Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Cl:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][Cl:7]
Reactant: C1=COCCC1
Reactant: OCCCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: ClCCCCCOC1CCCCO1
Reaction time: 4.5 h
Yield: 62.5 %

Procedure:
A stirred solution of pentamethylene chlorohydrin (10.0 g, 0.0816 mol) in Et2O (165 ml) under nitrogen was treated with 3,4-dihydro-2H-pyran (10.3 g, 0.122 mol) and p-toluenesulfonic acid hydrate (0.5 g) and kept at ambient temperature for 4.5 hours. The mixture was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was distilled to give 4.06 g, bp 79°-82° C. (0.1-0.07 mm Hg) and 10.54 g, bp 82°-84° C. (0.1-0.07 mm Hg) of 5-chloropentyl 2-tetrahydropyranyl ether.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:32])[NH:30][CH3:31])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10])(C)(C)C.ClCCCl>Cl.O1CCOCC1>[ClH:42].[NH2:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH:30][CH3:31])=[O:32])[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(N)Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
{1-(4-Chlorobenzyl)-2-[2-ethyl-4-(1-methylcarbamo yl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl]-carbamic acid tert-butyl ester, 44, (1.0 g, 1.6 mmol) is dissolved in 4M HCl in dioxane (20 mL). The reaction mixture is stirred for 60 minutes then 1,2-dichloroethane (20 mL) is added. Solvent is removed in vacuo to afford 1 g (quantitative yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([CH3:31])([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:33])[F:34])[CH:24]=3)[CH3:30])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(C)(C)c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.17 h

Procedure:
1.98 g (6.74 mmol) of [3-(4-chlorophenyl)-4-allyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 218A and 1.51 g (7.42 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]-ethylamine from Example 1A are placed in 50 ml of DMF and treated with 1.09 g (8.09 mmol) of HOBt. After 10 mins' stirring, 1.68 g (8.76 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with 500 ml of water. Next, the resulting precipitate is suction-filtered, washed with water and dried under high vacuum. 2.41 g (75% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:23])([CH3:22])[CH2:14]2)=[O:12])[N:3]=1.C(#N)C.[I-].[K+].C[Si](C)(C)Cl>O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:22])([CH3:23])[CH2:14]2)=[O:12])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2CC(C)(C)c3ccccc32)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CN(C(=O)Cc2nc(Cl)cc(=O)[nH]2)c2ccccc21
Yield: 70 %

Procedure:
106 mg of 2-(4-chloro-6-methoxypyrimidin-2-yl)-1-(3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone and 4 ml of acetonitrile are placed in a reactor suitable for microwave irradiation and then 0.45 g of potassium iodide and 347 μl of trimethylchlorosilane are added. The orangey-colored heterogeneous solution is stirred and irradiated at 100° C. for 1 hour. The resulting product is taken up in 25 ml of water and stirred, extraction is carried out with 3 times approximately 25 ml of EtOAc, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtered through a VF filter and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel, elution being carried out with methanol/dichloromethane (2.5/97.5). The fractions containing the expected compound are combined and evaporated under reduced pressure. 6-Chloro-2-[2-(3,3-dimethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated and characterized: 0.20 g in the form of a yellow solid; yield 70% (LCMS ES+ retention time Tr (min)=1.19; [M+H]+: m/z 318).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([NH2:7])=[NH:6].[C:8]1(=O)[CH2:12][CH2:11][CH2:10][C:9]1=O.[NH4+].[OH-]>O.C(O)C.Cl>[NH2:6][C:5]1[NH:7][C:9]2=[CH:10][CH:11]=[CH:12][C:8]2=[N:3][CH:4]=1
Reactant: O=C1CCCC1=O
Reactant: N=C(N)CN
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cnc2cccc-2[nH]1

Procedure:
A solution of aminoacetamidine dihydrochloride (Mengelberg, M. Chem. Ber. 89, 1185 (1956)) (2.4 g, 0.01 mol, 1 equiv.) in H2O (~10 mL) was added dropwise to a cold (0° C.) stirring solution of 1,2-cyclopentanedione (1.0 g, 0.01 mol) in ethanol (8-10 mL). After allowing the reaction mixture to come to room temperature, concentrated NH4OH (aq.) was added slowly until the pH was 8-9. Small amounts of concentrated NH4OH were added as needed in order to maintain a pH of 8-9. When the 1,2-cycopentanedione was no longer visible on TLC (30% EtOAc/hexanes) the reaction mixture was diluted with 5% HCl, washed (3×) with CH2Cl2 and the organic portions discarded. The aqueous portion was made basic with 6N NaOH (aq.), extracted (4×) with CH2Cl2 and the combined extracts dried over sodium sulfate. Concentration of the solution under reduced pressure gave 2-amino-cyclopent[b]pyrazine as a greenish-yellow solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(O)=O>C1COCC1>[C:26]1([CH2:25][C@H:16]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of dimethyl methylphosphonate (3.10 mL, 28.60 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to −78° C. and 2.5 N n-BuLi (2.70 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at −78° C. for 30 min and then a solution of compound 6 (1.00 g, 3.58 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at −78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3×50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded the compound dimethyl [(3S)-4-phenyl-3-[(tert-butyloxycarbonyl)amino]-2-oxobutyl]-phosphonate 7 as a clear oil (0.797 g, 59%), which crystallizes in hexane as a white solid; mp 78-81° C. (lit.1 mp 76-78° C.); Rf 0.38 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 1.38 (9H, s, (CH3)3), 2.84-3.32 (4H, m), 3.74 and 3.78 (6H, 2xs, 2xOMe), 4.55 (1H, q, J=8.4 Hz, —CH—), 5.28 (1H, d, J=8.4 Hz, —NH—), and 7.16-7.32 (5H, m, Ar—H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.N([O-])=[O:15].[Na+].OS(O)(=O)=O>Cl.O>[OH:15][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(O)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A solution of 9.73 g of 3-amino-5-methoxy-1-trifluoromethylbenzene in 400 ml of 2N HCl is cooled to 10° C., and a solution of 3.80 g of sodium nitrite in 20 ml of water is added in the course of 10 minutes. The mixture is left stirring for 30 minutes at 10° C., and a solution of 800 ml of concentrated H2SO4 in 800 ml of water is added while the temperature is maintained below 20° C. The mixture is then heated to 95° C. for 2 hours and left overnight at r.t. 1000 g of ice are added to the reaction medium, the mixture is extracted with ether, the organic phase is washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is evaporated off under vacuum. 9.8 g of 3-hydroxy-5-methoxy-1-trifluoromethylbenzene, m.p.≈75° C. (according to J. Chem. Soc., 1951, 2013) are obtained.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:16][CH3:15])=[O:9]
Reactant: CN
Reactant: O=C(O)c1ccccc1I
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (29.4 mL, 404 mmol) is added to a solution of (2-iodo-benzoic acid (50.0 g, 202 mmol) in dry toluene (600 mL). The mixture is heated to reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (600 mL) and cooled to 0° C. 40% methylamine (aq., 94.1 mL, 1.21 mol) is added dropwise at 0-5° C. during 30 minutes. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (300 mL) and extracted with ethyl acetate (3×300 mL) The combined organic fractions are washed successively with saturated sodium bicarbonate solution (250 mL) and brine (250 mL), dried (MgSO4) and concentrated in vacuo. This gives 50.8 g (96%) of crystalline 2-iodo-N-methyl-benzamide.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[C:10]([N:13]=[O:14])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2cccc(Br)n2n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1nn2c(Br)cccc2c1N=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (400 mg) in acetic acid (4 mL), an aqueous solution (2 mL) containing sodium nitrite (134 mg) was added and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed with water. After dissolving the obtained crude 7-bromo-2-methoxy-3-nitrosopyrazolo[1,5-a]pyridine, without further purification, in 1,2-dimethoxyethane (40 mL) and water (20 mL), 4,6-dimethyl-2-methoxyphenylboric acid (475 mg), tetrakis(triphenylphosphine)palladium (0) complex (203 mg) and barium hydroxide octahydrate (829 mg) were added and the mixture was heated and stirred at 80° C. for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (200 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:27][CH3:28])=[CH:16][CH:15]=1>CCCCCCC>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:21]([O:27][CH3:28])[CH:22]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: COc1cc(N)ccc1-c1ccc(Cl)cc1
Solvent: CCCCCCC
Product: COc1cc(NC(=O)NC(=O)c2ccccc2Cl)ccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 2-chlorobenzoylisocyanate (0.2 g, 1.1 mmol) in xylenes (40 ml) was added a solution of 4-(4-chlorophenyl)-3-methoxyaniline (0.2 g, 0.9 mmol) in xylenes (ml). The mixture was stirred at ambient temperature for 2.5 hours then diluted with n-heptane (60 ml) and stirred for an additional one-half hour. The resulting precipitate was collected by filtration and washed with cold pentane to provide 2-chloro-N-[{(2-methoxy4'-chloro[1,1'-biphenyl]-4-yl)amino}carbonyl]benzamide, m.p. 178-179° C. (Compound A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=Cc1cccc(C(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1C(=O)c1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol) was dissolved in DCM (2 ml). Aniline (18.08 mg, 0.194 mmol) and acetic acid (9.26 μL, 0.162 mmol) were added, and the mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (51.4 mg, 0.243 mmol) was added, and the mixture was stirred at RT overnight to achieve completion. The reaction mixture was diluted with DCM and extracted with water (2×). The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-((phenylamino)methyl)benzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (120 mg, 0.161 mmol, 100% yield). The compound was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:16][CH3:17])=[N:4][C:5]([CH:11]=[CH:12]N(C)C)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Cl.C(=O)([O-])[OH:20].[Na+].[BH4-].[Na+]>COCCOC.O>[Cl:1][C:2]1[C:3]([S:16][CH3:17])=[N:4][C:5]([CH2:11][CH2:12][OH:20])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C([O-])O
Reactant: CSc1nc(C=CN(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(CCO)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h
Yield: 44 %

Procedure:
3-Chloro-6-[2-(dimethylamino)ethenyl]-2-methylthio-5-nitropyridine (D10) (1.05 g, 3.84 mmol) was dissolved in DME (40 ml) and treated with 2.5M hydrochloric acid (8 ml). After 15h, the reaction mixture was treated with solid sodium hydrogen carbonate until pH7 was reached. Water (20 ml) was then added and the resultant mixture was cooled to 0° C. Sodium borohydride (0.581 g, 15.36 mmol) was added portionwise over 2-3 minutes with stirring. After 0.5 h, water (200 ml) was added, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were then dried (Na2SO4) and evaporated under reduced pressure to give a red/brown solid, which was purified by silica gel chromatography (3:1 petrol: EtOAc as eluant) to give the title compound as an orange solid (0.420 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][O:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[O:7][C:6]=2[C:23]=1[CH:24]=[N:25]O.[CH:27](OCC)(OCC)OCC>>[O:7]1[C:6]2=[C:23]3[C:2](=[CH:3][CH:4]=[C:5]2[O:10][CH2:9][CH:8]1[CH2:11][O:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[N:1]=[CH:27][N:25]=[CH:24]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(C=NO)c3O2)cc1
Reactant: CCOC(OCC)OCC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4ncncc4c3O2)cc1

Procedure:
Toluene-4-sulfonic acid (2R)-7-amino-8-(hydroximino-methyl)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester (3.0 g, 7.9 mmole) was suspended in triethyl orthoformate under nitrogen, brought to a rapid boil and refluxed for 18 hours. The reaction mixture was cooled and the solvent evaporated. The residue was dissolved in methylene chloride (100 mL) and the solution obtained was washed with saturated sodium chloride (100 mL), dried over magnesium sulfate and evaporated to a brown gum (2.7 g) which contained several impurities. Chromatography on silica gel using 1% methanol in chloroform and then 3% methanol in chloroform as eluants gave 0.9 g (30%) of the (R)-enantiomer of the title compound as an oil. 1H(DMSO-d6) singlet, 9.01 δ(1 H); singlet, 9.19 δ(1 H); doublet, 7.75 δ(2 H); doublet, 7.60 δ(1 H); doublet, 7.50 δ(1 H) doublet, 7.30 δ(2 H); multiplet, 4.75 δ(1 H); double doublet, 4.51 δ(1 H); double doublet, 4.46 δ(1 H) double doublet: 4.32 δ(1 H); double doublet, 4.22 δ(1 H); singlet, 2.32 δ(3 H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C(Cl)Cl>[C:1]([CH2:2][CH2:3][C:4]([Cl:13])=[O:5])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Cl

Procedure:
Mono-methyl succinate (1), wherein alk is methyl, was chlorinated with oxalyl chloride in dimethyl formamide and methylene chloride to afford 3-carbomethoxypropionyl chloride (2). Compound (2) was catalytically hydrogenated over palladium-charcoal catalyst in the presence of 2,6-lutidine to yield 3-carbomethoxypropionaldehyde (3) which was reacted with formylmethylene triphenylphosphorane under Wittig reaction conditions to obtain 5-carbomethoxy-2-pentanal (4). Compound 4 was epoxidized with aqueous hydrogen peroxide in the presence of 1N sodium bicarbonate to afford methyl-4,5-epoxy-6-oxohexanoate (5). Compound (5) was reacted with tridecyltriphenylphosphonium ylid to give methyl-4,5-epoxy-6(Z)-nonadecenoate (6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[BrH:19]>O>[Br:19][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: Br
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1Cl
Solvent: O
Product: O=[N+]([O-])c1cc(C(Br)c2ccccc2)ccc1Cl
Reaction time: 0.75 h
Yield: 99.3 %

Procedure:
A mixture of 58 parts of 4-chloro-3-nitro-α-phenylbenzenemethanol and 450 parts of a hydrobromic acid solution 48% in water was stirred for 45 minutes at reflux temperature. After cooling, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 71.4 parts (99.3%) of 4-(bromophenylmethyl)-1-chloro-2-nitrobenzene as a residue (int. 132).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].Br[C:16]1[C:17](=[O:33])[C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](=[O:32])[C:25]=1[NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>C(O)C>[CH2:10]([S:14][C:16]1[C:17](=[O:33])[C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](=[O:32])[C:25]=1[NH:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCS
Reactant: Cc1nc2c(s1)C(=O)C(Br)=C(NCCN(C)C)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCCSC1=C(NCCN(C)C)C(=O)c2nc(C)sc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
20 μl (0.115 mmol; 1.2 eq.) of diisopropylethylamine and 16 μl (0.154 mmol; 1.6 eq.) of butanethiol are added to 33 mg (96 μmol) of the compound of Example 35 in solution in 4 ml of anhydrous ethanol. The reaction mixture is maintained under stirring for 24 hours at 60° C., then after concentration under reduced pressure, the residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol 95/5) and the expected product is obtained, after taking up in ethyl ether, in the form of a violet-coloured powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[S:4].Cl[CH:9]([CH:15]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]1[S:4][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][N:5]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC(=S)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
A mixture of 11.22g of 2,2,2,-trifluorothioacetamide and 10.14g of ethyl 2-chloro-2-formylacetate was stirred for 30 minutes in an oil bath of 70° C. and then for 1.5 hours in an oil bath of 100° C., to which 100ml of dichloromethane were added. After removing an insoluble substance, the mixture was concentrated and the residue was subjected to a column chromatography [developing solvent: hexane-ethyl acetate (10:1)], to obtain 3.74g of ethyl 2-(trifluoromethyl)-5-thiazolecarboxylate as yellow liquid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.COCCOC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[NH:12][N:13]=[CH:14][N:15]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:45][CH:44]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 60 °C
Yield: 11.3 %

Procedure:
A mixture of 2-{3-bromo-5[-1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazolyl}perhydro-2H-pyran (300 mg, 0.508 mmol), 4-trifluoromethylphenylboronic acid (144 mg, 0.758 mmol, 1.49 equiv.), [1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladium (II) complex with dichloromethane (Aldrich), 41.5 mg (0.0508 mmol, 0.100 equiv.), 2.53 mL of anhydrous DME, and powdered potassium phosphate (K3PO4, 535 mg, 2.52 mmol, 4.96 equiv.) were refluxed for 5 days. The reaction was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel using 30–40% EtOAc in hexanes. To the purified material was added 5.00 mL of MeOH, and 5.00 mL of 6.0 N aq. HCl. The mixture was heated at 60° C. for 24 h. The reaction mixture was filtered. The solid was further purified by silica gel chromatography using EtOAc affording the title compound (69.3 mg). Further purification by prep HPLC afforded the title compound (18.9 mg, 11.3% yield): 1H NMR (CDCl3/CD3OD) δ 8.74 (s, 1H), 8.41–7.97 (m, 4H), 7.78 (d, 2H), 7.66 (d, 1H); ES-MS (m/z) 330 [M+1]+.