cl-].CCOC(C)=O>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:38]([CH3:39])=[CH:37][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-tert-butyl 4-(3-(6-(1-tert-butoxy-2-methoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)phenyl)piperazine-1-carboxylate (from above) in THF (4 mL) and methanol (4 mL) was added sodium hydroxide solution (1.0 mL, 2 mmol, 2 M aqueous solution). The mixture was stirred at 60° C. for 18 h. A saturated solution of NH4Cl (20 mL) and EtOAc (15 mL) were added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo and used without further purification. LCMS-ESI+: calc'd for C35H41ClN3O5S: 650.2 (M+H+); Found: 650.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH2:38][CH:37]2[C:40]([O-])=[O:41])[CH2:32][CH2:31]1)=[O:29])[CH3:26].[Li+]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:40]([CH:37]2[CH2:38][CH2:39][N:36]2[CH:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:34]2)=[O:41])[C@H:14]([C:17](=[O:18])[NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)[CH2:13]1)(=[O:10])=[O:11]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7A and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (58%). MS ISP (m/e): 610.3/612.2 (100/42) [(M+H)]+.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]([CH2:11][CH3:12])[CH2:7][C:8]([OH:10])=O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:41]=[C:40]([NH:42][NH2:43])[CH2:39][N:38]=[C:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:36]=2[CH:50]=1>O1CCCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:41]=[C:40]([NH:42][NH:43][C:8](=[O:10])[CH2:7][CH:6]([N:5]3[C:1](=[O:18])[C:2]4=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]4[C:4]3=[O:13])[CH2:11][CH3:12])[CH2:39][N:38]=[C:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:36]=2[CH:50]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCC(CC(=O)O)N1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)N1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 20, 3-phthalimidovaleric acid and carbonyldiimidazole are allowed to react in tetrahydrofuran. To this mixture is added 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine to give 3-phthalimidovaleric acid, 2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazide which is warmed with acetic acid to give N-[2-(8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)butyl]phthalimide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([O-:32])=O)=[CH:28][CH:27]=4)=[CH:14][N:15]3[C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH:43][CH2:42][CH2:41][N:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[O:32])=[CH:28][CH:27]=4)=[CH:14][N:15]3[C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: NCCN1CCOCC1
Reactant: CNc1cc(-n2cc(-c3ccc(C(=O)[O-])cc3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(-n2cc(-c3ccc(C(=O)NCCN4CCOCC4)cc3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Yield: 24 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU; 63 mg, 0.167 mmol) was added to a mixture solution of 4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzoate (50 mg, 0.111 mmol), 2-morpholinoethanamine (14.6 μL, 0.111 mmol) and diisopropylethylamine (DIPEA; 29 μL, 0.167 mmol) in THF (2 mL) at room temperature. 2 hours later, the mixture was added to saturated sodium bicarbonate aqueous solution and then extracted with methylene chloride. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C([O-])(=O)C.[Na+]>>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To an enzyme liquid, cellobiose (Wako Pure Chemical Industries, Ltd.) was added at 500 mg/L and sodium acetate buffer (pH 5.0) was added at 100 mM, followed by allowing the resulting mixture to react at 50° C. for 0.5 hour. This reaction liquid was prepared in a 1-mL tube, and the reaction was allowed to proceed with mixing by rotation under the above-described conditions. Thereafter, the tube was subjected to centrifugation, and the glucose concentration in the supernatant component was measured. The measurement of glucose concentration was carried out according to the method described in Reference Example 2. The concentration of glucose produced (g/L) was used as it is as the activity level of the cellobiose-degrading activity, and used for comparison of the amount of enzyme recovered.
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[N:14]=2)[CH2:5][CH2:4]1)C.[2H]C(Cl)(Cl)Cl.[2H][C:26]([2H])([2H])[O:27][2H]>>[CH3:26][O:27][CH:5]1[CH2:4][CH2:3][CH2:8][CH2:7]/[C:6]/1=[CH:9]\[C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=2[N:14]=1
Reactant: CCC1CCC(=Cc2nc3cc(O)ccc3o2)CC1
Reactant: [2H]OC([2H])([2H])[2H]
Agent: [2H]C(Cl)(Cl)Cl
Product: COC1CCCC/C1=C\c1nc2cc(O)ccc2o1

Procedure:
2-(4-Ethylcyclohexylidenemethyl)benzoxazol-5-ol (13C-NMR [CDCl3/CD3OD)]: 165.203, 160.259, 155.998, 145.294, 142.867, 114.835, 111.739, 109.631, 105.497, 40.269, 38.948, 35.672, 34.921, 31.423, 30.305, 12.672);
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][N:8]([N:11]=CC2C=CC=CC=2)[C:7]1=[O:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.CN(C)C=O>Cl.[Pd]>[ClH:21].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:32][C:31]([CH:33]=[N:11][N:8]3[CH2:9][CH2:10][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[C:7]3=[O:19])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: CN(C)CCCN1CCN(N=Cc2ccccc2)C1=O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.2 %

Procedure:
A solution of 4.8 g (0.017 mole) of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone (prepared as described in Part III above) in 125 ml of 2N HCl is treated with 1 g of 5% Pd/C (50% H2O) and placed on the Parr reduction apparatus, with the theoretical amount of H2 being absorbed over a 30 minute period. The catalyst is removed by filtration and the solvent is removed in vacuo. The residual oil is dissolved in 100 ml of dimethylformamide and treated all at once with 3.51 g (0.0170 mole) of 5-(4-chlorophenyl)-2-furancarboxaldehyde (prepared as described in U.S. Pat. No. 4,882,354 to Huang et al., (issued Nov. 21, 1989), assigned to Norwich Eaton Pharmaceuticals, Inc., see Example 3, cols. 7 & 8, hereby incorporated by reference herein) with dissolution. A 1.0 g portion of 3 Angstrom molecular sieves is added and the reaction is stirred 16 to 18 hours at ambient temperature. The resulting mixture is heated to reflux with dimethylformamide being added to dissolution. The molecular sieves are removed by filtration and the solvent is removed in vacuo. The residual semi-solid is crystallized by trituration with ether. The solid is recrystallized from S.D.A. #32, (activated charcoal) and dried in a vacuum pistol over refluxing ethyl acetate to yield 2.7 g of 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(3-dimethylaminopropyl)-2-imidazolidinone hydrochloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:28][CH2:27][N:26](C(OCC6C=CC=CC=6)=O)[CH2:25][CH2:24]5)=[N:21][CH:22]=4)[CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[N:21][CH:22]=4)[CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc(-c3ccnc(Nc4ccc5[nH]nnc5c4)n3)cn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: c1cc(-c2ccc(N3CCNCC3)nc2)nc(Nc2ccc3[nH]nnc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
A solution of N-(5-benzotriazolyl)-4-(2-(4-benzyloxycarbonylpiperazin-1-yl) pyrid-5-yl)-2-pyrimidineamine (200 mg, 0.39 mmol) and ammonium formate (400 mg, 6.35 mmol) in glacial acetic acid (5 ml) was treated with 10% palladium on charcoal (50 mg) and stirred for 24 h at room temperature. The mixture was filtered through Celite® washing with methanol, then evaporated and the residue subjected to column chromatography (silica, 0.88 ammonia-methanol-dichloromethane, 2:10:88) to afford the title compound (70 mg) as a white solid m.p. 280-283°. δH (d6DMSO) 2.79 (4H, m), 3.57 (4H, m), 6.92 (1H, d, J 9.1 Hz), 7.37 (1H, d, J 5.3 Hz), 7.59 (1H, d, J 9.1 Hz), 7.85 (1H, d, J 9.1 Hz), 8.27 (1H, m), 8.48 (1H, d, J 5.3 Hz), 8.57 (1H, s), 8.96 (1H, s) and 9.86 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:26])[CH2:19][C@@H:20]([CH3:25])[CH2:21][C:22](O)=[O:23].[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:26])[CH2:19][C@@H:20]([CH3:25])[CH2:21][C:22]([NH:35][CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:34])=[O:23]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)O)c2cc(Cl)ccc2n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)NC(C)c2ccccc2)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-(5-chloro-2-hexyl-1-methyl-1H-indol-3-yl)-3-(R)-methyl-5-oxopentanoic acid in methylene chloride was added (R)-1-phenylethanamine followed by the addition of DCC and DMAP and was stirred for 30 minutes. The reaction mixture was treated with sodium bicarbonate and methylene chloride. The product was purified by column chromatography.
Reaction SMILES: Cl[C:2]1([F:11])[C:7](F)([F:8])[CH2:6][C:5]([CH3:10])=[CH:4][CH2:3]1.ClC1(F)CC(C)=CCC1(F)F.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=1[F:11]
Reactant: CC1=CCC(F)(Cl)C(F)(F)C1
Agent: CC1=CCC(F)(F)C(F)(Cl)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Cc1ccc(F)c(F)c1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 4-chloro-1-methyl-4,5,5-trifluorocyclohexene and 5-chloro-1-methyl-4,4,5-trifluorocyclohexene (1.20 kg) prepared in Example 1 was added 42 g of benzyltriethylammonium chloride, and then the reaction mixture was heated to 85° C. followed by slowly adding 2.15 kg of 50% aqueous sodium hydroxide solution over 4.5 hours. The reaction mixture was stirred for an additional 1.5 hours at 90° C. and then the resultant was purified by steam distillation followed by separating the aqueous layer. The organic layer was dried with 32 g of calcium chloride, and then 0.64 kg of the desired product was collected by fractional distillation at temperature range of 112° C. as a colorless liquid.
Reaction SMILES: CO.[CH3:3][O:4][C:5](=[O:38])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:29])[OH:28])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH:13]C(OCC1C=CC=CC=1)=O.[H][H]>[C].[Pd].O>[CH3:3][O:4][C:5](=[O:38])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:28])[OH:29])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH2:13]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
In a solvent mixture of 75 ml of methanol and 75 ml of water was dissolved 2.1 g of N-benzyloxycarbonyl-D-alanyl-α-L-aspartyl-L-phenylalanine methyl ester, followed by reduction at room temperature for 4 hours in a hydrogen flow using palladium-carbon as a catalyst. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from water-acetone. Yield, 1.3 g; m.p., 228°-230° C.
Reaction SMILES: Cl.COC.[C:5]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)([O:7]C)=[O:6].[CH2:17]([C:21]1[N:22](CC2C=CC=CC=2Cl)[C:23](/[CH:26]=[C:27](\[CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)/[C:28]([OH:30])=[O:29])=[CH:24][N:25]=1)[CH2:18][CH2:19]C>>[CH2:17]([C:21]1[N:22]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:5]([OH:7])=[O:6])=[CH:10][CH:11]=2)[C:23](/[CH:26]=[C:27](\[CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)/[C:28]([OH:30])=[O:29])=[CH:24][N:25]=1)[CH2:18][CH3:19]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Reactant: COC(=O)c1ccc(CO)cc1
Agent: COC
Agent: Cl
Product: CCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of Example 1 replacing valermamidine methyl ether hydrochloride with butyramidine methyl ether hydrochloride and replacing 2-chlorbenzyl alcohol with 4-carbomethoxybenzyl alcohol; mp 250° C. (d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][N+:6]#[C-:7])[CH3:2].[CH:9]([CH:11]=[CH2:12])=[O:10]>C1C=CC=CC=1.[Cu-]=O>[CH2:1]([O:3][C:4]([CH:5]1[CH:9]([CH:11]=[CH2:12])[O:10][CH:7]=[N:6]1)=[O:8])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=CC=O
Agent: O=[Cu-]
Solvent: c1ccccc1
Product: C=CC1OC=NC1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g of red copper(I) oxide are added to 200 ml of benzene. With intensivestirring, a solution of 140 g of isocyanoacetic acid ethyl ester and 84 g of freshly distilled acrolein in 200 ml of benzene are added dropwise to this suspension within a period of 10 minutes. During the course of this addition the reaction temperature is maintained between 30° and 32° by cooling with ice. When the addition is complete the mixture is maintained at 30°-32° until the exothermic reaction has subsided, and then the whole is stirred for 1 hour at room temperature. After excess copper(I) oxide has been removed by filtration, the filtrate is concentrated by evaporation in vacuo at 30°. 600 ml of ether areadded to the residue, and the whole is filtered over celite and concentrated to dryness by evaporation in vacuo. In this manner 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form of a pale yellow oil, b.p. 100°-110° (5.3 Pa).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]([C:5]1[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=1)=[CH:14][N:15]([CH3:17])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C(=CN(C)C)c1ccncc1
Temperature: 80 °C

Procedure:
Methyl-4-pyridinylacetate (6.3 g) was dissolved in N,N-dimethylformamide (30 cm3) treated with N,N-dimethylformamide dimethyl acetal (15 cm3) and heated at 80° C. for 2 h. The reaction was then cooled and evaporated under high vacuum to afford crude methyl-3-dimethylamino-2-(pyridin-4-yl)propenoate (7.3 g) which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](=[O:26])(=[O:25])[N:21]=[C:22]([NH2:24])[NH2:23])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[NH2:24][C:22](=[N:21][S:20]([C:14]1[CH:13]=[C:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([OH:27])=[O:2])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])(=[O:25])=[O:26])[NH2:23]
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)N=C(N)N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(CC(=O)O)c2ccccc2)cc1S(=O)(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[3-(diaminomethylene-sulfamoyl)-4-methoxy-phenyl]-3-phenyl-propionic acid methyl ester (400 mg, 1.02 mmol) in a mixture of MeOH and water (30 mL of 1:1 solution) is added LiOH (73 mg, 3.06 mmol). The reaction mixture is stirred at RT overnight. 1 M aqueous HCl is added to neutralise the reaction mixture. The resulting solid is collected by filtration and dried under vacuum to afford the title compound that is used without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8].I[CH2:33][CH3:34].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([O:30][CH2:33][CH3:34])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(O)ccn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCC)ccn1
Temperature: 70 °C
Reaction time: 26 h
Yield: 43.1 %

Procedure:
K2CO3 (21 mg, 0.15 mmol) was added to II (31 mg, 0.10 mmol) in DMF (2 mL) at rt under Ar(g). After 15 min iodoethane (9 μL, 0.11 mmol) was added and the reaction was stirred at 70° C. for 26 h. Brine (50 mL) and EtOAc (25 mL) were added, then the phases were separated, and the aqueous phase was extracted with EtOAc (25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40) to furnish III as a colourless oil (16 mg, 43%).