Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](Cl)=[O:13])=[CH:10][N:11]=2)[CH:2]=1.C(N(CC)CC)C.Cl.[CH3:23][O:24][NH:25][CH3:26]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH3:23][O:24][N:25]([CH3:26])[C:12]([C:9]1[S:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][CH:10]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(Cl)c1cnc(-c2cccnc2)s1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A suspension of 2-(3-pyridyl)thiazole-5-carbonyl chloride (4.6 g, 19.5 mmol) prepared according to WO 2009/149858) in methylene chloride (100 ml) was cooled to 0° C. and treated with triethyl amine (6.03 g, 58.4 mmol), dimethylamino pyridine (12 mg, 0.097 mmol) and then N-methoxymethanamine hydrochloride (2.9 g, 29.2 mmol). The mixture was allowed to warm up to ambient temperature and monitored by TLC and LC/MS. After completion, the reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate, and the solvent removed by concentration in vacuo, to give 3.99 g (82%) of N-methoxy-N-methyl-2-(3-pyridyl)thiazole-5-carboxamide as a pale solid.
Reaction SMILES: [C:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([F:14])[C:4]=1C(O)=O)#[N:2].CC[N:17](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1COCC1>[NH2:17][C:4]1[C:8]([F:14])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(F)c(C(=O)O)c1C#N
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(N)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-cyano-6-fluoro-3-methoxy-benzoic acid (2 g, 10.3 mmol, 1.0 eq) in THF (40 mL) were added Et3N (3.6 mL, 25.8 mmol, 2.5 eq) and DPPA (2.97 g, 10.8 mmol, 1.05 eq). The reaction was stirred at room temperature 3 h then water (10 mL) was added and the mixture was heated at reflux for 2 h. The THF was removed in vacuo and the aqueous solution diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 5:1) to give the title compound as an off-white solid (900 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([CH2:18][CH2:19][F:20])([C:11]#[N:12])[C:13]#[N:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(c1ccc(Cl)cc1)C(C#N)C#N
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)C(C#N)(C#N)CCF
Yield: 44.6 %

Procedure:
Using 0.41 g of 2-(1-(4-chlorophenyl)ethyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.22 g of 2-(1-(4-chlorophenyl)ethyl)-2-(2-fluoroethyl)malononitrile (the present compound (53)).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(O)(=O)C>C1(C)C=CC=CC=1>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[C:14]([NH:15]/[C:2](/[CH3:9])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4.0 g (31 mmol) Ethyl 3-oxobutanoate, 5.0 g (31 mmol) 3-trifluoromethylaniline, and 1.86 g (31 mmol) acetic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as light yellow solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][N:12]2[C:15](=[O:17])[CH3:16])=[CH:8][C:7]=1Br)(=[O:5])=[O:4].C(N(CC)CC)C>CO.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][N:12]2[C:15](=[O:17])[CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cc2c(cc1Br)C(C)(C)CN2C(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc2c(c1)N(C(C)=O)CC2(C)C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
1-Acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonic acid methylamide (270 mg, 0.75 mmol), Pd/C (10%, 79 mg) and triethylamine (209 μL, 1.5 mmol) were suspended in MeOH (10 mL). The reaction was stirred under a hydrogen atmosphere for 1 h, then the mixture was filtered through Celite and filtrate was evaporated in vacuo to give the title compound (160 mg) as a white solid. 1H NMR (CDCl3): 8.65 (1H, s), 7.62 (1H, d), 7.26 (1H, d), 4.52 (1H, s), 3.88 (2H, s), 2.70 (3H, d), 2.26 (3H, s), 1.40 (6H, s). MS: [M+H]+=283.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5](C)([C:11](OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Li+].O>CS(C)=O>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)(Cc1ccccc1Br)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)Cc1ccccc1Br
Temperature: 180 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of diethyl 2-(2-bromobenzyl)-2-methylmalonate (108 g, 310 mmole) in dimethylsulfoxide (350 ml) were added 26.4 g of lithium chloride (620 mmole) and 5.6 ml of water (310 mmole). After stirring at 180° C. for 8 hours, the product was extracted with n-hexane and concentrated to give 84.1 g of ethyl 3-(2-bromophenyl)-2-methylpropionate as a yellow oil (yield, 100%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.Cl.[NH2:13][C:14](=[NH:27])[CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+]>C(O)C>[O:10]=[C:8]1[NH:27][C:14]([CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:13][C:2]2[CH2:7][CH2:6][O:5][CH2:4][C:3]1=2
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Reactant: COC(=O)C1COCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (51.1 g, 323 mmol) and benzyl 2-amino-2-iminoethylcarbamate hydrochloride (78.8 g, 323 mmol) in anhydrous ethanol was added sodium ethoxide (122 mL, 323 mmol, 21% in ethanol). The mixture was mechanically stirred, heated at reflux for 24 h, cooled down to ambient temperature, and filtered to give the title compound (55.6 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br. s., 1H), 7.69 (t, J=5.8 Hz, 1H), 7.15-7.44 (m, 5H), 4.99-5.08 (m, 2H), 4.35 (s, 2H), 4.04-4.11 (m, 2H), 3.84 (t, J=5.3 Hz, 2H), 2.48-2.57 (m, 2H). MS m/z 316.2 (M+1), retention time=1.10 min.
Reaction SMILES: C(Cl)Cl.[Si:4]([O:11][CH2:12][CH2:13][CH2:14][OH:15])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[Si:4]([O:11][CH2:12][CH2:13][CH:14]=[O:15])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69024.3 %

Procedure:
Tetrapropylammonium perruthenate (0.18 g, 5.3 mmol) was added to a mixture of methylene chloride (20 mL) and acetonitrile (2 mL) containing 3-(tert-butyldimethylsilyloxy)-propanol (2 g, 0.01 mmol), N-methylmorpholine N-oxide (1.76 g) and 4 Å molecular sieves. The reaction mixture was stirred at RT overnight and then filtered through a pad of silica gel. The filtrate was concentrated under vacuo to afford 3-(tert-butyldimethylsilyloxy)-propionaldehyde (1.3 g, 66%).
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([OH:20])[C:17]([O:21][CH3:22])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[N+:26]([O-])([OH:28])=[O:27].O>[Cl-].[Na+].O>[C:1]([C:9]1[C:19]([N+:26]([O-:28])=[O:27])=[C:18]([OH:20])[C:17]([O:21][CH3:22])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(O)cc1C(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a mixture of ethyl 2-benzoyl-4-hydroxy-5-methoxy-benzoate (reference example 17-1) (550 mg) and dichloromethane (10 mL) was added fuming nitric acid (85 μL) at room temperature. After stirring for 20 minutes, water and dichloromethane were added to the mixture. The separated organic layer was brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (806 mg).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n1)CCN(CC(C)O)CC2
Yield: 67 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine. The product was isolated as a yellow foam (75 mg, 67%). MS (ESI+): 587 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1H), 3.89 (s, 4H), 3.28 (m, 4H), 2.92-2.52 (m, 10H), 2.27 (t, J=9 Hz, 1H), 1.79 (m, 4H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[N:13]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:12]1=[NH:27].[CH3:28]O>>[ClH:1].[CH3:28][O:17][C:16]([CH:14]1[CH2:15][N:11]([C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:3])[C:12](=[NH:27])[N:13]1[C:19]1[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:18]
Reactant: CO
Reactant: Cc1cccc(C)c1N1CC(C(=O)O)N(c2c(C)cccc2C)C1=N
Agent: Cl
Product: COC(=O)C1CN(c2c(C)cccc2C)C(=N)N1c1c(C)cccc1C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Dry, gaseous hydrochloric acid is introduced into a solution of 1.7 g (4.55 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acid hydrochloride, obtained as described in Example 33, in 20 ml of dry methanol at 0° to +5° C. After one hour the introduction of the gas is stopped, and the mixture is allowed to stand at +5° C. for 24 hours. The fluffy insolubles floating in the solution are filtered off, and the solvent is evaporated in vacuo. The residue is triturated with dry diethyl ether, the separated precipitate is filtered off, washed with diethyl ether, and dried. 1.6 g (90.9%) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acid methylester hydrochloride are obtained as a colourless, hygroscopic crystalline substance; m.p.: 113°-115° C. (in sealed tube).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[O:5][CH:6](O)[CH3:7].S(Cl)([Cl:17])=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[O:5][CH2:6][CH2:7][Cl:17]
Reactant: COc1cccc(OC)c1OC(C)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cccc(OC)c1OCCCl
Reaction time: 0.33 h

Procedure:
A solution of 7.77 g of 2,6-dimethoxyphenoxyethanol in 30 ml of pyridine was cooled and 4.7 g of thionylchloride was added with stirring. After 20 minutes, stirring, the reaction mixture was heated on the steam bath for 2 hours. After cooling, the reaction mixture was evaporated in reduced pressure. The residue was extracted with CHCl3, purified with silicagel chromatography (eluent: EtOAc) 1.82 g of objective compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[CH:26]([CH3:27])[CH3:28])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Using General Procedure I; A solution of ethyl 4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound 99, 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24 mg (92%) the title compound as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Nc1nc(S)n[nH]1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(SCc2ccccc2)n[nH]1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
5-Amino-3-mercapto-1,2,4-triazole (40.36 g) in ethanol (450 ml) was treated at room temperature with solid sodium hydroxide (13.9 g), and benzyl chloride (44.3 g) was added dropwise. The solution was stirred overnight, filtered, and the residue was recrystallised from ethyl acetate and dried to give 64.97 g of desired product, mp 104° C.
Reaction SMILES: [I:1][Si](C)(C)C.[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29]OC(=O)C)=[O:12])([CH3:9])[CH3:8]>>[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29][I:1])=[O:12])([CH3:9])[CH3:8]
Reactant: CC(=O)OCC=CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)[C@H]2SC1
Reactant: C[Si](C)(C)I
Product: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCI)CS[C@H]12
Reaction time: 15 h

Procedure:
0.71 ml of iodotrimethylsilane are added at 0° to the solution, produced as described under a), of 7-trimethylsilylamino-3-(3-acetoxy-1-propen-1-yl)-3-cephem-4-carboxylic acid trimethylsilyl ester. The solution is stirred for 15 hours at 0°. Due to the extreme hydrolyzability, characterization is again effected by NMR.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6](O)[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].[C:12]([O-])([O-])=[O:13].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][O:13][CH2:12][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCc1ccc(O)c(O)c1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1)COO2
Temperature: 117.5 °C

Procedure:
4-Propyl catechol (10.7 g; 70 mmols) was dissolved in a 90:10 (v/v) DMF/dichloromethane mixture (17 ml). The resulting solution was added very slowly to a suspension of anhydrous K2CO3 (14.1 g; 87 mmols) in a 90:10 (v/v) DMF/dichloromethane mixture (85 ml), maintained at 115-120° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH2:9][C:10](Br)=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>O1CCCC1>[Br:8][CH2:9][C:10]([NH:18][C:17]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:11]
Reactant: O=C(Br)CBr
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CBr)cc(OC)c1OC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Add triethylamine (1.53 mL, 11.0 mmol) and bromoacetyl bromide (0.87 mL, 10.0 mmol) dropwise to a 0° C. solution of 3,4,5-trimethoxy-aniline (1.74 g, 9.5 mmol) in tetrahydrofuran (30 mL). Allow the reaction to warm to room temperature overnight. Filter the mixture, wash with tetrahydrofuran, and concentrate. Dissolve the resulting brown solid in chloroform, wash with 1N HCl, saturated aqueous sodium bicarbonate solution, brine; dry over magnesium sulfate; and concentrated. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 2.50 g of the title compound as an orange solid, 87% yield. 1H NMR: consistent with structure. MS (ion spray) 304 (M+).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH2:35]1[C:39]2([CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:38][N:37]=[N:36]1>N1C=CC=CC=1>[C:17]([SiH2:16][O:15][C:14]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]=[C:3]([N:36]2[N:37]=[CH:38][C:39]3([CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35]2)[S:2][CH3:1])(=[O:7])=[O:6])=[CH:13][CH:12]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CSC(=NS(=O)(=O)c1ccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc1)SC
Reactant: C1CCC2(C1)CN=NC2
Solvent: c1ccncc1
Product: CSC(=NS(=O)(=O)c1ccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc1)N1CC2(C=N1)CCCC2
Temperature: 90 °C
Yield: 153 %

Procedure:
To 15 mL pyridine, 400 mg N-(bis-methylsulfanyl-methylene)-4-(tert-butyl-diphenyl-silanyloxymethyl)-benzenesulfonamide and 111 mg 2,3-diaza-spiro[4.4]non-2-ene were added. The mixture was heated for two nights at 90° C. degrees, concentrated under reduced pressure and dried in vacuo to provide 700 mg of product (LC-MS Rt 3.91 min) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.10-1.12 (m, 9H), 1.63-1.94 (m, 8H), 4.82 (s, 2H), 7.01 (s, 1H), 7.65-7.71 (m, 4H), 7.92-7.96 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[CH3:30]I>>[CH3:30][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:12]1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]2
Reactant: CI
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(C)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.111 g, 69%) from {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using MeI and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.4 Hz, 3H), 1.08-1.26 (m, 4H), 1.47-1.62 (m, 2H), 2.69 (t, J=8.2 Hz, 2H), 3.61 (s, 3H), 5.48 (s, 2H), 7.09 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.68-7.80 (m, 2H), 8.08 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H); mass spectrum [(+) ESI], m/z 461/463 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:43]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44]1>C(#N)C>[CH:43]1([NH:48][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: NC1CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NC1CCCC1
Yield: 79.9 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.212 g, 0.56 mmol, 1.0 eq), and triethylamine (96 uL, 65 mg, 0.65 mol, 1.15 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (77 uL, 86 mg, 0.59 mmol, 1.05 eq) followed by cyclopentylamine (111 uL, 96 mg, 1.13 mmol, 2.0 eq). Workup as above provided 198 mg (79%) of L-isoleucine, N-[1-[2-(N-cyclopentylamino)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [Cl-].[Li+].[C:3]([O:7][C:8](=[O:19])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](I)[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>CN(C=O)C>[C:3]([O:7][C:8](=[O:19])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH:20]=[CH2:21])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1N
Temperature: 90 °C

Procedure:
A 50 ml two-neck round bottom flask was filled with argon gas and the solution of tetrakis(triphenyl phosphine)palladium(0) (123.7 mg, 0.107 mmol, 0.06 eq.) and lithium chloride (211.9 mg, 4.998 mmol, 2.8 eq.) in DMF was put into the flask. To the solution was added (4-amino-3-iodobenzyl) carbamic acid t-butyl ester (621.4 mg, 1.875 mmol, 1 eq.) and tributylvinyltin (782.5 mg, 2.678 mmol, 1.5 eq.). The mixture solution was heated to 90° C. to reflux for one night. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylenechloride, washed with water and brine, dried over Na2SO4, filtered and evaporated. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=3/1) to yield brown liquid.