Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:29][CH:30]1[O:35][C:34](=[O:36])[CH2:33][C:32](=[O:37])[CH2:31]1.OC1C=C(C)OC(=O)C=1>CN(C)C1C=CN=CC=1.ClCCl>[OH:37][C:32]1[CH2:31][CH:30]([CH3:29])[O:35][C:34](=[O:36])[C:33]=1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CC1CC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1cc(O)cc(=O)o1
Solvent: ClCCl
Product: CC1CC(O)=C(C(=O)Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
4-Nitrophenylacetic acid (6.7 g, 37 mmol) and then dicyclohexylcarbodiimide (8.0 g, 39 mmol) were added, at room temperature, to a dichloromethane (100 ml) suspension of 6-methyl-dihydro-2,4-pyrandione (4.73 g, 36.9 mmol) which was synthesized by the hydrogenation of 4-hydroxy-6-methyl-2-pyrone, after which 4-dimethylaminopyridine (0.23 g, 1.9 mmol) was added and stirring carried out for 1 hour and then further 4-dimethylaminopyridine (0.46 g, 3.8 mmol) added and stirring carried out for 23 hours at room temperature. The dicyclohexylurea was filtered off while the solution was still warm, then the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification performed by column chromatography. When recrystallization was performed from ethanol, 4-hydroxy-6-methyl-3-(4-nitrophenylacetyl)-5,6-dihydro-2-pyrone (5.9 g, 55%) was obtained as yellow crystals. Tetrahydrofuran (100 ml), methanol (35 ml) and concentrated hydrochloric acid (10 ml) were added to the compound (2.00 g, 6.9 mmol) obtained, then Pd-C (5%, containing 100% of water, 300 mg) added and the atmosphere replaced by hydrogen. The raw material was consumed in 4 hours and then the hydrogen replaced by argon. The precipitate was filtered off, washed with hot methanol, and the filtrate concentrated. When the solid obtained was recrystallized from ethanol, 3-(4-aminophenylacetyl)-4-hydroxy-6-methyl-5,6-dihydro-2-pyrone hydrochloride (1.43 g, 70%) was obtained. A chloroform (15 ml) solution of the compound obtained (500 mg, 1.68 mmol) was ice-cooled and 2-thiopheneacetyl chloride (0.25 ml, 2.1 mmol) added. Next, pyridine (0.41 ml, 5.4 mmol) was added and stirring carried out for 3 hours. After returning to room temperature, stirring was carried out for 15 hours, then dilute hydrochloric acid added and extraction performed with dichloromethane. The organic layer was dried with anhydrous sodium sulphate, and the solvent distilled off. When recrystallization was performed from ethanol, Compound 6 (317 mg, 49%) was obtained as pale yellow crystals.
Reaction SMILES: N1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#N)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3]C=1.CC(O)=O.[CH3:24][N:25](C=O)C.[PH2]([O-])=[O:30].[Na+]>N1C=CC=CC=1.O.[Ni]>[N:25]1[CH:24]=[CH:6][CH:5]=[C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:30])=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:3]=1
Reactant: N#Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: O=[PH2][O-]
Reactant: CN(C)C=O
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a suspension of (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonitrile (984 mg, 3 mmol) in pyridine (30 mL) was added HOAc (8 mL), followed by DMF (30 mL). The resulting mixture was heated and sonicated to make a clear solution. After cooling to 0° C., a solution of sodium hypophosphite (1.408 g, 16 mmol) in H2O (8 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.8 mL). The resulting mixture was heated at 60° C. (oil temp.) for 1 h before cooling to rt. H2O (50 mL) was added and the mixture was extracted with EtOAc (100 mL+50 mL×2). The combined extracts were dried (Na2SO4). Removal of low boiling point solvents gave a yellow solution in DMF (about 30 mL); H2O (500 mL) was added with swirling and a yellow precipitate formed. After standing 10 min, the resulting precipitate was collected by suction filtration, rinsed with H2O and dried under high vacuum to give the title compound (500 mg, 50%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.90 (s, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H, partially overlapping with the singlet at 8.18 ppm), 8.18 (s, 1H, partially overlapping with the doublet at 8.19 ppm), 7.75 (d, J=16.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.59 (d, J=16.8 Hz, 1H), 7.43 (dd, J=8.0 Hz, 5.2 Hz, 1H); MS ESI 250.0 [M+H]+, calcd for [C15H11N3O+H]+ 250.1.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 187 %

Procedure:
A mixture of 1.85 g of 2-amino-5-chloro-3-methylbenzoic acid, 0.90 g of triphosgene and 10 ml of tetrahydrofuran was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and a precipitated crystal was washed with water to obtain 1.20 g of 6-chloro-8-methyl-1H-benzo[d]-1,3-oxazine-2,4-dione of the formula:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]([CH3:54])([CH3:53])[CH2:23][N:24]1[C:29](=[O:30])[C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]2[N:49]=[C:50]([CH3:52])[N:51]=[C:25]12)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH2:21][C:22]([CH3:53])([CH3:54])[CH2:23][N:24]1[C:29](=[O:30])[C:28]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[NH:45][C:4](=[O:7])[O:5][N:3]=3)=[CH:36][CH:37]=2)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]2[N:49]=[C:50]([CH3:52])[N:51]=[C:25]12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)(C)CO)c2nc(C)nn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogen carbonate (1.51 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 2.2 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.26 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(CN)nc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Agent: Cl
Product: CCOC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2N2CC(Oc3cccc(F)c3)C2)nc1

Procedure:
The title compound (D158) (59 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (50 mg, 0.154 mmol) and ethyl 6-(aminomethyl)nicotinate hydrochloride (33.56 mg, 0.154 mmol, commercially available at Chemimpex#23882).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:20][O-:21].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:13]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([O:21][CH3:20])[CH:11]=[CH:10]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ccc2cccc(OCc3ccccc3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
The crude 2-chloro-8-benzyloxyquinoline from above was dissolved in toluene (10 mL) and added to a stirred 25 wt % solution of NaOMe in MeOH (50 mL). The reaction solution was heated with stirring overnight at 70° C. After cooling to room temperature, the reaction solution was poured onto ice and extracted with toluene. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a colorless oil (6.14 g, 92%). The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].S(Cl)(Cl)=O.C[N:18](C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc(C(N)=O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of 3-bromo-5-(methyloxy)benzoic acid (9.6 g, 41.6 mmol) in toluene (60 mL), thionyl chloride (9.89 g, 83.1 mmol) and DMF (0.10 mL) were added and stirred at 50° C. for 4 h. The reaction was allowed to cooled to room temperature, and then the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL) and the mixture was added to a solution of ammonia (25%, 50 mL). A precipitate formed and was filtered off using Celite, and dried, to afford 3-bromo-5-(methyloxy)benzamide (8.70 g, 90%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(CC2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.0 g (3.36 mmol) of 1-(cyclopropylmethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 8 ml of acetonitrile was added 0.51 g (3.36 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.43 g (3.36 mmol) of 3-[(ethylamino)methyl]pyrrolidine each in 1 ml of acetonitrile. The mixture was refluxed for two hours and stirred overnight at room temperature. The mixture was filtered, and washed with ether to give 0.935 g of 1-(cyclopropylmethyl)-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecrboxylic acid, mp 185°-188° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CC(S(C(SC)C)=[O:19])SC.C(Cl)Cl.S(=O)(O)[O-].[Na+].C1[CH2:36][O:35][CH2:34][CH2:33]1>C(OCC)(=O)C.[Cl-].[Na+].O>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][C:36]([O:35][CH2:34][CH3:33])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CSC(C)S(=O)C(C)SC
Reactant: C1CCOC1
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(1-imidazolyl)benzaldehyde (5.08 g, 29.5 mmol) and methyl(methylthio)methylsulfoxide (2.57g, 21 mmol) in THF (5 mL) was treated with a 40% methanolic solution of TRITON® B (3 mL). The reaction mixture was refluxed for 4 hours, additional methyl(methylthio)methylsulfoxide (1.09 g, 8.5 mmol) was added and the reaction mixture was refluxed for an additional 2 hours. The reaction mixture was cooled to room temperature, CH2Cl2 was added and the organic layer was washed with water, then brine and then was dried over MgSO4, filtered and stripped. The residue was taken up in ethanolic HCl (180 mL) and refluxed for 16 hours. The reaction mixture was cooled, the ethanol was stripped and the residue was treated with water (200 mL) and extracted with ethyl acetate (250 mL). The aqueous layer was treated with dilute NH4OH and extracted with ethyl acetate (2×) and then the organic layer was washed with brine, dried over MgSO4, filtered and stripped to afford crude product. The crude product was taken up in ethyl acetate, shaken with 25% sodium bisulfite and then brine. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered and stripped to afford 1.93 g of ethyl 4-(1-imidazolyl)phenylacetate.
Reaction SMILES: [OH-].[K+].O.CO.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4C=CC=[C:29]([O:33][CH3:34])[C:28]=4OCOC)=[CH:24][CH:25]=3)[N:20](S(C3C(C)=CC(C)=CC=3C)(=O)=O)[N:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(O)(=O)C[C:53](CC(O)=O)(C(O)=O)[OH:54].[CH2:64]1[CH2:68][O:67][CH2:66][CH2:65]1>>[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:65]=[CH:64][C:68]([O:67][CH2:66][O:54][CH3:53])=[C:29]([O:33][CH3:34])[CH:28]=4)=[CH:24][CH:25]=3)[NH:20][N:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: C1CCOC1
Reactant: COCOc1c(OC)cccc1-c1ccc2c(C=Cc3ccc(OC)c(OC)c3)nn(S(=O)(=O)c3c(C)cc(C)cc3C)c2c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1ccc(-c2ccc3c(/C=C/c4ccc(OC)c(OC)c4)n[nH]c3c2)cc1OC
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A 1M solution of KOH (1.0 g, 17.8 mmol) in 1:1 water/MeOH (18 mL total) was prepared under argon and was degassed by vacuum/purge cycles with argon (5 times). In a separate flask, 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy, methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (289 mg, 0.461 mmol, 1.0 equiv) was dissolved in THF (8 mL) under argon. To this solution was added the above 1M KOH solution (10 mL, 1:1 water/MeOH). The reaction was warmed to 30° C. and was allowed to stir for 7 h. The reaction mix was neutralized by the addition of 20% citric acid (7 mL). The resulting mix was partitioned between ethyl acetate (150 mL) and water (100 mL). The organic material was separated, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give cis and trans 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (used crude): Rf sm 0.46, p1 0.17, p2 0.23 (ethyl acetate-hexane 1:1); 1H NMR cis isomer (CDCl3) δ 7.55 (s, 1H), 7.3-7.1 (m, 6H), 7.02 (dd, 1H, J=1.9, 8.3 Hz), 6.85 (d, 1H, J=12.5 Hz), 6.78 (d, 1H, J=12.5 Hz), 6.74 (d, 1H, J=8.3 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 3.43 (s, 3H), 3.42 (s, 3H). MS (ES) [m+H]/z Calc'd 447, found 447, [m−H]/z Calc'd 445, found 445.
Reaction SMILES: [CH3:1][S:2][O-].[Na+].[Cl:5][CH2:6][C:7]1([CH3:26])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:22]([F:25])([F:24])[F:23])=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2F)[CH2:8]1.O.C(OCC)(=O)C>CN(C)C=O>[Cl:5][CH2:6][C:7]1([CH3:26])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:22]([F:25])([F:24])[F:23])=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[S:2][CH3:1])[CH2:8]1
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Reactant: CS[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1SC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.21 g (9.0 mmoles) of sodium methyl thioalcoholate (in the form of a 15% aqueous solution) was added, at room temperature, into a solution of 1.08 g (3.0 mmoles) of 5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein to obtain a crude product of 5-chloromethyl-3-(1-ethyl-5-methylthio-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([NH:20]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)([CH3:19])[CH2:9][O:10][C@@:11]([C:17]#[N:18])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]2([CH3:19])[CH2:9][O:10][C@@:11]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:17]([NH2:18])=[N:20]2)[CH:7]=1
Reactant: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@]1(c2cc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 80 °C

Procedure:
To a solution of N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide (6.54 g, 11.8 mmol) and N-acetyl-cysteine (2.4 g, 26.0 mmol) in MeOH (80 ml) was added K2CO3 (3.62 g, 26.0 mmol) and the reaction mixture was heated at 80° C. for 16 h. After removal of the solvent the residue was dissolved in water and extracted with EtOAc. Combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after chromatographic purification over silica gel (hexane-EtOAc 10:1 to 1:2 containing 0.03% NEt3) as a yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.58; HPLC RtH5=0.843 min; ESIMS: 369, 371 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 7.66 (dd, 1H), 7.35 (m, 1H), 6.91 (dd, 1H), 3.97 (m, 2H), 1.53 (s, 3H), 1.49 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>O1CCCC1>[C:29]([NH:1][CH2:2][CH:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(CN)CCC2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(CNC(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
A solution of methyl 8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.78 g, 0.0036 mol) and triethylamine (0.55 mL, 0.40 g, 0.004 mol) in aqueous tetrahydrofuran (50%, 75 mL) was added, portionwise as a solid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.99 g, 0.004 mol). All was stirred at ambient temperature over 3 hours. The solution was concentrated to half volume and extracted with diethylether. The aqueous layer was then acidified to a pH of 1.0 using hydrochloric acid (1N) and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography using hexane:ethyl acetate::8:2 to give methyl N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.54 g, 0.0017 mol, 47%) as a white solid. mp=72°-80° C.; 1H NMR (DMSO) d 13.8 (s, 1H), 7.8-7.65 (m, 3H), 7.6-7.5 (m, 3H), 7.25-7.20 (m, 1H), 7.15-7.05 (m, 1H), 3.9-3.8 (m, 1H), 3.2-2.8 (m, 4H), 1.8-1.6 (m, 3H), 1.4 (s, 6H).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][C:7]=1[NH:18][CH:19]=[CH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:5])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:5][C:4]1[C:20]([C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[CH:19][N:18]=[C:7]2[S:8][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([CH3:11])[C:6]=12
Reactant: CCOC(=O)c1c(NC=CC(=O)C(C)C)sc(-c2ccccc2)c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: Cc1c(-c2ccccc2)sc2ncc(C(=O)C(C)C)c(O)c12
Yield: 80.6 %

Procedure:
The compound obtained in Example 13 (50 g) and diphenylether (500 ml) were mixed and the ethanol formed as the reaction proceeded was distilled off while continuing the heating under reflux for 4 hours. After allowing to cool followed by distilling diphenylether off under reduced pressure a crude crystal was precipitated and washed with n-hexane to obtain the title compound (35.1 g, 80.6%).
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[CH3:31][S:32]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(S(C)(=O)=O)C4)cc2)C(=O)O1
Yield: 20 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (100 mg, 0.28 mmol) in dry DCM (5 mL) were added triethylamine (0.15 mL, 1.12 mmol) and methane sulfonyl chloride (0.03 mL, 0.42 mmol) at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to provide the title compound (22 mg, 21.4%) as white solid.