Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[CH:10][C:9]2=[O:24])=[CH:4][C:3]=1[O:25][CH3:26].[F-].[Cs+].[N+](C1C=C(S(O[CH2:42][C@H:43]2[CH2:45][O:44]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.C(Cl)Cl>[CH3:26][O:25][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)=[CH:10][C:9]2=[O:24])[CH:6]=[CH:7][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:45][O:44]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A mixture of 1-(4-hydroxy-3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one Part B of Procedure 14 (38 mg, 0.105 mmol) and cesium fluoride (48 mg, 0.32 mmol) in DMF (1 mL) was stirred at RT for 30 min. Then, (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (35 mg, 0.13 mmol) was added and stirred overnight at RT. Diluted with DCM, washed with water, sat. NaHCO3, dried (Na2SO4), and concentrated. The crude was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient) to afford the desired product (R)-1-(3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one 15A (32.1 mg, 0.08 mmol, 73.1% yield) as a light yellow solid. LC/MS 418 (M+H)+, tR 0.93 min (method 5).
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]1[N:49]=[C:48]([N:50]([CH3:54])[CH2:51][CH2:52][NH2:53])[CH:47]=[C:46]([CH3:55])[N:45]=1>CN(C=O)C>[CH:1]1(/[CH:4]=[CH:5]/[C:6]([NH:53][CH2:52][CH2:51][N:50]([C:48]2[CH:47]=[C:46]([CH3:55])[N:45]=[C:44]([O:43][CH3:42])[N:49]=2)[CH3:54])=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/C1CC1
Reactant: COc1nc(C)cc(N(C)CCN)n1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COc1nc(C)cc(N(C)CCNC(=O)/C=C/C2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-3-Cyclopropylprop-2-enoic acid (11.2 mg, 0.1 mmol) and diisopropylethylamine (17.4 μl, 1 mmol) were dissolved in anhydrous DMF (0.5 ml), HBTU (39 mg, 0.1 mmol) was added and the mixture was stirred for 15 minutes at room temperature. N-(2-methoxy-6-methyl-pyrimidin-4-yl)-N-methyl-ethane-1,2-diamine (19.6 mg, 0.1 mmol) and diisopropylethylamine (17.4 μl, 0.1 mmol), dissolved in anhydrous DMF (0.5 ml) were added and the mixture was stirred at room temperature overnight. The mixture was purified directly by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 13.7 mg (0.047 mmol, 47.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:29])[CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:49])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:29])[CH:3]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3C)c3ccc(Cl)cc3F)c[nH]c12
Product: Cc1cc(F)ccc1C(c1ccc(Cl)cc1F)c1c[nH]c2c(CS(C)=O)cccc12

Procedure:
The title compound was prepared starting from 100 mg (0.23 mmol) of the compound from Example 287 in analogy to the synthesis of the compound from Example 296. 99 mg (95% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][C:18](C)([O-])C.[K+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31]C(C=O)=[CH:27][C:26]=1[O:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1.Cl>O1CCCC1>[CH2:17]([C:3](=[CH:2][C:1]1[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[C:26]([O:33][CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=2)[CH:27]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:18]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1OCCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OC)c(OCCc2ccc(C(F)(F)F)cc2)c1)CC
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, a solution of triethyl 2-phosphonobutyrate (555 mg, 2.20 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to a solution of potassium tert-butoxide (250 mg, 2.23 mmol) in anhydrous tetrahydrofuran (10 mL), and then the mixture was stirred for 20 minutes. Following this, a solution of 4-methoxy-3-[2-[4-(trifluoromethyl)phenyl]ethoxy]benzaldehyde (650 mg, 2.00 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise and then the mixture was stirred for 1 hour under cooling with ice and for 4 hours at room temperature. Cooled 0.5 mol/L hydrochloric acid (30 mL) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 842 mg (99%) of the title compound as a colorless oily product.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[CH3:8])[C:3](=O)[CH3:4].[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14]>>[CH3:10][O:11][C:12](=[O:15])[CH2:13][N:14]1[C:7]([CH3:8])=[CH:6][C:2]([CH3:1])=[C:3]1[CH3:4]
Reactant: CC(=O)CC(C)C(C)=O
Reactant: COC(=O)CN
Product: COC(=O)Cn1c(C)cc(C)c1C

Procedure:
By a procedure analogous to Example 1, 3-methylhexan-2,5-dione (J. Amer. Chem. Soc., 1929, 51, 3514) is reacted with glycine methyl ester to give methyl(2,3,5-trimethyl-1H-pyrrol-1-yl)acetate.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH2:25])[CH3:21]>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:25][C:24]2[CH:26]=[C:27]([O:36][CH2:37][CH3:38])[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:29][C:23]=2[O:22][CH2:20][CH3:21])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1N
Product: CCCCN1C(=O)C(Nc2cc(OCC)c(N3CCOCC3)cc2OCC)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2,5-diethoxy-4-morpholin-4-ylaniline in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (400 MHz, CD3CN): δ 7.46 (bs, 1H), 7.27-7.22 (m, 1H), 7.18-7.09 (m, 4H), 6.25 (d, 2H), 3.86-3.80 (m, 2H), 3.76-3.70 (m, 6H), 3.53-3.47 (m, 2H), 2.91-2.87 (m, 4H), 1.85-1.77 (m, 2H), 1.52-1.42 (m, 2H), 1.36 (t, 3H), 1.22 (t, 3H), 0.99 (t, 3H); Mass Spectrum: M+H+ 530.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH2:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH:20][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:25]5[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=5)[CH:29]=4)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccc(F)cc3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccc(F)cc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 27 %

Procedure:
This compound was synthesized from (4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (11 mg, 27% yield): 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.23 (d, J=6.4 Hz, 1H), 7.98 (d, J=6.4 Hz, 1H), 7.85 (t, J=5.1 Hz, 2H), 7.55 (t, J=7.7 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=7.7 Hz, 2H) 3.94 (m, 2H), 3.87 (m, 2H), 3.21 (m, 2H), 2.28 (m, 2H), 2.04 (m, 2H). MS (ESI) m/z: Calculated for C25H20F4N4O3S: 532.12. found: 533.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([Mg]Br)[CH:8]=[CH2:9].O.Cl.O1C[CH2:17][CH2:16][CH2:15]1>C(OCC)C>[Cl:1][CH2:2][CH2:3][C:4]([OH:5])([CH2:17][CH:16]=[CH2:15])[CH2:7][CH:8]=[CH2:9]
Reactant: C1CCOC1
Reactant: O=C(Cl)CCCl
Reactant: C=CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C=CCC(O)(CC=C)CCCl
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3-Chloro-propionyl chloride (5.00 g) dissolved in tetrahydrofuran (50 mL) is added dropwise to a 1 M solution of allylmagnesium bromide in diethyl ether (72 mL) cooled to −15° C. The solution is warmed in the cooling bath to room temperature over a period of 2 h and stirred at room temperature overnight. Water is then added and the resulting mixture is neutralized using 4 M aqueous hydrochloric acid. The mixture is extracted with diethyl ether (3×) and the combined extracts are washed with water (2×). The organic phase is dried (Na2SO4) and the solvent is evaporated to afford the crude title compound. Yield: 7.87 g (ca. 85% pure).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[C:16]([CH3:24])[C:15]=1[O:25][CH3:26].[Cr](O)(O)(=O)=[O:28].S(=O)(=O)(O)O>>[CH3:26][O:25][C:15]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:28])=[O:1])=[C:19]([CH3:20])[C:18]([O:21][CH3:22])=[C:17]([CH3:23])[C:16]=1[CH3:24]
Reactant: O=[Cr](=O)(O)O
Reactant: COc1c(C)c(C)c(OC)c(CCCCC#CCCCC#CCO)c1C
Agent: O=S(=O)(O)O
Product: COc1c(C)c(C)c(OC)c(CCCCC#CCCCC#CC(=O)O)c1C

Procedure:
By a similar manner to Example 1, 3.56 g (10 mmoles) of 1-(12-hydroxydodeca-5,10-diynyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (II: R=R1 =CH3, Y=CH2OH) was oxidized with chromic acid-sulfuric acid, whereby 12.62 g of 1,4-dimethoxy-2,3,5-trimethyl-6-(11-carboxyundeca-5,10-diynyl)benzene was obtained as an oily substance. In a mixed solvent of acetonitrile (40 ml) and water (20 ml) were dissolved 2.60 g (7.0 mmole) of the compound obtained above and 3.80 g (7.0×3 mmoles) of 2,6-dicarboxypyridine N-oxide, and the solution was stirred under cooling with ice. An ice-cooled solution of ceric ammonium nitrate (11.4 g, 7.0×3 mmoles) in 50% aqueous acetonitrile (60 ml) was added dropwise to the above solution over a period of 30 minutes, followed by stirring under the same conditions for 30 minutes and at room temperature for 30 minutes. After the completion of the reaction, insolubles were filtered out, and the acetonitrile was distilled off under reduced pressure. To the residue were added isopropyl ether (100 ml) and water (20 ml) for extraction, and the organic layer was washed with saturated sodium bicarbonate and aqueous sodium chloride, successively and dried (over MgSO4), followed by distilling off the organic solvent under reduced pressure. The residue was chromatographed on a column of silica gel developing with isopropyl ether:ethyl acetate (98:2 to 95:5) to give 2.10 g of 2,3,5-trimethyl-6-(11-carboxyundeca-5,10-diynyl)-1,4-benzoquinone. m.p. 49°-51° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[C:12]([O:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)=[O:18])(=[O:14])[CH3:13]
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-4-chlorobenzothiazole (4.6 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.6 g) having the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([Cl:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[ClH:38].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][S:35]([C:32]4[CH:31]=[CH:30][C:29]([C:26]5[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=5)=[CH:34][CH:33]=4)(=[O:36])=[O:37])=[CH:17][CH:16]=3)=[O:14])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: Nc1ccc(C(=O)N2CCN(c3ccncc3)CC2)cc1
Product: Cl
Product: O=C(c1ccc(NS(=O)(=O)c2ccc(-c3ccc(Br)cc3)cc2)cc1)N1CCN(c2ccncc2)CC1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 89, 4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]aniline was reacted with 4'-bromo-4-biphenylylsulphonyl chloride to give N-{4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl}-4'-bromo-4-biphenylylsulphonamide hydrochloride salt in 90% yield, m.p. 201-205° C.;
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: BrCCc1ccccc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2-bromoethyl)benzene and isolated as light-yellow gum (7.3 mg, 46%). MS (m/e): 387.4 (MH+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O:20][C:21]1[CH:22]=[C:23]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:24][CH2:25][CH2:26][CH:27]=[N:28][NH:29][C:30]([NH2:32])=[S:31])(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([N:29]([C:30](=[NH:32])[SH:31])[N:28]=[CH:27][CH2:26][CH2:25][O:24][C:23]1[CH:33]=[C:34]([CH3:36])[CH:35]=[C:21]([O:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])(=[O:19])=[O:18])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NNC(N)=S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NN(Cc2ccccc2)C(=N)S)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A solution of benzyl bromide (15.5 μL, 0.13 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.5 mL) was added dropwise over 20 minutes to a mixture of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-propionaldehyde thiosemicarbazone (55.3 mg, 0.13 mmol, as prepared in the preceding step) and sodium bicarbonate (28.8 mg, 0.34 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.5 mL). The reaction was stirred for 5 hours at ambient temperature, then additional benzyl bromide (15.5 μL, 0.13 mmol) in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The reaction was stirred overnight at ambient temperature then concentrated to remove solvents. The residue was triturated with dichloromethane and filtered through Celite. After concentration, crude product was purified by flash column chromatography through silica gel (1:1 diethyl ether/hexane) to give the title compound as an oil (42 mg, 1:4 mixture of isomers, 62%). 1H-NMR (300 MHz, CDCl3) δ 7.80-7.85 (m, 2H), 7.57-7.63 (m, 1H), 7.23-7.40 (m, 5H), 6.98-7.12 (m, 2H), 6.59 (br s, 1H), 6.52 (br s, 1H), 6.46 (t, 1H, J=2 Hz), 4.29 and 4.28 (s, 1H), 4.10 (t, 2H, J=6.5 Hz), 4.01 (s, 3H), 2.94 and 2.73 (q, 2H, J=6 Hz), 1.55 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H27N3O5S2 : 514.1 (M+H). Found: 513.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14]C)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1cnc(-c2ccc(Cl)cc2)nc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cnc(-c2ccc(Cl)cc2)nc1
Yield: 88 %

Procedure:
To a stirred solution of 2-(4-chloro-phenyl)-5-methoxy-pyrimidine (100 mg, 0.45 mmol) was added hydrogen bromide in acetic acid (3 mL of a 33% by weight solution). The resulting mixture was stirred at reflux for 4 hours. The mixture was then partitioned between diethyl ether (25 mL) and saturated sodium hydrogen carbonate solution (25 mL). The organics were further washed with water (25 mL), brine (25 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting precipitate was washed with pentane (10 mL) and then dried under reduced pressure to afford the title compound as a white solid in 88% yield, 82 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Li]C(C)(C)C.[CH3:16][CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18](=[O:19])[CH:17]([CH3:16])[CH2:22][CH2:21][OH:20])=[C:3]([CH3:10])[CH:4]=1
Reactant: CC1CCOC1=O
Reactant: COc1ccc(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C)CCO)c(C)c1
Temperature: -68 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a 200 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added a solution of 4-bromo-3-methylanisole (2.77 g, 16.3 mmol) in 40 mL of THF under nitrogen. The solution was cooled to −68° C. with a dry ice/acetone bath. To this solution was slowly added t-BuLi (21.0 mL, 1.70 M in pentane, 35.8 mmol) followed by the addition of a solution of α-methyl-γ-butyrolactone (2.30 m L, 24.4 mmol) in THF (10.0 mL). The internal temperature was controlled <−55° C. After 1 h stirring at <−55° C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness to give 3.85 g of 1-(4-methoxy-2-methylphenyl)-4-hydroxy-2-methylbutan-1-one as light yellow oil, which was combined with another batch of material and subjected to column chromatography to give 1.26 g (18%) of clear oil. This material was used for Swern oxidation. To a 100 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added DMSO (1.75 mL, 24.6 mmol) and CH2Cl2 (20 mL). The solution was cooled to −80° C. with a MeOH/liquid nitrogen bath. To this solution was added oxalyl chloride (1.10 mL, 12.3 mmol) slowly via syringe pump. The mixture was stirred at −80° C. for 15 min followed by the addition of a solution of the above 1-(2-methyl-4-methoxyphenyl)-4-hydroxy-2-methylbutan-1-one (1.23 g) in CH2Cl2 (3.0 mL) slowly via syringe pump. After stirring at <−70° C. for 1 h, to the mixture was added Et3N (7.70 mL, 55.0 mmol). The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with hexanes (120 mL) and washed with water. The aqueous layer was extracted with hexanes. The combined organic solutions was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 0.326 g (27%) of light yellow oil as the title compound: compound: 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J=8 Hz, 1H), 6.83 (d, J=3 Hz, 1H), 6.81 (s, 1H), 3.94–3.86 (m, 4H), 3.20–3.13 (m, 1H), 2.62–2.56 (m, 1H), 2.51 (s, 3H), 1.21 (d, J=7 Hz, 3H); MS m/z 221.1 (M++H).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([O:30][CH2:31][CH2:32][C:33]1[N:34]2[CH:40]=[N:39][CH:38]=[C:35]2[S:36][CH:37]=1)(=[O:29])[NH2:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([CH2:32][CH2:31][O:30][C:27](=[O:29])[NH2:28])[N+:34]4=[CH:40]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: NC(=O)OCCc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CCOC(N)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 23.8 %

Procedure:
The same procedure as in Example 1 was repeated except that 95 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 110 mg of 3-(2-carbamoyloxyethyl)imidazo[5,1-b]thiazole were used, thereby obtaining 26.9 mg of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]2[C@@H:20]([OH:24])[CH2:21][C@@H:22]([OH:23])[C@@H:9]2[CH:8]=[CH:7]1.[O:25]=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:19])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:25])=[O:18])[C:20](=[O:24])[CH2:21][C@H:22]1[OH:23]
Reactant: CCCCC[C@H]1C=C[C@@H]2[C@@H](CC=CCCCC(=O)O1)[C@@H](O)C[C@H]2O
Reactant: O=[Cr](=O)=O
Agent: CCCCC[C@H]1/C=C/[C@@H]2[C@@H](C/C=C\CCCC(=O)O1)[C@@H](O)C[C@H]2O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.33 h

Procedure:
The mono-trimethylsilyl derivative of PGF2α 1,15-lactone (above) was dissolved in 6 ml of methylene chloride and added in one portion to the rapidly stirred Collins reagent. The ice bath was removed and the reaction mixture was allowed to stir for 20 min. longer. The mixture was then poured onto a column containing 150 g of neutral silica. With the aid of a house-vacuum, the column was eluted into a 2-liter round bottom flask with 1000 ml of ethyl acetate. Removal of the solvent gave PGE2, 1,15-lactone, 11-trimethylsilyl ether.
Reaction SMILES: [CH2:1]1[CH2:8][O:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[H-].[NH2:10][NH2:11]>CO>[S:4]([CH2:3][CH2:2][CH2:1][CH2:8][NH:10][NH2:11])([OH:7])(=[O:6])=[O:5]
Reactant: O=S1(=O)CCCCO1
Reactant: NN
Agent: [H-]
Solvent: CO
Product: NNCCCCS(=O)(=O)O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
103 ml of 1,4-butanesultone was added to 378 g of hydrazine hydride (80%) dropwise slowly, and stirred for 30 minutes at room temperature and for further 1 hour at 70° C. Water and hydrazine hydride were removed to obtain white crystals. These crystals were dispersed in 1.5 liters of methanol, and then refluxed for 1 hour and allowed to stand at room temperature. The crystals were collected, twice washed with 100 ml of methanol, and dried to obtain 115 g of 4-sulfobutylhydrazine. (m.p.: 152°-154° C.)