Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>C1COCC1.CO>[Br:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][NH:14][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCc2ccc(Br)cc21

Procedure:
Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas. The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallised from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g). 1H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES+) 212 (M+). b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate Prepared in a similar manner to that of Example 1a using 6-bromo-2,3-dihydro-isoindol-1-one. 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd, J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES+) 226 (M+). c) (6-Bromo-3H-isoindol-1-yl)hydrazine 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7 g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was added followed by hydrazine (1 M in THF, 35 ml). After an hour the solid which had precipitated was filter off and dried to give title compound (2.8 g) 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H, dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 and 1 Hz), 4.49 (2H, s). m/z (ES+) 226 (M+). d) 8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10% trifluoroacetic acid in dichloromethane (40 ml) and 5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and the reaction was stirred for 0.5 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated sodium hydrogen carbonate, dried, filtered and evaporated. The residue was taken up into methanol and dichloromethane, sodium acetate was added and the stirred suspension was treated dropwise with bromine (0.5 ml). The reaction was diluted with water and extracted into dichloromethane and dried, filtered and evaporated. The product was purified by silica chromatography using ethyl acetate as eluant to yield the title compound (1.46 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
(S)-(4-benzylmorpholin-2-yl)methanol 36 g (173.68 mmnol) was dissolved in CH2Cl2 (400 ml), and TsCl (49.6 g, 260.52 mmol), DMAP (2.12 g, 17.36 mmol), and Et3N (36.31 ml, 260.52 mmol) were added, followed by stirring at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was extracted with H2O and EA, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and then the residue was purified by column chromatography (EA:Hex=1:4), to give (S)-(4-benzylmorpholin-2-yl)methyl 4-methylbenzene sulfonate as a white solid (62.15 g, 99%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:49])[CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:49])[CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN(C(=O)CCl)C1CCOCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 36.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.9 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.Cl.[CH3:21][NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:23][N:22]([CH3:21])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(Cl)ncn2)c1
Reactant: CNCC(C)(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)ncn2)c1
Temperature: 110 °C
Yield: 93.6 %

Procedure:
To a solution of 3-(6-chloro-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (0.4 g, 1.44 mmol) in DMSO (3 mL), N-methylneopentylamine hydrochloride (0.4 g, 2.9 mmol) and DIEA (0.5 mL, 2.9 mmol) were added. The resulting solution was heated at 110° C. for 4 days. The product was purified by silica gel column chromatography using ethyl acetate as eluent to afford the product (0.46 g, yield 99%). MS (m/z): 342 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2O.P(Cl)(Cl)([Cl:27])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:27]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: Cc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A round-bottomed flask containing a mixture of 6-bromo-2-methyl-3-(4-(trifluoromethyl)benzyl)quinolin-4-ol (5.00 g, 12.6 mmol, Intermediate 26: step b), phosphorous oxychloride (5.90 mL, 63.1 mmol) and acetonitrile (42 mL) was warmed to 90° C. After 3 hours, the reaction mixture was cooled to room temperature. The acetonitrile and excess phosphorous oxychloride was removed by rotary evaporation. The residue was dissolved in dichloromethane (100 mL) and the solution was cooled in an ice-water bath. Ice (100 mL) was added. Concentrated aqueous ammonia solution was added dropwise until the pH=˜9 by litmus paper test. The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried with magnesium sulfate and the dried solution was filtered. Celite® (5 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.C1COCC1>>[N:31]1([C:22]2[N:21]=[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:28])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:30])([F:29])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])[C:25]([Br:26])=[CH:24][CH:23]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCC2)ccc1Br
Temperature: 150 °C

Procedure:
To a microwave tube containing (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (330 mg, 0.637 mmol) was added a 2M solution of azetidine in THF (4 mL, 8 mmol). The tube was sealed and the reaction was heated at 150° C. for 30 minutes in the microwave. The reaction was cooled and concentrated. The residue was purified via flash chromatography on silica gel (0 to 75% ethyl acetate/hexanes) to afford (4S,5R)-3-[(6-azetidin-1-yl-3-bromopyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=537.9 and 539.8 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.78 (s, 2H), 7.51 (d, J=8.6 Hz, 1H), 6.10 (d, J=8.7 Hz, 1H), 5.77 (d, J=8.6 Hz, 1H), 4.86 (d, J=17.0 Hz, 1H), 4.35 (m, 1H), 4.20 (d, J=16.9 Hz, 1H), 4.01 (m, 4H), 2.40 (m, 2H), 0.78 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].S(Cl)(Cl)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=[CH:6][CH:7]=1)=[N+:16]=[N-:17]
Reactant: CCc1ncccc1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCc1ncccc1CN=[N+]=[N-]

Procedure:
The product of Example 124A, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 163 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH:13]=[CH2:14])=[CH2:12].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:26]([CH:27]1[CH2:28][CH2:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([F:25])([F:5])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:13][CH2:14]1)=[O:29])[CH3:32]
Reactant: C=CC(=O)OCC
Reactant: C=CC(=C)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=C(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a slurry of aluminum chloride (0.1 equi) in toluene (1 mL/mmole), ethyl acrylate (1 equi.) (1 equi.) was added at ice temperature. The reaction mixture was stirred at ice temperature for 10 min. Then a solution 2-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-buta-1,3-diene (40) (0.5M in THF) (1 equi.) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at ice temperature for 10 h, water, extracted with hexane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (hexanes) gave 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-cyclohex-3-enecarboxylic acid ethyl ester (41) as a colorless oil (88%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.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>[NH2:6][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH3:9]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
[step 2] Under a nitrogen atmosphere, 4-bromo-6-methyl-2-nitroaniline (2.80 g, 12.1 mmol) obtained in step 1 was dissolved in DMF (60 mL), phenylboronic acid (4.40 g, 36.3 mmol), cesium carbonate (7.90 g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (1.40 g, 2.42 mmol) were added, and the mixture was stirred at 100° C. for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1) to give 4-amino-3-methyl-5-nitrobiphenyl (2.25 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:2]3[CH:15]=[CH:14][CH:13]=[CH:4][CH:3]=3)([OH:17])[C:4]=2[CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Solvent: C1CCOC1
Product: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.9 g (17 mmol) of 2-bromo-9,10-anthraquinone was put in a 300 mL three-neck flask, the atmosphere in the flask was substituted by nitrogen, and 100 mL of tetrahydrofuran (THF) was added thereto and dissolved well. Then, 18 mL (37 mmol) of phenyllithium was dropped into this solution and stirred at room temperature for approximately 12 hours. After reaction, the solution was washed with water, and an aqueous layer was extracted with ethyl acetate. The extracted solution and an organic layer were dried with magnesium sulfate. After drying, the mixture was subjected to suction filtration, and the filtrate was concentrated, so that 2-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol (about 7.6 g), which was the object of the synthesis, was obtained.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].Cl[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>C1(C)C=CC=CC=1>[CH:2]([NH:4][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:1]
Reactant: CC(C)N
Reactant: CCOC(=O)CCl
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(C)C
Temperature: 25 °C
Yield: 48.2 %

Procedure:
Propan-2-amine (2001)(59 g, 1.0 mol) and ethyl chloroacetate (122 g, 1.0 mol) were dissolved in toluene (200 mL) and the mixture was stirred at reflux for 2 h. The reaction mixture was allowed to cool to RT, poured into ice-water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, ethyl 2-(isopropylamino)acetate (2002) (70 g, 51% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26]>C(O)(=O)C>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]3[CH:29]=[CH:30][CH:31]=[C:27]3[C:25]([O:24][CH3:23])=[O:26])[CH:11]=2)[NH:6][C:7](=[O:19])[C:8]1=[O:18])[CH3:15]
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Reactant: COC(=O)C1(OC)CCC(OC)O1
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3C(=O)OC)cc21
Temperature: 0 °C
Yield: 27.1 %

Procedure:
3.0 g (9.8 mmol) of 7-amino-1-(2-ethylbutyl)-6-nitro-2,3(1H,4H)-quinoxalinedione (Example 40 h) and 1.8 g (9.8 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran were refluxed in 150 ml of concentrated acetic acid for 1 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction to yield 1.1 g (28%) of the product. Melting point 240°-241° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[S:15])([CH3:4])([CH3:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]=[CH:20][N:21]([CH3:23])[CH3:22])=[S:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCNC(N)=S
Product: CN(C)C=NC(=S)NCCCCCNC(=O)OC(C)(C)C
Yield: 54 %

Procedure:
The title compound was synthesized from (5-Thioureido-pentyl)-carbamic acid tert-butyl ester and Dimethylformamide dimethyl acetal according to the procedure described for Example C in 54% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[Mg].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].[NH4+].[Cl-]>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=2)[OH:20])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccc(C2OCCO2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1.0 mL aliquot of 2-(3-bromophenyl)-1,3-dioxolane is added into magnesium (610 mg; 25 mmol) and THF (5 mL) under Argon. After the reaction is started, the residue of 2-(3-bromophenyl)-1,3-dioxolane (total: 5.73 g; 25 mmol) in THF (20 mL) is added dropwise into the reaction mixture. The resulting solution is stirred at room temp for six hours, and then at 50-60° C. for 20 hours. After the mixture is cooled, a solution of 3-(trifluoromethyl)-benzaldehyde (4.35 g; 25 mmol) in THF (20 mL) is added dropwise and the reaction is stirred at room temp for 24 hours. A saturated solution of NH4Cl (50 mL) is added and stirred for 30 minutes. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×100 mL). The organic layers are combined and dried over anhydrous Na2SO4. The solvent is removed and the residue is purified by column chromatography on silica gel. Eluting with ethyl acetate/hexanes (20:80) provide a colorless oil (3.23 g; 40%) as (3-(1,3-dioxolan-2-yl)phenyl)[3-(trifluoromethyl)phenyl]-methan-1-ol: MS 307.0 (M−17).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:37]=[CH:36][C:16]2[CH2:17][CH2:18][C:19]3[C:20]([C:33]([NH2:35])=[O:34])=[N:21][N:22]([C:24]4[CH:32]=[CH:31][C:27]5[O:28][CH2:29][O:30][C:26]=5[CH:25]=4)[C:23]=3[C:15]=2[CH:14]=1>>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([N:22]3[C:23]4[C:15]5[CH:14]=[C:13]([NH:12][C:9]([C:3]6[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=6)=[O:11])[CH:37]=[CH:36][C:16]=5[CH2:17][CH2:18][C:19]=4[C:20]([C:33]([NH2:35])=[O:34])=[N:21]3)=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(Cl)ccc3Cl)cc1-2

Procedure:
The title compound was synthesized from 1.653 g of 3,6-dichloro-2-pyridine carboxylic acid (CP92740, prepared by the method of E. Marzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001, 1371–1376) and the title compound of step 4 of Example 161 (2.0 g) by the same procedure used for Example 211. The title compound is a brown solid (2.4 g, 80%), m.p. 263–265° C. Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (d6-DMSO): δ 2.82–3.01 (m, 4H)), 6.11 (s, 2H), 6.97–7.07 (m, 2H), 7.38 d, 1H, J=1 Hz), 7.81 (s, 1H), 7.33–7.42 (m, 3H), 7.52 (s, 1H), 7.51 (d, 1H, J=9 Hz), 8.15 (d, 1H, J=9 Hz), 10.57 (s, 1H). ESI mass spectrum for C25H18Cl2N5O4+: 522 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)=[C:7]([F:21])[C:6]=1[F:22])=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:22])=[C:7]([F:21])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[C:9]([F:12])[C:10]=1[F:11])=[O:4]
Reactant: COC(=O)c1c(F)c(F)c(-c2ccc(C=O)cc2)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(-c2ccc(CO)cc2)c(F)c1F
Temperature: -10 °C
Yield: 86.9 %

Procedure:
2,3,5,6-Tetrafluoro-4′-formyl-biphenyl-4-carboxylic acid methyl ester (1.26 g, 4.03 mmol) was dissolved in methanol (30 mL) and cooled to −10° C. Sodium borohydride (0.76 g, 20.19 mmol) was added portion wise and reaction mixture stirred by maintaining the same temperature. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness. The obtained residue was redissolved in ethyl acetate (50 mL) and washed with water (20 mL×2) followed by brine, dried over anhydrous sodium sulphate and concentrated to get colorless solid (1.1 g, 86.75%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:25](=[O:26])[CH2:24][CH:23]3[C:18]([C:19]4[CH:29]=[CH:28][S:27][C:20]=4[CH2:21][CH2:22]3)=[N:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([C:28]1[S:27][C:20]2[CH2:21][CH2:22][CH:23]3[C:18]([C:19]=2[CH:29]=1)=[N:17][N:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)[C:25](=[O:26])[CH2:24]3)(=[O:7])[CH3:6]
Reactant: O=C1CC2CCc3sccc3C2=NN1c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5.7 g of aluminum chloride in 100 ml of methylene chloride was added 2.0 ml of acetyl chloride under ice-cooling and the mixture was stirred at room temperature for 10 minutes. 4.5 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno-[2,3-h]cinnolin-3(2H)-one was added under ice-cooling, and the mixture was refluxed for 2 hours. After cooling, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was concentrated in vacuo. The resulting crystal was recrystallized from a mixed solvent of chloroform and ethanol to give 4.7 g of 8-acetyl-2-(4-chlorophenyl)-4,4a,5,6tetrahydrothieno-[2,3-h]cinnolin-3(2H)-one as a white crystal, melting at 155°-157° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.O[CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([C:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH:23]=3)=[C:17]([F:35])[CH:16]=2)[CH2:10]1>>[O:1]=[C:2]1[CH:6]=[CH:5][O:4][N:3]1[CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]([F:35])[C:18]([C:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH:23]=3)=[C:19]([F:21])[CH:20]=2)[CH2:10]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Product: O=C1O[C@@H](Cn2occc2=O)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
During the Mitsunobu reaction the ambident nucleophile 3-hydroxyisoxazole reacts with 5(R)-Hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one to give a quantity of 5(R)-(3-Oxo-isoxazol-2-ylmethyl)-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one. Failure to purify (e.g. by suitable column chromatography) the product from the Mitsunobu reaction described in GB99/01753 before subsequent reaction with 1-chloroethyl chloroformate and work-up using hydrochloric acid gives a quantity of 5(R)-(3-Oxo-isoxazol-2-ylmethyl)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one as the hydrochloride salt, which is identified in the mixture by correlation TOCSY NMR (TOtal Correlation SpectroscopY)— methylene carbon attached to the nitrogen of the isoxazolone ring has a shift of 48 ppm (characteristic of this linkage), and by LC-MS (MH+ 378-less chloride) using C-18 Hichrom RPB column, 5 mm, 25 cm×0.46 mm i.d; Eluant—650 ml Water, 350 ml Acetonitrile, 1 ml TFA (biograde); Flow—1.5 ml/min; Retention Times N-linked-Piperidene—Rt=2.0 min, O-linked Piperidene—Rt=3.25 min.