Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:31]/[O:32][CH2:33][CH3:34])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:35][C:36]1[N:41]2[CH:42]=[N:43][CH:44]=[C:40]2[CH:39]=[CH:38][CH:37]=1>>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:31]/[O:32][CH2:33][CH3:34])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:43]4[CH:44]=[C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[N:41]5[CH:42]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Reactant: Cc1cccc2cncn12
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc4cccc(C)n4c3)CS[C@H]12)c1nsc(N)n1

Procedure:
By the procedure of Example 1, 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid is reacted with 5-methylimidazo[1,5-a]pyridine to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC)=[O:22])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.O1CCCC1.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCOC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Yield: 94.7 %

Procedure:
12.6 g (37 mmol) of ethyl 4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-carboxylate, 150 ml of tetrahydrofuran, 15 ml of methanol, a few drops of water and 7.4 g (186 mmol) of sodium hydroxide pellets are introduced into a round-bottomed flask. The mixed is refluxed for 18 hours. The reaction medium is placed in water, acidified to pH 2 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 11.4 g (94%) of the desired product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].Cl[CH:15]([O:17]C)Cl.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:15]=[O:17])=[CH:10][CH:11]=1)([CH3:5])[CH3:12]
Reactant: COC(Cl)Cl
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
6.80 g (38 mmol) of 2-methyl-2-phenyl-propionic acid methyl ester was dissolved at rt in 200 mL MeCl2 and 7.01 ml (90.4 g=76 mmol) of dichloromethylmethylether was added and the mixture cooled down to 0° C.; 21.47 mL (36.93 g=191 mmol) TiCl4 was added over 15 min and the reaction warmed up to ambient temperature; stirring was continued for 16 hours. The reaction mixture was then treated at 0° C. with 20 ml of HCl (37% in water) and extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography (silicagel, eluent:gradient of n-heptane/EtOAc) to yield 5.00 g of the title compound as yellow oil. MS: 206.1 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:15]2)=[O:13])=[CH:7][C:6]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:32])[C:12]([CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:15]2)=[O:13])=[CH:7][C:6]=1[OH:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CCOC(=O)N1CC(C(=O)Nc2ccc(C(C)(C)C)c(O)c2)Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CC(C(=O)N(C)c2ccc(C(C)(C)C)c(O)c2)Oc2ccccc21
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
To a solution of ethyl 2-(4-tert-butyl-3-hydroxyphenylcarbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (50 mg, 0.13 mmol) in THF at 0° C. was added NaH (10 mg, 0.25 mmol) and the mixture stirred for 10 min. Methyl iodide (23 mg, 10 μL, 0.16 mmol) was added and mixture was stirred for 1 h at room temperature. HPLC purification (20-99% MeOH/water) provided ethyl 2-((4-tert-butyl-3-hydroxyphenyl) (methyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (18 mg, 32% yield). LC/MS m/z 413.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.57 (d, J=6.9 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.00 (t, J=7.1 Hz, 1H), 6.88-6.79 (m, 4H), 4.79 (br s, 1H), 4.21-4.11 (m, 2H), 4.02-3.98 (m, 1H), 3.65 (d, J=13.4 Hz, 1H), 3.10 (s, 3H), 1.35 (s, 9H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([O:16]CC)[CH3:15])[S:10][C:9]2=[S:19])=[CH:4][CH:3]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([OH:16])[CH3:15])[S:10][C:9]2=[S:19])=[CH:6][CH:7]=1
Reactant: CCOC(C)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
To a mixture of 32 g. (0.1 m.) of 3-(4'-chlorophenyl)-5-(1'-ethoxyethylidene)-rhodanine in 400 ml. of water and 250 ml. of methanol is added 85 ml. of 5% sodium hydroxide solution and the resulting suspension is stirred at room temperature for 5 hours. The reaction mixture is filtered and the filtrate is decolorized, then acidified with dilute hydrochloric acid to give 3-(4'-chlorophenyl)-5-(1'-hydroxyethylidene)-rhodanine, m.p. 200°-205°C.
Reaction SMILES: [CH2:1]([Sn:5](Cl)(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[F-:12].[F-:13].[NH4+].[NH4+]>>[CH2:1]([Sn:5]([F:13])([F:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: [F-]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: [NH4+]
Product: CCCC[Sn](F)(F)CCCC

Procedure:
Advantageously, dibutyl tin chloride and an ammonium difluoride are reacted to form a dibutyl tin difluoride precipitate. Dibutyl tin dichloride (DBTCl) is solubilized in an alcohol, preferably methanol, in a first reaction vessel. In a second such vessel, ammonium difluoride (NH4F, HF) is dissolved in a solvent which is preferably water. The contents of one reaction vessel are poured into the other and, on contact of the two solutions, a dibutyl tin difluoride precipitate is formed. The mixture is stirred to enhance the contact between the two solutions and to maximize the yield of precipitate. The resulting precipitate is recovered, drained, washed with water, washed with a solvent such as acetone to eliminate any remaining water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH:6]=[N:22][NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)[CH3:2]
Reactant: CCOC(=O)C(=CO)c1cccnc1
Reactant: NNc1ccccn1
Solvent: CCO
Product: CCOC(=O)C(C=NNc1ccccn1)c1cccnc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.90 g (15.0 mmol) of the compound from Example 2A and 1.72 g (15.8 mmol) 2-pyridylhydrazine are dissolved in 75 ml ethanol and the mixture is stirred at RT for 4 d. The reaction mixture is freed from the solvent on a rotary evaporator and the residue is chromatographed over silica gel 60 (mobile phase: methylene chloride→methylene chloride/methanol 10:1→methylene chloride/methanol 2:1). The product fractions are combined and the solvent is removed on a rotary evaporator. After drying in vacuo, 3.95 g (93% of th.) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=1[CH3:14])=[O:6].[Cl:16]N1C(=O)CCC1=O.CO>>[Cl:16]/[C:4](=[CH:3]\[N:2]([CH3:1])[CH3:15])/[C:5]([C:7]1[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=1[CH3:14])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1nc(C)c(C(=O)/C=C/N(C)C)s1
Solvent: CO
Product: CNc1nc(C)c(C(=O)/C(Cl)=C/N(C)C)s1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a well stirred solution of (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl) prop-2-en-1-one (2 mmol) in 50 ml methanol N-chlorosuccinimide (2.5 mmol) was added. The reaction mixture was stirred for 30 minutes. The mixture was evaporated to dryness and the residue was purified by column chromatography using EtoAc to yield (Z)-2-chloro-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one as light yellow solid (43%). 1H-NMR (DMSO-d6) δ: 2.37 (s, 3H, CH3), 2.98 (s, 3H, CH3), 3.25 (s, 6H, 2×CH3), 6.43 (s, 1H, NH), 7.42 (s, 1H, CH). HR-MS (m/z): calcd for C10H14ClN3OS, 259.0546; found 260.0541 [M+H]+.
Reaction SMILES: [C:1]([CH:3](C#N)[CH2:4][S:5][CH2:6][CH:7](C#N)[C:8]#[N:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:20]Br>ClC(Cl)C>[C:1]([CH2:3][CH2:4][S:5][CH:6]=[C:7]([Br:20])[C:8]#[N:9])#[N:2]
Reactant: BrBr
Reactant: N#CC(C#N)CSCC(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: N#CCCSC=C(Br)C#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 17.2 %

Procedure:
28 g of bis-cyanoethyl sulphide were dissolved in 50 ml of dichloroethane, and 110 g of potassium carbonate were added. 64 g of bromine were then added dropwise at 20° to 30° C. The mixture was stirred at 40° C. for 16 hours, a further 40 g of potassium carbonate were added and the mixture was stirred at 60° C. for 16 hours. The mixture was filtered, the filtrate was washed with water and concentrated and the residue was chromatographed. 5.5 g of 2-bromo-2-cyano-vinyl 2-cyano-ethyl sulphide were obtained as an oil, 1H-NMR: δ=2.6-3.0 (2H), 3.0-3.4 (2H) and 7.5-7.9 (1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:16][CH:17]([CH2:19]O)O>>[CH:10]1([CH2:9][C:7]2[CH:6]=[C:5]3[C:3](=[C:2]([Br:1])[CH:8]=2)[N:4]=[CH:19][CH:17]=[CH:16]3)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: OCC(O)CO
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Product: Brc1cc(CC2CCCC2)cc2cccnc12

Procedure:
2-bromo-4-(cyclopentylmethyl)aniline and glycerol can be combined to form 6-(cyclopentylmethyl)-8-bromoquinoline,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH:31](O)[CH3:32]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH:31]([C:23]1[S:22][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=1)[CH3:32])=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Reactant: CC(O)c1nc2ccccc2s1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)c1nc2ccccc2s1
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a solution of 108 mg 2-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 72 mg 1-benzothiazol-2-yl-ethanol and 372 mg diphenyl-[4-[1H,1H,2H,2H-perfluorodecyl]phenyl]phosphine in 2.5 mL dry THF a solution of 322 mg bis(1H,1H,2H,2H-perfluorooctyl)azodicarboxylate in 2.5 mL dry THF was added slowly at 0° C. After 16 h at room temperature and under argon atmosphere 372 mg diphenyl-[4-[1H,1H,2H,2H-perfluorodecyl]phenyl]phosphine and 322 mg bis(1H,1H,2H,2H-perfluorooctyl)azo-dicarboxylate were added. After additional 24 h the solvent was evaporated, the residue taken up in 5 mL methanol and purified using a FluoroFlash-SPE cartridge with methanol/water 80/20. After removal of methanol the remaining phase was extracted with ethyl acetate twice. The combined organic fractions were washed with 2 M sodium hydroxide and water, dried over magnesium sulphate, filtrated and condensed to yield 137 mg 2-{[1-(1-benzothiazol-2-yl-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: [C:1]1([CH:7]2[N:12]3[CH:8]2[CH:9](O)O[CH:11]3[CH:13]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:14]2)[CH:6]=[CH:5]C=CC=1.NC1C=CC=CC=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.O.C(O)(=O)C>[C:7]1([NH:12][CH2:11][C@H:13]2[C@H:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:14]2)[CH:1]=[CH:6][CH:5]=[CH:9][CH:8]=1
Reactant: OC1OC(C2NC2c2ccccc2)N2C(c3ccccc3)C12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(NC[C@@H]2N[C@H]2c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
In a flamed-dried round bottom flask equipped with a rubber septum in order to maintain a nitrogen atmosphere was added 2a (58.8 mg, 0.2 mmol) and aniline (43.7 μl, 0.48 mmol) dissolved in 5 ml of anhydrous MeOH. The reaction was stirred for 10 minutes, then NaCNBH3 (40.2 mg, 0.64 mmol) was added. The reaction was allowed to stir for 5 hours while maintaining pH 7 through addition of acetic acid when required. NaHCO3 was then carefully added to the reaction mixture and stirred for 5 minutes. Water was added and the aqueous mixture was extracted 3 times with Et2O. The collected organic phases were washed with water, then brine, and dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using flash column chromatography (silica gel; 5% MeOH in CH2Cl2) to afford the title compound as a white solid in 99% yield. Mp=96-97° C. 1H NMR (200 MHz. CDCl3) δ:7.40-7.10 (m, 7H), 6.78-6.62 (m, 3H), 3.51 (dd, J=13.6 Hz, 4.2 Hz, 1H), 3.4 (very bs, 2H), 3.28 (dd, J=13.6 Hz, 7.5 Hz, 1H), 2.86 (d, J=2.8 Hz, 1H), 2.50-2.35 (m, 1H) ppm. 13C NMR (50 MHz. CDCl3) δ: 148.3, 139.7, 129.5, 129.4, 128.8, 127.4, 125.8, 118.1, 115.3, 113.2, 46.4, 40.3, 38.0 ppm. Rf=0.14 (7:3 hexanes/EtOAc).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[CH2:22][CH3:23])C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[CH2:22][CH3:23]
Reactant: CC[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1N

Procedure:
The title compound was prepared in quantitative yield by hydrogenation of (−)-(6R,7S)-7-dibenzylamino-6-ethyl-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 225.3 (M+H+, 100).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][N:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)nc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 69.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 6-chloromethyl-3-methoxypyridine (0.47 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.63 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[O:4][N:3]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Br:7][C:6]1[C:2]([NH:1][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[N:3][O:4][C:5]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)c1onc(N)c1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Amino-4-bromo-5-tert-butylisoxazole (219 mg, 1.0 mmol) was dissolved in dry pyridine (1 ml). Benzenesulfonyl chloride (0.14 ml, 1.1 mmol) and 4-dimethylamino-pyridine (5 mg) were added and the solution was stirred at 50° C. for 6 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (50 ml) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography (9:1 hexanes/ethyl acetate). A crystalline solid was obtained after recrystallization from ethyl acetate/hexanes, m.p. 139-141° C.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12](=O)[CH3:13])=[CH:7][C:6]=1[CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH:12]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:13])=[CH:7][C:6]=1[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)c(OCC(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cc(C)c1OCC(F)F
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (0.89 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3,5-dimethylphenyl)ethanone (0.68 g, 2.98 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].O.Cl[C:13]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[O:14]>O1CCOCC1.C(OCC)(=O)C>[NH:10]=[C:8]([NH:9][C:13](=[O:14])[O:15][CH2:16][CH2:17][CH2:18][Cl:19])[S:7][CH3:6]
Reactant: CSC(=N)N
Reactant: O=C(Cl)OCCCCl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CSC(=N)NC(=O)OCCCCl
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (5.56 g, 20.0 mmol) in water (50 mL) sodium bicarbonate (6.73 g, 80.0 mmol) was added and the reaction mixture was cooled to 0° C. A solution of 3-chloropropyl chloroformate (2.41 mL, 20.0 mmol) in 1,4-dioxane (20 mL) was added dropwise and it was stirred for 15 hour at room temperature. The reaction mixture was diluted with ethyl acetate (250 mL) and the organic layer was separated. It was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting crude product was purified by silica gel flash chromatography (hexane:ethyl acetate 7:3 to 1:1 eluent) to give 3-chloropropyl [imino(methylthio)methyl]carbamate (2.70 g, 64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 8.58 (br.s, 1H), 4.06 (t, 2H), 3.67 (t, 1H), 2.32 (s, 3H), 2.02 m, 2H); MS (EI) for C6H11ClN2O2S: 211 (MH+).
Reaction SMILES: C([C:4]1([OH:16])[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH2:5]1)C=C.N[C@H:18]([C:27](O)=O)[CH2:19]C1C=CC(O)=CC=1.C(Br)C=C>>[CH2:27]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:16])=[CH:15][CH:14]=1)[CH:18]=[CH2:19]
Reactant: C=CCC1(O)C=CC(C[C@H](N)C(=O)O)=CC1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: C=CCBr
Product: C=CCN[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The compound of Formula II, 4-ally-L-tyrosine, is synthesized according to the scheme set forth in FIG. 13. A protected tyrosine, e.g., an Nboc or Fmoc protected tyrosine, is reacted with allyl bromide, resulting in a protected allyl tyrosine, which is then typically deprotected to yield 4-allyl-L-tyrosine. For example, N-(tert-Butoxycarbonyl)-L-tyrosine (2.95 g, 10 mmole) was dissolved in 80 ml of DMF. The solution was chilled to 5° C. and NaH (0.63 g, 26 mmole) was added. The reaction mixture was allowed to warm up to 10° C. and stirred for additional 2 hours. After that, allyl bromide (1.33 g, 11 mmole) was added to the mixture and reaction was warmed to room temperature. The reaction mixture was stirred for 4 hours. Water was added to work up the reaction. The aqueous layer was extracted with ethyl acetate and CH2Cl2. The organic layer was dried over anhydrous MgSO4. The organic solvent was removed to give white solid. This compound was then refluxed in 4M HCl in 1,4-dioxane for 4 hours. All the solvent was evaporated to give the desired product as white solid (1.9 g, 86%). 1HNMR (CD3OD): d ppm 3.1 (m, 2H), 4.1 (t, 1H), 4.5 (d, 2H), 5.3 (q, 1H), 5.9 (m, 1H), 6.9 (d, 2H), 7.1 (d, 2H). Calculated molecular weight: 221, obtained molecular weight: 222.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N+:33]([O-])=O)=[CH:27][C:26]=3[Cl:36])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CO.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]([CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][C:26]=3[Cl:36])[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 4-[4-((S)-1-{tert-butoxycarbonyl-[2-(2-chloro-5-methoxy-4-nitro-phenyl)-ethyl]amino}-ethyl)phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 0.53 mmol) in methanol (12 mL), a saturated solution of NH4Cl (8 mL) and zinc powder (0.175 g, 2.66 mmol) were added at room temperature and the reaction was stirred at 80° C. for 2 hours. The mixture was allowed to cool to room temperature and then filtered through cotton wool. Water (50 mL) was added and the mixture extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (0.28 g, 89%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.BrC1C=C2C(=CC=1)C(N[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=NC=C2>>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][N:3]=[C:2]2[NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:8]=1
Reactant: O=C(Nc1nccc2cc(Br)ccc12)c1ccccc1
Reactant: Nc1nccc2ccc(Br)cc12
Product: O=C(Nc1nccc2ccc(Br)cc12)c1ccccc1

Procedure:
Compound 37e was prepared from 37d using the procedure described for 1e, 1H-NMR 200 MHz (CDCl3) δ: 6.98 (1H, d, J=6 Hz), 7.37-7.57 (6H, m), 8.41-8.48 (2H, m), 9.14 (1H, d, J=2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[NH2:26]C1C=NC=CC=1>>[NH2:20][C:8]([NH:4][C:5]1[CH:7]=[N:26][CH:1]=[CH:2][CH:6]=1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: Nc1cccnc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)Nc2cccnc2)cc1

Procedure:
The compound of Example 24 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 3-aminopyridine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 290.34; found mol. wt. (M+H) 291.1; 580.9 (Dimer)