Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1[C:8]([CH2:9][C:10](O)=[O:11])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[NH:6][N:5]=1.C([N:23](CC)CC)C.C(=O)=O.CC(C)=O.ClC(OCC)=O.N>C(Cl)Cl>[CH3:2][N:3]([CH3:20])[C:4]1[C:8]([CH2:9][C:10]([NH2:23])=[O:11])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[NH:6][N:5]=1
Reactant: Cc1ccc(-c2[nH]nc(N(C)C)c2CC(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(-c2[nH]nc(N(C)C)c2CC(N)=O)cc1
Temperature: 0 °C

Procedure:
A mixture of 4.5 g (0.015 mole) of 3-(dimethylamino)-5-(4-methylphenyl)pyrazole-4-acetic acid monohydrochloride and 4 ml (0.03 mole) of triethylamine in 75 ml of methylene chloride was stirred under nitrogen until all the solids dissolved, then cooled to -30° C. in a dry ice/acetone batch and treated with 1.7 g (0.0152 mole) of ethyl chloroformate added dropwise through a septum with a syringe and needle. The reaction mixture was cooled to 0° C. with an ice-brine bath and ammonia (5 ml in 10 ml of methylene chloride) was added. The reaction was stirred for 16 hours as it warmed to ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.Cl.[N:10]#[C:11][NH2:12].[OH-].[K+]>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11]([NH2:12])=[NH:10]
Reactant: Cc1ccccc1N
Reactant: N#CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1NC(=N)N
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To 150 g of o-toluidine (product of Tokyo Chemical Industry) was added 109 g of a 35 to 37% aqueous solution of hydrochloric acid (product of Wako Pure Chemical Industries) and, after heating to 85° C., 128 g of a 50% aqueous solution of cyanamide (product of Sigma-Aldrich Corp.) was added dropwise. After completion of the dropping of the aqueous cyanamide solution, a further 26.8-g portion of the aqueous hydrochloric acid was immediately added, and the mixture was stirred at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and then neutralized with 236 g of a 50% aqueous solution of potassium hydroxide (product of Wako Pure Chemical Industries) to give 1-(o-tolyl)guanidine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][NH:7][CH2:8][CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[C:22](=[O:44])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH3:39])=[O:37])=[CH:27][CH:26]=1>C(#N)C>[CH2:8]([N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][CH:10]=1)[C:22](=[O:44])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH3:39])=[O:37])=[CH:29][CH:30]=1)[CH3:9]
Reactant: CCNCc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(Cc1ccc(F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
N-(4-Fluorobenzyl)ethanamine (0.114 g, 0.745 mmol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 nmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]-ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred overnight at room temperature. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.223 g of methyl 2-[2-(4-{2-[ethyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 83.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[O:3]1.ClC[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C(OCC)(=O)C.CC(C)=O>[CH3:11][C:2]1([CH3:1])[O:3][C:4](=[O:10])[CH:5]([CH2:9][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=2)[C:6](=[O:8])[O:7]1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=Cc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell, and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 10.6 g (0.0632 mol) of p-(chloromethyl)styrene, 35 g (0.2528 mol) of potassium carbonate and 200 mL of acetone. Approximately 1 g of phenothiazine was added as a stabilizer. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl acetate and filtered through a bed of Celite. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to a light brown oil which spontaneously crystallized. The crystals were collected and washed with 35-65 petroleum ether to yield 3.5 g of 2,2-dimethyl-5-(4-vinylbenzyl)-1,3-dioxane-4,6-dione as shown by formula (III).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:14]1([CH3:28])[CH:19]=[CH:18][C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Br:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:34]=[CH:35][C:30]([N:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[C:17]3[CH:16]=[CH:15][C:14]([CH3:28])=[CH:19][CH:18]=3)=[CH:31][CH:32]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(Br)cc3)cc2)cc1
Temperature: 120 °C
Yield: 2.9 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium (353 mg, 0.385 mmol), and tri-tert-butyl phosphine (3.11 g of a 10% solution in hexanes) was degassed in toluene (anhydrous, 50 mL) for 20 minutes. Di-p-tolylamine (3.00 g, 15.2 mmol), and 4,4′-dibromobiphenyl (4.80 g, 15.4 mmol) were added and the mixture was further degassed for 15 minutes. Sodium tert-butoxide (2.4 g, 25 mmol) was added, and mixture was further degassed for 10 minutes. The whole was heated overnight at 120° C. under argon. After cooling, the mixture was poured into DCM, and solids were filtered off. Filtrate was washed with water and brine. The organic layer was collected and dried over sodium sulfate, then loaded onto silica gel. A flash column (gradient of 2-20% ethyl acetate in hexanes) gave 190 mg of material (3% yield); confirmed pure by HNMR.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=2)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:33]([C:22]1[N:21]=[C:20]([NH:19][C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[CH:25]=[N:24][CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2cncc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method X (but with no addition of K2CO3) with 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (150 mg) and phenol, the title compound was obtained (127 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.31 (s, 9H), 3.54 (s, 3H), 6.77 (s, 2H), 7.16-7.23 (m, 3H), 7.41 (t, 2H, J=7.9 Hz), 7.75 (s, 1H), 7.95 (s, 1H), 9.53 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.33, 60.03, 95.77, 120.55, 121.17, 124.47, 128.42, 129.74, 132.15, 136.29, 150.52, 152.69, 153.86, 153.86, 157.23. m/z 354.1 [(M+H)+ calcd for C19H19N3O4 353.1].
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([Br:11])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:12][O:13][CH2:14]Cl>C1COCC1>[Br:11][C:5]1[C:6]([O:10][CH2:12][O:13][CH3:14])=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: Nc1cccc(O)c1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccc(N)c1Br

Procedure:
20.0 g (500 mmol) of sodium hydride (60% by weight in mineral oil) are added in portions to a solution of 94.0 g (500 mmol) of 3-amino-2-bromophenol [100367-36-0] in 1000 ml of THF, and the mixture is stirred until the evolution of gas is complete. 38.0 ml (500 mmol) of methoxymethyl chloride [107-30-2] are then added dropwise, and the mixture is stirred at 60° C. for a further 6 h. After cooling, the THF is removed in vacuo, the residue is taken up in 1000 ml of dichloromethane, the organic phase is washed twice with 300 ml of 0.1N NaOH each time, once with 300 ml of saturated sodium chloride solution, dried over potassium carbonate, and the solvent is removed in vacuo. Yield: 112.6 g (485 mmol), 97%. Purity: 99.0% (NMR).
Reaction SMILES: C(OC(C1SC(C2C=CC(O)=CC=2)=NC=1C)=O)C.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)[S:28][C:27]=2[CH:39]=1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[S:28][C:27]=2[CH:39]=1)=[O:22]
Reactant: COC(=O)c1ccc2cc(-c3ccc(OC)cc3)sc2c1
Agent: CCOC(=O)c1sc(-c2ccc(O)cc2)nc1C
Product: COC(=O)c1ccc2cc(-c3ccc(O)cc3)sc2c1
Yield: 12 %

Procedure:
The title compound (57 mg, 12%) is prepared essentially according to the preparation of 2-(4-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester using 2-(4-methoxy-phenyl)-benzo[b]thiophene-6-carboxylic acid methyl ester. LC-ES/MS m/e 283 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[C:4]([OH:9])=[CH:5][C:6](=[O:8])[CH:7]=1.C1C(C(O)=O)=C[C@@H](O)[C@@H](O)[C@@H]1N.P(OC[C@@H](O)[C@@H](O)C=O)(O)(O)=O.C(C(C(O)=O)=O)[C@@H](O)[C@H](O)[C@H](O)COP(O)(O)=O.P(OC[C@@H](O)[C@@H](O)[C@H](N)CC(=O)C(O)=O)(O)(O)=O.C=C(OP(O)(O)=O)C(O)=O.NC1C=C(C=C(O)C=1)C(O)=O.NC1C(O)=C(C=C(O)C=1)C(O)=O>>[NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10]
Reactant: NC1=CC(=O)C=C(O)C1=O
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: N[C@@H]1CC(C(=O)O)=C[C@@H](O)[C@H]1O
Agent: N[C@H](CC(=O)C(=O)O)[C@H](O)[C@H](O)COP(=O)(O)O
Product: Nc1cc(O)cc(O)c1O

Procedure:
Biosynthesis of the 2-amino-6-hydroxy-benzoquinone component of the compound of Formula II, requires components derived from the aminoshikimate pathway. FIG. 14b depicts the series of enzymatic reactions involved in the biosynthesis of this constituent. ORF 21 (ALDB) (SEQ ID NO: 42) resembles aldolases involved in the generation of precursors of D-erythrose-4-phosphate which is part of the aminoshikimate pathway used for the generation of 2-amino-6-hydroxy-[1,4]-benzoquinone. ORF 33 (DAHP) (SEQ ID NO: 67) catalyzes the initial step in the aminoshikimate pathway that corresponds to the formation of 3,4-dideoxy-4-amino-D-arabino-heptulosonic acid 7-phosphate (amino DAHP) from phosphoenolpyruvate (PEP) and erythrose 4-phosphate (E-4Ph). Subsequent reactions leading to 3-amino-5-hydroxy-benzoic acid are catalyzed by enzymes provided by primary metabolism biosynthetic pathways present in Micromonospora sp. strain 046-ECO11. ORF 25 (HOXV) (SEQ ID NO: 50) hydroxylates 3-amino-5-hydroxy-benzoic acid at position 2, generating 3-amino-2,5-dihydroxy-benzoic acid. This intermediate is further modified by ORF 32 (HOYH) (SEQ ID NO: 65) that catalyzes a decarboxylative oxidation reaction yielding 6-amino-benzene-1,2,4-triol. A final oxidation reaction is performed by ORF 16 (OXDS) (SEQ ID NO: 32) yielding 2-amino-6-hydroxy-[1,4]-benzoquinone (FIG. 14b).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:15][C:16]1[C:17]([C:14]#[C:13][CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: C#CCNS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNS(=O)(=O)c3ccc(C)cc3)c21

Procedure:
Using Method C above, 4-Methyl-N-(prop-2-ynyl)-benzenesulfonamide (130 mg, 0.62 mmol) (Example 119A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (Z)-N-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-4-methyl-benzenesulfonamide was obtained after HPLC purification with 40% EtOAc in hexanes and precipitation out of THF with excess of hexanes. (Yield 42 mg, 44%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([CH:10]([CH2:15][CH2:16][CH3:17])[C:11]([O:13]C)=[O:12])=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:7]=[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26]2)[N:5]=1>CO>[CH3:3][C:4]1[C:9]([CH:10]([CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:7]=[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26]2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(c3ccccc3)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCC(c3ccccc3)C2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 30.6 %

Procedure:
A solution of sodium hydroxide 5N (0.5 mL) was added to a mixture of methyl 2-(4-methyl-2-(3-phenylpiperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.047 g; 0.103 mmol) in methanol (1.5 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 3 and 4 by addition of a solution of hydrochloric acid 6N. The aqueous layer was extracted with ethyl acetate, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 4) furnished 0.014 g (31%) of the title compound as a white solid.
Reaction SMILES: O[CH2:2][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[OH-].[K+]>CO>[CH2:2]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C1c2ccccc2-c2ccccc21

Procedure:
9-Hydroxymethylfluorene (10 g) and 1 g KOH were dissolved in 90 ml of methanol and reacted at 60° C. for 1 hour, and the methanol was evaporated. From the solid thus obtained, dibenzofulvene was extracted using hexane and water, and washed with water until the hexane phase containing dibenzofulvene was neutral. After separating off the hexane phase, the hexane was evaporated, and the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v) to obtain dibenzofulvene. The melting point of the dibenzofulvene was 50-52° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:24]>>[ClH:24].[NH2:15][CH:4]([CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(O)CCc1ccccc1
Agent: Cl
Product: NC(C(=O)O)C(O)CCc1ccccc1

Procedure:
Reaction was carried out in the same manner as in Example 27, except that 2.5 g of N-Boc-glycine methyl ester was used in place of 1-dimethylethyl-(2R)-(2,6-dichlorophenyl)-5-oxo-3-((1′R)-phenylethyl)tetrahydro-1H-1-imidazolecarboxylate to obtain 3.3 g of 2-(N-Boc-amino)-3-hydroxy-5-phenylpentanoic acid methyl ester as a white solid (yield: 78%). Further, 11.0 g of 2-(N-Boc-amino)-3-hydroxy-5-phenylpentanoic acid methyl ester was mixed with a 6 M hydrochloric acid, and the mixture was refluxed for 4 hours. Thereafter, the solvent was removed in reduced pressure to obtain 2-amino-3-hydroxy-5-phenylpentanoic acid hydrochloride. The retention time of the respective isomers was confirmed using the product. Further, the pH of the aqueous solution of the hydrochloride salt was adjusted to 6 to 7 by a 30% aqueous solution of sodium hydroxide to obtain 346 mg of 2-amino-3-hydroxy-5-phenylpentanoic acid as a white solid (yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:23])(=[O:15])=[O:16])[CH2:10]2)=[CH:32][CH:31]=1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: O=C(NCC1CCCCC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 0.025 cm3 of aminomethylcyclohexane. 44 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclohexylmethylbenzamide are thus obtained in the form of a pale yellow powder whose characteristics are the following [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.92 (mt, 2H), 1.17 (mt, 4H), from 1.45 to 1.80 (mt, 5H), 2.97 (s, 3H), 3.10 (d, J=6 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.47 (t, J=6 Hz, 1H)].
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:30][CH2:31]2)=[N:21]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)C1CCN(Cc2ccn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)n2)CC1
Solvent: ClCCl
Product: CC(C)(C)C1CCN(Cc2ccn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)n2)CC1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-((4-tert-butylpiperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinamide (200 mg, 0.386 mmol) as described in example 1.4, recrystallization of the crude product from CH2Cl2/MTB gave the title compound as white amorphous solid; 34 mg, ESI-MS [M+H]+: 517.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.94 (m, 1H), 8.52 (m, 1H), 8.30 (m, 1H), 8.05 (m, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.43 (m, 5H), 6.37 (m, 1H), 5.36 (m, 1H), 3.27 (m, overlapping with water), 2.88 (m, 3H), 1.75 (m, 2H), 1.54 (m, 2 h), 1.15 (m, 2H), 0.82 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])=[CH:4][C:3]([O:2][CH3:1])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C#Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: COC(=O)C=C(c1ccccc1Cl)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 43 %

Procedure:
The title compound was synthesized from (2-chloro-phenyl)-propynoic acid methyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 43% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.54–7.30 (m, 6H), 7.18 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H), 6.68–6.50 (m, 2H), 6.35 (s, 0.33H), 5.95 (s, 0.67H), 4.39 (m, 2H), 3.78 (m, 2H), 3.64 (s, 3H), 3.22 (m, 2H), 2.73 (m, 2H), 1.92 (m, 2H), 1.52 (s, 9H). Mass Spectrum (LCMS, ESI) calculated for C28H27ClN3O3 488.2 (M-Boc+H); found 488.4.
Reaction SMILES: [CH3:1][S:2]SC.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH:10]([SH:14])[CH:11]([CH3:13])[CH3:12]>>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH:10]([S:14][S:2][CH3:1])[CH:11]([CH3:13])[CH3:12]
Reactant: CSSC
Reactant: CC(C)C(S)c1nccs1
Product: CSSC(c1nccs1)C(C)C

Procedure:
According to the same procedure, from dimethyldisulphide and 1-(2-thiazolyl)-2-methylpropyl-mercaptan there is obtained [1-(2-thiazolyl)-2-methylpropyl]-methyl-disulphide. nD20 = 1.5770. IR (liq.): bands inter alia at 1500, 1470, 1430, 1420, 1390, 1370, 1195, 1140, 1055, 730 cm-1. Odour and flavour: earthy, fruity (cassis), sulphur-like, vegetable-like (celery).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14]OS(C(F)(F)F)(=O)=O)[O:12][C:11](=[O:23])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:13]([CH2:14][N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[O:12][C:11](=[O:23])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: c1c[nH]cn1
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COS(=O)(=O)C(F)(F)F)O1
Solvent: C1CCOC1
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@@H](Cn2ccnc2)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (4S, 5R) 4-(3,4-difluorophenyl)-5-(trifluoromethanesulfonyloxymethyl)-oxazolidin-2-one (approximately 1.7 g, 4.6 mmol maximum) in tetrahydrofuran (40 mL) was added imidazole (1.6 g, 23 mmol) and the mixture stirred at ambient temperature 45 min. The volatiles were removed and the residue taken up in ethyl acetate (100 mL), washed with water (2×50 mL), brine (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to provide an oil. The oil was purified by pressurized silica gel chromatography (5-7% methanol in dichloromethane containing 0.5% NH4OH) to provide (4S, 5R) 4-(3,4-difluorophenyl)-5-(imidazol-1-ylmethyl)-oxazolidin-2-one as a white solid.