Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].Cl.[NH2:14][OH:15].[OH-].[Na+]>O>[F:1][C:2]([F:12])([F:11])[C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[O:15][N:14]=1)([CH3:10])[CH3:9]
Reactant: NO
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(c1cc(N)on1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) and hydroxylamine hydrochloride (0.407 g, 5.86 mmol) in water (30 mL) was added NaOH (0.447 g, 11.16 mmol). Then the mixture was stirred at 100° C. for 3 h. After cooling to rt, the mixture was extracted with DCM (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to yield a light yellow solid of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (700 mg, 3.39 mmol, 61% yield): 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 1H), 4.41 (s, 2H), 1.49 (s, 6H); ES-LCMS m/z 195 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[N:41][CH:40]=[N:39]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:33]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[N:41][CH:40]=[N:39]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: c1ncn(CCCCNC2CCCC2)n1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCCn2cncn2)C2CCCC2)c1)c1ccncc1
Yield: 37.1 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.040 g), cyclopentyl-(4-[1,2,4]triazol-1-yl-butyl)-amine (0.055 g) and EEDQ (0.050 g) in acetonitrile (2 ml) was stirred at reflux, under nitrogen, for 4 h. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (95:5:0.5 then 90:10:1 v/v/v) to give the title compound as an orange oil (0.022 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12])(=O)C.CNC.N1CCOCC1.C(S)C.OC(CO)COC1C=C(C=CC=1)C(N)=O.CN(CC(O)COC1C=C(C=CC=1)C(N)=O)C.O1CCN(CC(O)COC2C=C(C=CC=2)C(N)=O)CC1.COCC(O)COC1C=C(C=CC=1)C(N)=O.C(SCC(O)COC1C=C(C=CC=1)C(N)=O)C>CO>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12]
Reactant: CC(=O)OCCOc1cccc(C(N)=O)c1
Agent: CCSCC(O)COc1cccc(C(N)=O)c1
Agent: CN(C)CC(O)COc1cccc(C(N)=O)c1
Agent: CNC
Solvent: CCS
Solvent: C1COCCN1
Solvent: CO
Product: NC(=O)c1cccc(OCCO)c1

Procedure:
In an analogous manner, but effecting lysis of the epoxide ring in the 3-(2,3-epoxy-n-propoxy)benzamide of Example 3, B, using aqueous solution, dimethylamine, morpholine, methanol, or ethyl mercaptan, the corresponding compounds of the invention--3-(2,3-dihydroxy-n-propoxy)benzamide, 3-(3-(N,N-dimethylamino)-2-hydroxy-n-propoxy)benzamide, 3-(3-morpholino-2-hydroxy-n-propoxy)benzamide, 3-(3-methoxy-2-hydroxy-n-propoxy)benzamide, and 3-(3-ethylthio-2-hydroxy-n-propoxy)benzamide--are prepared.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].Cl[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:2]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(C#N)cccc21
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21

Procedure:
(S)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)(2-(dimethylamino)-2-oxoethyl)carbamate INT-60 was prepared analogously to INT-59 from (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-53 and 2-chloro-N,N-dimethylacetamide.
Reaction SMILES: [N:1]1([C:7]2[CH:32]=[CH:31][C:10]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:40][CH2:41][C:42](Cl)=[O:43].C(OCC)(=O)C>CN(C=O)C>[Cl:40][CH2:41][C:42]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:31][CH:32]=2)[CH2:2][CH2:3]1)=[O:43]
Reactant: O=C(Nc1ccc(Oc2ccc(N3CCNCC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(N3CCN(C(=O)CCl)CC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[6-(4-piperazinophenoxy)-3-pyridyl]-4-(trifluoromethyl)benzamide (885 mg, 2.00 mmol) in DMF (20 mL) were added triethylamine (0.418 mL, 3.00 mmol) and chloroacetyl chloride (0.191 g, 2.40 mmol), and the resulting reaction solution was stirred for 10 minutes at room temperature. To this reaction solution was added ethyl acetate. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 1.00 g of the title compound.
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][C:15]1[C:16]([O:28]CC[Si](C)(C)C)=[C:17]2[C:21](=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:20][O:19][C:18]2=[O:27])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>CN(C=O)C>[OH:28][C:16]1[C:15]([CH2:14][CH:13]=[C:12]([CH3:35])[CH2:11][NH:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:23]([O:24][CH3:25])[C:22]([CH3:26])=[C:21]2[C:17]=1[C:18](=[O:27])[O:19][CH2:20]2
Reactant: CCOP(=O)(CNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CNCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of ({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonic acid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) was added TMSBr (49 μL, 0.38 mmol) and 2,6-lutidine (44 μL, 0.38 mmol). The solution was stirred at room temperature for 1 hour when it was quenched by addition of methanol. The product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.6 mg of the product as a white solid. 1H NMR (300 MHz, CD3OD and CDCl3) δ 1.93 (s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J=11 Hz), 3.42-3.53 (m, 2H), 3.60 (s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 8.5 ppm; MS (m/z) 372.2 [M+H]+, 743.2 [2M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][NH:12]3)[C:6]=2[CH:7]=1.O1CCN[C@@H]2CCOC3C=CC=CC=3[C@@H:18]12.[ClH:32]>>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][N:12]3[CH3:18])[C:6]=2[CH:7]=1
Reactant: Fc1ccc2c(c1)[C@H]1OCCN[C@@H]1CCO2
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Agent: Cl
Product: CN1CCO[C@@H]2c3cc(F)ccc3OCC[C@H]21

Procedure:
In a similar way, substituting trans-10-fluoro-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine for the trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine above and using hydrogen chloride instead of maleic acid, results in the formation of trans-10-fluoro-3,4,4a,5,6,11b-hexahydro-4-methyl-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride having a mp. of 244°-245° C.
Reaction SMILES: CO.C1(C)C=CC(S(O[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[C:14]#[N:15])(=O)=O)=CC=1.[Na].[SH:32][C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>O.COCCOC>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[S:32][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)[C:14]#[N:15]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Reactant: Sc1nc2ccccc2s1
Agent: [Na]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: N#CC(Sc1nc2ccccc2s1)c1cccc(C(=O)c2ccccc2)c1
Yield: 83.4 %

Procedure:
Methanol (6 ml) and 3 ml of DME were added to 1.18 g of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile, and the mixture was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (570 mg) was added, and the mixture was stirred for 1.5 hours under ice cooling. Water (50 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 40 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; methylene chloride) to afford 972 mg (yield 83%) of alpha-(2-benzothiazolylthio)-(m-benzoylphenyl)acetonitrile as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9](Cl)=[O:10].[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[CH:22]([OH:25])[C:23]#[CH:24])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O:25][CH:22]([C:23]#[CH:24])[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:18][C:17]2[CH:29]=[CH:30][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:20]=1)=[O:10]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: C#CC(O)c1cccc(Oc2ccc(Cl)cc2)c1
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C#CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
In 120 ml of dry benzene was dissolved 11.4 g of 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (cis-/trans-ratio=50:50, approx.) followed by addition of 12.9 g. of 3-(4-chlorophenoxy)-α-ethynylbenzyl alcohol and further by dropwise addition of 7.9 g of pyridine. The mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was diluted with 100 g of water and the benzene layer was separated, washed with dilute hydrochloric acid and water and dried over anhydrous magnesium sulfate. The low-boiling fraction was then distilled off under reduced pressure to recover an oil. This oily product was purified by preparative liquid chromatograpy [column: Water's Associates' Prep LC/System 500, Prep PAK® 500/SILICA; solvent system: diethyl ether:n-hexane=2:98]. The above procedure yielded 20.2 g of 3-(4-chlorophenoxy)-α-ethynylbenzyl 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (yield 90%). The separation of cis- and trans-isomers from each other can be effected by the above-mentioned preparative liquid chromatography. The NMR spectra of such isomers are indicated below.
Reaction SMILES: C(OC([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:8][CH:9]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Solvent: ClCCl
Product: CN(C)C(=O)C(N)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
The acid compound 33 (0.3 g) was dissolved in CH2Cl2 (20 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temp for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 37 as a white amorphous solid (0.15 g, 59%). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 7.47 (d, J=9.2 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 5.49 (s, 1H), 2.90 (s, 3H), 2.81-2.84 (m, 5H), 2.54 (t, J=8.0 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5].Cl>C(O)C.[Fe]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:11]([N:2]([CH3:1])[C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5])=[O:12])=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@H](C(C)C)N(C)C(=O)c1ccc(-c2ccc(N)cc2)cc1
Yield: 75.8 %

Procedure:
To a solution of methyl N-methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.70 g, 1.9 mmol) in 85% ethanol (20 mL) was added iron powder (1.05 g, 18.9 mmol) and 2N aqueous HCl solution (0.41 mL). The resulting mixture was heated at reflux for 2 h. The mixture was then filtered through a pad of Celite® and concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to afford methyl N-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]-N-methyl-L-valinate (0.49 g, 76%). 1H NMR (400 MHz, CD3OD) δ 0.85 (dd, 3H), 1.06 (dd, 3H), 2.35 (m, 1H), 3.02 (d, 3H), 3.75 (d, 3H), 4.05 (d, 0.5H), 4.78 (d, 0.5H), 6.78 (d, 2H), 7.42 (m, 4H), 7.63 (d, 2H); LC-MS m/z 341.2 (MH+), retention time 2.37 minutes.
Reaction SMILES: Br[C:2](Br)([F:4])[F:3].CN(P(N(C)C)N(C)C)C.O=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(OCC)C>O1CCCC1>[F:3][C:2]([F:4])=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCC(C)=O
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC(C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Reaction was carried out under nitrogen atmosphere. To 650 ml of tetrahydrofuran, 80 g (0.38 mol) of dibromodifluoromethane was dissolved, followed by drop-wisely adding 121 g (0.74 mol) of tris(dimethylamino)phosphine at −10° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour, followed by further drop-wisely adding 24.9 g (0.17 mol) of methyl 5-oxohexanoate dissolved in 250 ml of tetrahydrofuran, at −20° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature overnight. To this mixture, diethyl ether was added, followed by washing with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (diethyl ether:hexane=1:4) to obtain 27 g (yield: 88%) of methyl 6,6-difluoro-5-methyl-5-hexenoate.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[N:8][OH:9].O.[OH-].[K+]>C(OC(O)C)C>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[O:9][N:8]=1
Reactant: COc1ccccc1C(=NO)c1sccc1Br
Agent: CCOC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1noc2ccsc12
Reaction time: 0.17 h

Procedure:
A solution of 12.0 g of (3-bromothien-2-yl) (2-methoxyphenyl)methanone oxime in 220ml of ethoxyethanol was combined with 15 ml of water containing 4.3 g of potassium hydroxide pellets (85%) and the mixture was stirred at 110° for 10 minutes and thereafter 0.28 g of cuprous chloride was added. Stirring was maintained at this temperature under nitrogen for one hour.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1)[CH3:2].[Cl:10]CCCl.P(Cl)(Cl)(Cl)=O>O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: ClCCCl
Reactant: CCc1cc(O)ncn1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(Cl)ncn1

Procedure:
To 12.4 g (0.1 mole) of 6-ethyl-4-hydroxypyrimidine was added 50 ml of 1,2-dichloroethane, and 18.4 g (0.12 mole) of phosphorus oxychloride was added thereto. The mixture was refluxed by heating for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 10.38 g of 4-chloro-6-ethylpyrimidine as slightly red liquid.
Reaction SMILES: [O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][O:42][C:41]1=[O:48])[C@H:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(CCC1C=CC=CN=1)C(=O)CN[C@H](C1C=CC=CC=1)C.CC([C@H]1COC(=O)N1C(=O)CCC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C.BrCC(OCC1C=CC=CC=1)=O>>[O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:46])[CH3:47])[CH2:43][O:42][C:41]1=[O:48])[CH:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[C@H]1COC(=O)N1C(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[C@H](NCC(=O)N(C)CCc1ccccn1)c1ccccc1
Agent: O=C(CBr)OCc1ccccc1
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
3-{1,4-Dioxo-4-(phenylmethoxy)-2(R)-{[1-(triphenylmethyl)-1 H-imidazol-4-yl]methyl}butyl}-4-(S)-(1-methylethyl)-2-oxazolidinone: By following the procedure of example 2, section (f), but replacing the product of section (e) of that example with 4(S)-(1-methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1 H-imidazol-4-yl]propyl}-2-oxazolidinone of section (b) of this example, and replacing tert-butyl 2-bromoacetate with benzyl 2-bromoacetate, 3-{1,4-dioxo-4-(phenylmethoxy)-2-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4-(S)-(1 -methylethyl)-2-oxazolidinone was obtained as a mixture of 2(R)- and 2(S)-epimers in a 8 to 1 ratio by weight. Separation of the epimers by flash chromatography (SiO2, eluent: hexane-EtOAc, 1:2) yielded the desired 2(R)-epimer (Rf=0.25, eluent: hexane-EtOAc,1:2). The 1H NMR(CDCl3) of the 2(R)-epimer showed 6 7.34-7.28 (m, 15H), 7.13-7.08 (m,6H), 6.59 (d, J=1.3 Hz,1H), 5.06 (s,2H), 4.55-4.45 (m, 1H), 4.38 (td, J=3.9 Hz,5.4 Hz,1H), 4.15-4.10 (m,2H), 2.97 (dd, J=10.3 Hz,16.9 Hz,1H), 2.88 (dd, J=6.3 Hz,14.3 Hz,1H), 2.73 (dd, J=7.0 Hz,14.3 Hz,1H), 2.59 (dd, J=4.4 Hz,16.9 Hz,1H), 2.32 (hept d, J=3.9 Hz,7.0 Hz,1H), 0.87 (d, J=7.1 Hz,3H), 0.85 (d, J=6.8 Hz,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].[CH2:14]([OH:17])[CH2:15]Br.O>CN(C)C=O>[N+:9]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][CH:14]([OH:17])[CH3:15])([O-:11])=[O:10]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)Oc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2.5 mols (434 g) of 4-chloro-3-nitrophenol are dissolved in 1,300 ml of dimethylformamide heated to 70° C. beforehand. 3 mols of powdered potassium hydroxide (210 g of 80% pure potassium hydroxide) are added to this solution, and 3 mols (534 g) of glycol bromohydrin are then introduced in the course of 30 minutes, with stirring and whilst keeping the temperature at 70° C. When the addition has ended, the reaction medium is kept at 70° C. for 1 hour. 1 mol of powdered potassium hydroxide (70 g of 80% pure potassium hydroxide) and 1 mol of glycol bromohydrin (178 g) are then added. After heating for 1 hour, a further 1 mol of potassium hydroxide and 1 mol of glycol bromohydrin are added. The heating is continued for a further 1 hour and the cooled reaction medium is then poured into 7.5 liters of iced water. The expected product precipitates. It is filtered off and washed carefully with a 3N solution of sodium hydroxide and then with water. After drying in vacuo, it melts at 96° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:12][S:13]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:15])=[O:14]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (0.40 g, 0.0025 mol) was dissolved in chloroform (10.0 mL) and the resulting mixture was cooled at 0° C. To the mixture was added TEA (0.49 mL, 0.0035 mol) and methanesulfonyl chloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[C:8]([F:22])[CH:7]=1>C(O)=O>[F:22][C:8]1[CH:7]=[C:6]([CH:2]=[O:1])[CH:21]=[CH:20][C:9]=1[O:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C3OCCO3)cc2F)cn1
Solvent: O=CO
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Combine formic acid (90%, 453 mL) and crude 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyrazine-2-carboxamide (Example 737, Part D) (32.81 g, approximately 0.09 mole) and stir initially a clear yellow solution, which becomes a thick slurry in an hour at room temperature. Stir overnight at room temperature till the reaction complete by HPLC. Quench the reaction with deionized water (1 L) and extract with dichloromethane (4× 4 L). Combine the extracts and mix with aqueous sodium bicarbonate solution. Concentrate on a rotary evaporator to give a slurry of a solid in water (when the separation of layers not possible). Extract the mixture with ethyl acetate (4× 1 L) and concentrate the combined extracts to a yellow solid (29.65 g). Form slurries successively four times with boiling methanol (1 L) and filter while hot. Combine the filter cakes and dissolve in enough boiling methanol to give a clear solution. Concentrate the solution to approximately 1 liter and allow to crystallize at 0° C. Filter the resulting slurry at 0° C. and dry the filter cake under vacuum at room temperature to give the title compound (17.79 g, 75.7%). 1H NMR (DMSO-d6) δ 7.70 (t, 1H, ArH), 7.78 (s, 1H. HetH), 7.86-7.93 (m, 2H, ArH), 8.14 (s, 1H, HetH), 8.73 (d, 2H, amide), 10.0 is, 1H, CHO); 13C NMR (DMSO-d6) δ 116.884, 124.606, 126.980, 133.186, 134.967, 140.765, 144.016, 152.493, 154.974, 159.276, 164.057, 190.777; MS (ES+) m/z 262.3 (M+H).