Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[Br:1])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
102.2 g (0.64 mole) of bromine are added dropwise at room temperature, with stirring, to a suspension of 100 g (0.52 mole) of 4-acetamidophenylacetic acid in 1 liter of glacial acetic acid; during this dropwise addition, a solution forms intermittently. Subsequently, heating to 60° C. is effected for 12 hours, followed by cooling to room temperature, diluting with 2 liters of water and extracting three times with diethyl ether. The organic phase is washed with sodium hydrogen sulfite solution and water, dried and concentrated to dryness. The residue is recrystallized from acetonitrile to yield 78 g (55.3% of theory) of 4-acetamido-3-bromophenylacetic acid (m.p. 157° to 159° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[OH:15].[CH3:16]/[C:17](/[CH3:26])=[C:18](/[O:24][CH3:25])\[O:19][Si](C)(C)C.CN(C)C=O>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[F-].[Zn+2].[F-]>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([OH:15])=[C:2]([C:17]([CH3:26])([CH3:16])[C:18]([O:24][CH3:25])=[O:19])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])cc1O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4-tert-butyl-5-nitrophenol (15.00 g, 54.72 mmol), bis(tri-tert-butylphospine)palladium(0) (1.422 g, 2.783 mmol), zinc fluoride (2.82 g, 27.27 mmol), methyl trimethylsilyl dimethylketene acetal (MTDA) (19.35 g, 111.0 mmol), and dimethylformamide (150 mL) was heated at 70° C. for 18 h. The mixture was cooled to room temperature and diluted with water. After stirring for one hour, the aqueous phase was extracted with MTBE. The organic phase was dried in vacuo to afford the crude product as a brown solid. Purification of the product was accomplished by trituration in n-heptane. 1H-NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H); 7.37 (s, 1H); 6.79 (s, 1H); 3.54 (s, 3H); 1.45 (s, 6H); 1.32 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:12](OC(OCC)OCC)C>CCCCCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:11][C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1nc(Cl)ccc1N
Solvent: CCCCCC
Product: O=c1[nH]cnc2ccc(Cl)nc12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A suspension of 3-amino-6-chloropicolinamide (2.56 g, 14.9 mmol) in triethylorthoformate (45 mL, 271 mmol) was refluxed for 6 h. The reaction mixture was cooled to room temperature, diluted with hexane, and then filtered. The filter cake was washed with hexane and dried under vacuum to give 6-chloropyrido[3,2-d]pyrimidin-4(3H)-one (2.55 g, 94%) as a pale yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.88 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=8.4 Hz), 8.20 (1H, s), 12.65 (1H, brs). m/z=182.06 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](C=O)[CH:5]=[CH:4][C:3]=1[F:10].[CH:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])OCC>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:3]([F:10])=[CH:4][CH:5]=[C:6]([CH:11]([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(F)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(OCC)c1ccc(F)c(Cl)n1
Yield: 81.3 %

Procedure:
To a mixed solution of a commercially available product of 6-chloro-5-fluoropyridine-2-carbaldehyde (820 mg, 5.14 mmol) and ethanol (10.0 mL) were added triethyl orthoformate (2.56 mL, 15.4 mmol) and pyridinium p-toluenesulfonate (64.6 mg, 0.257 mmol) at room temperature. The resultant mixture was stirred at 80° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure, water was added to the residue, and the resultant solution was extracted with ethyl acetate two times. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, to give a crude product (977 mg) of the title compound. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([NH:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)=[O:29])=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: NOC1CCCCO1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)NOC4CCCCO4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (50 mg, 0.115 mmol) was dissolved in DMF (2 mL). The vial was charged with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (27.0 mg, 0.230 mmol), HATU (65.6 mg, 0.173 mmol), and DIEA (0.060 mL, 0.345 mmol). The reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by column chromatography (SiO2, 1-80% Heptanes/EtOAc) to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.48-1.73 (m, 3H), 1.73-1.96 (m, 3H), 2.36 (s, 3H), 3.56-3.70 (m, 1H), 3.89 (s, 3H), 3.98-4.14 (m, 1H), 4.96 (br. s., 1H), 6.35 (d, J=15.66 Hz, 1H), 6.79-6.95 (m, 3H), 6.95-7.07 (m, 2H), 7.26-7.39 (m, 2H), 7.39-7.48 (m, 3H), 7.52 (d, J=16.17 Hz, 1H). LC/MS (m/z, MH+): 534.1.
Reaction SMILES: [I-].[K+].[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH3:27])=[C:23]([CH2:25]Cl)[CH:24]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH3:27])=[C:23]([CH2:25][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][CH:7]=2)[CH:24]=1)=[O:19]
Reactant: COC(=O)c1cc(CCl)c(C)o1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
D Potassium iodide (32 mg) and a solution of biphenyl-4-ylamine (74 mg, 0.438 mmoles) in tetrahydrofuran (1 ml) was added to a mixture of 4-chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester (159) (75 mg, 0.398 mmoles) and potassium carbonate (83 mg) in tetrahydrofuran (1 ml). The mixture was stirred at room temperature under an argon atmosphere for 16 hours, and then refluxed with the exclusion of light for 16 hours. After cooling, the mixture was concentrated and the residue was purified by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158 (91 mg). LC/MS System A; Rt=3.93 mins, m/z (ES+)=322 (M+H for C20H19NO3).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[C:33]1([CH2:39]C=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)[CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(CCc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (1.21 g, 3.49 mmol) in 5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (5.0 mL) and phenylacetaldehyde (5.3 mL, 2M/in DMF, 5.3 mmol) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 1.18 g, 5.3 mmol.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×60 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×10 mL), brine (30 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography to give 6. IR (film, cm−1) 3060, 3026, 2934, 2854, 2800, 2765, 1662, 1495, 1452, 1401, 1262, 1203, 1150, 1106, 966, 1033, 775, 749; LRMS 351.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
3-Bromo-4-fluorobenzonitrile (25 g, 0.125 mol) was dissolved in concentrated sulfuric acid (200 ml), and at 0° C., fuming nitric acid was dropwise added at 0° C., taking 1 hour. After stirred for 30 minutes at the same temperature, this was heated up to room temperature, taking 1.5 hours. This was gradually poured into ice. The formed precipitate was collected by filtration with washing with water, and dried under reduced pressure. The collected yellow powder was fractionated with chloroform and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was well dried under reduced pressure to obtain the entitled compound (14.7 g, 48%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:5].[H-].[Na+].[CH3:28]I.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:16]=[C:15]([N:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])[CH3:28])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:5]
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccccc1C(=O)c1ccc(N(C)c2ccc(F)cc2C)cc1Cl
Reaction time: 18 h

Procedure:
A solution of 2-chloro-4-(4-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone (Compound 116)(105 mg) in N-methyl-2-pyrolidinone (2.0 ml) was added sodium hydride (14 mg) in one portion under stirring. After 10 min at 0° C. methyl iodide (47 mg ) was added and the reaction mixture was stirred for 4 hours at room temperature followed by 18 hours at 100° C. The reaction mixture was poured into water and extracted with EtOAc. The organic phases were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography using a mixture of diethylether/pentane 1:4 as eluant to yield the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1cc(O)nc(/C=C/c2ccc(C#N)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2ccc(C#N)cc2)n1
Yield: 76.9 %

Procedure:
In analogy to example 12c), by heating (E)-4-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (0.71 g, 3 mmol) in POCl3 (5.49 ml, 60 mmol) at 130° C. for 4.5 h there was obtained (E)-4-[2-(4-chloro-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (0.59 g, 76%) as a pink solid. EI mass spectrum, m/e: 255 (M calculated for C14H10ClN3: 255).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH:10]([S:15][CH3:16])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1.FC(F)(F)C([OH:33])C(F)(F)F.OO>>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH:10]([S:15]([CH3:16])=[O:33])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCN(C(=O)CC(SC)C(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: OO
Product: CCN(C(=O)CC(S(C)=O)C(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a 20 mL vial was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylthio)butanamide (82 mg, 0.209 mmol) and hexafluoroisopropanol (1.5 mL). Hydrogen peroxide (0.054 mL, 0.626 mmol, 35% solution in water) was added in one portion and the solution was stirred at room temperature. After 3 hours the reaction was quenched with saturated sodium sulfite solution and extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by chromatography (0-10% MeOH/DCM) to give N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylsulfinyl)butanamide (76 mg, 0.186 mmol, 89% yield) as white semi-solid: 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=2.3 Hz, 1H), 8.63 (td, J=4.8, 2.4 Hz, 1H), 8.14-8.01 (m, 2H), 7.46 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 4.26 (dd, J=17.2, 8.4 Hz, 1H), 3.89-3.61 (m, 2H), 3.01 (dd, J=17.6, 8.2 Hz, 1H), 2.77 (s, 2H), 2.48 (dd, J=17.7, 3.3 Hz, 1H), 1.19 (t, J=7.2 Hz, 3H) (only one isomer shown); ESIMS m/z 409 ([M+H]+); IR (Thin film) 1652 cm−1.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([OH:17])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])=[CH:6][CH:5]=1.N1C2C(=CC=CC=2)C=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:15][CH:14]1[CH2:13][CH2:12][C:11]([C:10]([CH3:19])([CH3:18])[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=2)([CH3:16])[O:17]1
Reactant: BrBr
Reactant: C=CCCC(C)(O)C(C)(C)COc1ccc(Cl)cc1
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(Cl)cc1)C1(C)CCC(CBr)O1
Yield: 90.4 %

Procedure:
16 g (0.1 mole) of bromine are added dropwise to 28.2 g (0.1 mole) of 7-(4-chlorophenoxy)-5-hydroxy-5,6,6-trimethyl-hept-1-ene in 200 ml of absolute chloroform at room temperature, with stirring, followed by 13 g (0.1 mole) of quinoline, at -10° C. with cooling. The reaction mixture is stirred at room temperature for a further 2 hours and concentrated in vacuo, the residue is taken up in ether, the mixture is filtered and concentrated again in vacuo and the residue is stirred at 95° C. on a water-bath for 1 hour. The resulting mixture is taken up in ether and filtered and the filtrate is washed with 15% strength hydrochloric acid and then with water, dried over sodium sulphate and freed from the solvent in vacuo. 32.7 g (90% of theory) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-5-methyl-tetrahydrofuran are obtained as an oil, which can be used in the next stage without further purification. ##STR142##
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH2:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(OCC)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH2:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(CC(=O)c1ccc(Br)cc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(CC(=O)c1ccc(Br)cc1)C(=O)N1CCC[C@@H]1C(=O)O

Procedure:
The preceding compound, (72 g.) is converted to N-hydroxysuccinimide ester, m.p. 99°-104° C., as for Example 7 and the activated ester (94.6 g.) is coupled as for Example 9 with 44.9 g. of L-proline to give 70.7 g. of 1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as a gum (mixture of diastereomers). The gum is dissolved in hot ethyl acetate (200 ml.) and hexane (250 ml.) added. Chilling gives 19.3 g. of solid which is recrystallized from ethyl acetate to give 10.3 g. of (S)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline, m.p. 165°-167° C. (isomer A). From the mother liquors additional isomer A is obtained and purified by chromatography on silica gel. From the column (R)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline (isomer B) is obtained. To a mixture of 10.2 g. of isomer A in 125 ml. of acetic acid is added 4.43 g. of bromine in 20 ml. of acetic acid. Anhydrous hydrogen bromide is added and the mixture stirred 3 hours. The mixture is concentrated to 1/3 volume and poured into ice and water. The mixture is extracted with dichloromethane and the extract washed with water, brine and dried (MgSO4). The solvent is removed under vacuum to give 12.7 g. of a glass (mixture of diastereomers). A mixture of 10.5 g. of the preceding glass in 150 ml. of acetonitrile is added dropwise to a mixture of sodium thioacetate (prepared from 2.9 ml. of thiolacetic acid and 1.4 g. of NaH (60% oil dispersion) in 150 ml. of acetonitrile. The mixture is stirred at room temperature for 18 hours, 30 ml. of acetic acid is added and the solvent is removed under vacuum. The residue is partitioned between dichloromethane and water. The dichloromethane layer is separated, washed with water, saline and dried (MgSO4). The solvent is removed and the residue chromatographed on a silica gel column with ethyl acetate-hexane-acetic acid (5:5:0.2) as solvent. The early fractions containing mainly one component are combined and chromatographed on silica gel to give 5.1 g. of solid. Crystallization from ethyl acetate-hexane gives 3.5 g. of [S-(R*,S*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as white crystals, m.p. 136°-138° C.; [α]D +211°+1(c, 0.971, ethanol). The latter fractions from the column chromatography containing one component by thin layer chromatography are combined to give 1.2 g. of [S-(R*,R*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as a white gla-s; [α]D -69±1(c, 0.983 ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H:9](O)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[O:24][C:18](=[O:19])[NH:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)c1)[C@H](O)c1cccnc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N[C@@H](c2cccc(Br)c2)[C@H](c2cccnc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a mixture of (±)-tert-butyl (1R,2R)-1-(3-bromophenyl)-2-hydroxy-2-(pyridin-3-yl)ethylcarbamate (1.1 g, 2.80 mmol), was added 50 mL 4N HCl/Dioxane. The reaction mixture was allowed to stir at ambient temperature overnight and which time the white slurry was concentrated in vacuo and placed on high vac for 18 h. The resulting colorless solid was dissolved in tetrahydrofuran (25 mL) and Hunig's Base (0.586 mL, 3.36 mmol). To this solution was added carbonyldiimidazole (0.544 g, 3.36 mmol) and after 1 h, the reaction mixture was concentrated in vacuo and loaded with dichloromethane onto a 90 g silica gel cartridge prepacked with 25% ethyl acetate/hexanes. Elution was performed with 25 to 100% ethyl acetate/hexanes over 1200 mL then 100% ethyl acetate for 500 mL. Fractions containing the top spot (Rf=0.45 in 75% ethyl acetate/hexanes; UV) were pooled and concentrated to give 266 mg of trans-4-(3-bromophenyl)-5-(pyridin-3-yl)oxazolidin-2-one as a colorless solid. Anal. Calcd. for [M+H]+ C14H11BrN2O2: 319.00. found 318.85. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.66 (1H, dd, J=4.88, 1.53 Hz), 8.49 (1H, d, J=2.14 Hz), 7.72 (1H, dt, J=7.93, 1.98 Hz), 7.48-7.57 (2H, m), 7.40 (1H, dd, J=7.78, 4.73 Hz), 7.27-7.33 (1H, m), 7.22 (1H, d, J=7.63 Hz), 6.87 (1H, s), 5.30 (1H, d, J=7.63 Hz), 4.77 (1H, d, J=7.32 Hz). 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 158.53, 150.80, 147.61, 140.18, 133.76, 132.84, 132.57, 131.09, 129.48, 125.23, 124.07, 123.64, 83.74, 64.20.
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([O:18][C:20]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=2[CH:22]=[O:23])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
tBuOK (948 mg; 8.44 mmol; 1.2 eq.) was added to a solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.46 g; 8.44 mmol; 1.2 eq.) in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 15 minutes whereupon a solution of 2,4-difluoro-benzaldehyde (1 g; 7.04 mmol; 1 eq.) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes then diluted with water. The solution was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (705 mg, 34%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.41 (d, J=0.8 Hz, 1H), 7.93 (dd, J=8.7, 6.8 Hz, 1H), 6.99-6.72 (m, 1H), 6.33 (dd, J=10.2, 2.2 Hz, 1H), 5.07-4.85 (m, 1H), 4.40 (ddd, J=9.9, 6.4, 1.1 Hz, 2H), 4.10 (ddd, J=9.9, 4.0, 1.1 Hz, 2H), 1.48 (s, 9H). HPLC (max plot) 96.4%; Rt 4.22 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]1[C:9]=2[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([CH3:30])OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:28]([CH3:30])[CH2:29][NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:8]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]1[C:9]=2[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc3c(c2[nH]1)CCC3
Product: CCOC(=O)c1cc2ccc3c(c2n1[C@H](C)CNC(=O)OC(C)(C)C)CCC3

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from b) 1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.