Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]=O)=[N:14][CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CN(C)C=O>[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[CH:10][C:8]([O:7][CH2:3][CH3:4])=[O:9])=[N:14][CH:15]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 186.8 %

Procedure:
To a solution of 2.2 g of triethyl phosphonoacetate in 20 ml of dimethylformamide, 0.39 g of sodium hydride (about 60%, in oil) is added slowly, and then 2.0 g of 5-t-butoxycarbonyl-2-pyridinecarbaldehyde is added. The resulting mixture is stirred at room temperature overnight and concentrated, and 20 ml of water is added. The aqueous solution is extracted with three 40-ml portions of chloroform. The combined extracts are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel with chloroform to give 2.5 g of ethyl 3-(5-t-butoxycarbonyl-2-pyridyl)acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](C)([CH2:11][CH2:12][CH2:13][CH2:14]C)C)[CH:6]=[C:5]([O:17][CH3:18])[C:4]=1[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1.[Li]CCCC.B1(OC(C)C)OC(C)(C)C(C)(C)O1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[C:5]([O:17][CH3:18])[C:4]=1[B:19]1[O:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:25])[O:23]1
Reactant: CCCCCC(C)(C)c1cc(OC)c(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1cc(OC)c(B2OC(C)(C)C(C)(C)O2)c(OC)c1

Procedure:
The title compound was prepared by the general procedure described for compound 3, using 4-alkyl resorcinol dimethylether 2 0.104 g (0.5 mmol) in 4 ml of THF, n-BuLi 0.34 ml (0.55 mmol, 1.6 M solution in hexane) and PINBOP 0.15 ml (0.75 mmol). The product was obtained as a non-separable mixture 0.165 g of pinacol aryl boronate 4 and 4-alkyl resorcinol dimethylether 2 (in ratio 4:3 according to GC-MS analysis) and was used as it is in Suzuki coupling reaction. 1H NMR (300 MHz, CDCl3) δ ppm 6.28 (s, 2H), 3.76 (s, 6H), 2.55 (t, J=7.53 Hz, 2H), 1.55-1.63 (m, 2H), 1.27 (s, 6H), 1.26 (s, 6H), 1.24 (m, 4H), 0.87 (m, 3H). Exact mass calculated for C27H34O3 m/e 334.23. found 334.62.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([N:19]2[CH2:20][CH2:21][CH:17]([OH:16])[CH2:18]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: OC1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenyl bromide (21.1 g), 3-hydroxypyrrolidine (6.53 g), tris(dibenzylideneacetone)dipalladium(0) (1.47 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.99 g) and sodium tert-butoxide (10.6 g) in toluene (140 ml) was stirred under an argon gas atmosphere at 100° C. for 18 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 95:5-70:30) to give the title compound (13.2 g, yield 61%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:61]([NH:63][C@H:64]([C:69]([O:71]C(C)(C)C)=[O:70])[CH2:65][C:66](=[O:68])[NH2:67])=[O:62])[CH2:59][OH:60])=[O:56])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8].C([O-])(=O)C>FC(F)(F)C(O)=O.O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:61]([NH:63][C@H:64]([C:69]([OH:71])=[O:70])[CH2:65][C:66](=[O:68])[NH2:67])=[O:62])[CH2:59][OH:60])=[O:56])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: CC(C)C[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 1 h

Procedure:
In 8 ml of trifluoroacetic acid is dissolved 200 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-(D)-Leu-Gly-Ser-Asn-OBut and the solution is allowed to stand at room temperature for 60 minutes. The trifluoroacetic acid is distilled off under reduced pressure and the residue is precipitated with ether and recovered by filtration. The powders thus obtained are dissolved in a small amount of water and passed through a column of Amberlite IRA-410 (acetate-form) (1.5×7 cm). The effluent is combined with washings and lyophilized. The powdery lyophilizate is dissolved in a small amount of 1 N-acetic acid and put onto a chromatographic column of Sephadex LH-20(2.5×125 cm), elution being carried out with 1 N-acetic acid. The fractions from 190-205 ml are pooled and lyophilized. Yield 65 mg; [α]D22 -45.4° (c=0.4, H2O); Rf4 (Avicel)=0.37; amino acid analysis (acid hydrolyzate): Lys, 1.04(1); Asp, 0.98(1); Ser, 1.86 (2); Glu, 2.14(2); Gly, 0.93(1); Ala, 1.00(1); Leu, 1.00 (1); average recovery, 71.2%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[CH3:16]O>>[CH3:16][O:13][C:12]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)=[O:14]
Reactant: O=C(O)c1cc2c(cc1O)CCCC2
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2c(cc1O)CCCC2
Reaction time: 2 h

Procedure:
A 281 g sample of 3-hydroxy-5,6,7,8-tetrahydro-2-naphthoic acid was dissolved in 1.4 l of methanol, and while hydrogen chloride gas was supplied, the solution was first exposed to room temperature for 2 hours, and then heated at 60° to 70° C. for 4 hours. Methanol was distilled off under vacuum, water was added to the residue, which was then extracted with ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate until it became neutral, and then it was dehydrated and concentrated. The residual oily product was distilled under vacuum to provide 279 g of the title compound (1) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[CH3:51][O:52][CH2:53][C:54]#[CH:55].C(N(C(C)C)CC)(C)C.N1C=CC=CC=1>C(#N)C.O.FC(F)(F)C(O)=O.[Cu]I.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.ClCCl.O.CN1CCCC1=O>[NH2:1][C:2]1[N:23]=[C:22]([C:55]#[C:54][CH2:53][O:52][CH3:51])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: C#CCOC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCC#Cc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 7.2 %

Procedure:
A mixture of 2-aminochloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (15 mg, 0.042 mmol), methylpropargyl ether (3.5 mg, 0.050 mmol), diisopropylethylamine (0.023 mL, 0.13 mmol), pyridine (0.011 mL, 0.13 mmol), catalytic amount of copper(I) iodide, tetrakis(triphenylphosphine)palladium(0) (9.6 mg, 0.0083 mmol) and N-methylpyrrolidinone (1 mL) was stirred for 4 hours at 120° C. After cooling, water and dichloromethane were added to the reaction solution for extraction, and the organic layer was filtered through a membrane filter. The solvent was evaporated in vacuo, then, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), trifluoroacetic acid salt of the title compound (1.5 mg, 0.00030 mmol, 7.2%) was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([Br:26])=[CH:19][C:8]=1[NH:9]S(C1C=CC=CC=1)(=O)=O>O>[Br:6][C:7]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([Br:26])=[CH:19][C:8]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)c(NS(=O)(=O)c2ccccc2)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cc(Br)c([N+](=O)[O-])cc1Br
Temperature: 0 °C

Procedure:
15 ml of water are added, with due care, to 115 ml of concentrated sulphuric acid; the temperature rises to 70° C. 0.105 mole (46 g) of 2,5-dibromo-4-nitro-N-benzenesulphonylaniline are then added. The temperature is maintained at 70°-78° C. for 2 hours. The reaction mixture is poured into 1 kg of ice and water; the expected product precipitates. After filtration and washing to neutrality the product is recrystallized from 450 ml of ethanol. It melts at 178° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[C:34]([CH3:35])[CH:33]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cc1C
Temperature: 80 °C
Yield: 59.4 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (70 mg, 0.18 mmol), 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) in 1,2-dimethoxyethane (2.0 mL), 2 M Na2CO3 (276 μL, 0.55 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 20 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (50 mg, 58%). ESI-MS m/z calc. 467.4. found 468.7 (M+1)+. Retention time 1.96 minutes.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[Cl:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>C(#N)C>[Cl:7][CH2:8][CH2:9][C:10]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:11]
Reactant: COC(=O)NN
Reactant: O=C(Cl)CCCl
Solvent: CC#N
Product: COC(=O)NNC(=O)CCCl
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 45 g. (0.5 moles) of methyl carbazate in 375 ml. of acetonitrile 63.5 g. (0.5 moles) of 3-chloro-propionyl chloride are added dropwise. The reaction mixture is heated to boiling for 16 hours, clarified and cooled. The precipitated crystals are filtered. Thus 70.5 g. of the desired compound are obtained in the form of white crystals. Yield: 78.3%. M.p.: 129° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=S1C=Nc2c(Cl)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CS(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
4-Chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in a solution of sodium hydroxide (3.19 g, 0.075 mole) in water (220 ml), and tetra-n-butylammonium bromide (0.48 g, 0.0015 mole) and toluene (80 ml) were added thereto. Dimethyl sulfate (9.40 g, 0.075 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 9.80 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals. Yield 98.2%, purity 98.2%, m.p. 130°-132° C.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:10][CH2:9][CH:8]2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]1([CH:7]2[O:12][C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:10][CH2:9][CH:8]2[O:18][C:26](=[O:27])[NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CN=C(c2cccs2)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)OC1CN=C(c2cccs2)OC1c1ccccc1
Yield: 77.4 %

Procedure:
Working in a manner similar to that described in Example 12, but starting with (5RS, 6SR)-6-phenyl-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazin-5-ol (1.55 g) and phenyl isocyanate (0.8 g), and after recrystallization in isopropanol, (5RS, 6SR)-6-phenyl-5-phenylcarbamoyloxy-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazine (1.75 g), m.p. 98° C., is obtained.
Reaction SMILES: [Cl:1]C1C=CC(B(O)O)=CC=1.[C:11]1(C)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:21][N:20]=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]=1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[C:30]([Cl:41])[CH:29]=1>>[Cl:41][C:30]1[CH:29]=[C:28]([O:27][CH2:26][C:18]2[C:19]([C:22]([F:24])([F:25])[F:23])=[N:20][S:21][C:17]=2[C:12]2[CH:13]=[CH:14][C:15]([Cl:1])=[CH:16][CH:11]=2)[CH:33]=[CH:32][C:31]=1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1ccc(OCc2c(C(F)(F)F)nsc2-c2ccccc2C)cc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)nsc2-c2ccc(Cl)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 172 following Step 1-6 using (4-chloro-phenyl)boronic acid for coupling and then hydrolysis of ethyl 3-(4-((5-(o-tolyl)-3-(trifluoromethyl)isothiazol-4-yl)methoxy)-2-chloro-phenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.53-7.59 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 6.81-6.85 (m, 1H), 5.06 (s, 2H), 2.99 (t, J=8.1 Hz, 2H), 2.60 (t, J=8.1 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H14Cl2F3NO3S, 474.0 (M−H). found 474.0.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5]>C1COCC1.[OH-].[Li+]>[C:7]1([NH:6][C:4](=[O:5])[C:3]([OH:17])=[O:2])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)Nc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To N-Naphthalen-1-yl-oxalamic acid methyl ester (0.14 g, 0.61 mmol) stirring in THF (2 mL) was added 2 mL of a IN lithium hydroxide solution. The reaction was heated to 50° C. and stirred for 2 h. The resulting mixture was concentrated in vacuo to afford a yellow residue that was acidified with 1N HCL. The resulting mixture was extracted with DCM (3×50 mL), dried over MgSO4 and concentrated under vacuum to afford crude product. The crude material was purified by flash chromatography (0-20% MeOH:DCM, silica gel) to afford the desired product (0.128 g, 98%) as a thick oil. Expected mass=215. Observed mass=216.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:34]([NH2:35])=[C:33]([CH:36]([CH3:38])[CH3:37])[C:25]2[S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1)([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[C:34]([N:35]2[CH2:2][CH2:3][N:4]=[C:5]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:33]([CH:36]([CH3:38])[CH3:37])[C:25]2[S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1)([CH3:21])[CH3:20]
Reactant: O=C(NCCCl)c1ccccc1
Reactant: CC(C)c1cc2c(sc3ccccc32)c(C(C)C)c1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc2c(sc3ccccc32)c(C(C)C)c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
N-(2-chloroethyl)benzamide (4.3 g, 23.42 mmol), was dissolved in 50 mL anhydrous m-xylene under nitrogen. Phosphorus pentachloride (7.31 g, 35.1 mmol) was then carefully added and the mixture heated to reflux under nitrogen for 2 h. The solution was allowed to cooled to room temperature and 2,4-diisopropyldibenzo[b,d]thiophen-3-amine (7.30 g, 25.8 mmol) was added. The reaction mixture was heated to reflux for 20 h. After cooling, the precipitate was filtered and the solid imidazoline product was collected and washed with toluene followed by hexanes. The resultant crude product was dissolved in methylene chloride and washed twice with 50% NaOH. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford title product (4.8 g, 50%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCCC1.C(OCC)(=O)C>[CH:18]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1)=[CH2:19]
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Temperature: 150 °C
Yield: 66.2 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1 Steps 1 and 2, 410 mg, 1.52 mmol), tributyl(vinyl)tin (535 mg, 1.69 mmol) and tetrakis-(triphenylphosphine)palladium(0) (87 mg) were combined in tetrahydrofuran (10 mL) in three batches in 5 mL microwave vials. The vials were heated to 150° C. for 10 minutes in a Smith synthesiser microwave reactor. The combined reactions were diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10–20% ethyl acetate/isohexane gave 2-vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine as a colourless solid (265 mg, 66%). δH (500 MHz, d6 DMSO): 9.03 (1H, s), 8.30 (1H, dd, J=1.4, 8.3 Hz), 7.51 (1H, td, J=7.9, 0.85 Hz), 7.43 (1H, dd, J=9.1, 10.6 Hz), 6.92 (1H, dd, J=10.7, 17.4 Hz), 6.43 (1H, dd, J=1.2, 17.4 Hz), 5.70 (1H, dd, J=1.2, 10.7 Hz); m/z (ES+) 364 [MH+].
Reaction SMILES: [CH:1]([CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1)([CH3:3])[CH3:2].C([Li])CCC.[CH:15](=[O:19])[CH2:16][CH2:17][CH3:18]>O1CCCC1>[CH:1]([C:4]1([CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])[S:9][CH2:8][CH2:7][CH2:6][S:5]1)([CH3:3])[CH3:2]
Reactant: CCCC=O
Reactant: CC(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(O)C1(C(C)C)SCCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of (100) (4 g, 24.7 mmol) in anhydrous tetrahydrofuran (50 mL) at −20° C. was dropwise added n-butyl lithium (1.6M in hexane, 18.5 mL, 29.6 mmol). The stirred mixture was allowed to warm room temperature over 4 h and then cooled to −20° C. again. To this solution was added slowly a solution of n-butyraldehyde (2.7 mL, 29.6 mmol) in anhydrous tetrahydrofuran (10 mL). The resulting mixture was stirred for 16 h between −20° C. and room temperature. The reaction was quenched with saturated ammonium chloride solution and the mixture extracted with ethyl acetate. The organic layer was separated and dried over Na2SO4. After removing the solvent under reduced pressure, flash column chromatography of the residue on silica gel, eluting with 5% ethyl acetate/hexane provided 5 g (85%) of the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 0.96 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.8, Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.42-1.52 (m, 2H), 1.76 (m, 1H), 1.87-1.95 (m, 2H), 2.04 (m, 2H), 2.62 (m, 4H), 2.94 (m, 2H), 4.03 (d, J=5.2 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C:25](=[O:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4].CO>O1CCCC1>[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C@@H:25]([OH:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4]
Reactant: CC#CCCC(=O)/C=C/[C@@H]1[C@H]2C[C@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCC[C@H](O)/C=C/[C@@H]1[C@H]2C[C@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Reaction time: 1 h

Procedure:
At -40°, 210 mg. of sodium borohydride is added in incremental portions to a solution of 390 mg. of (1S,5R,6R,7R,3S)-7-acetoxy-6-[(E)-3-oxo-1-octen-6-ynyl]-3-(4-methoxycarbonyl-1-butyl)-2-oxabicyclo[3,3,0]octane in 12 ml. of methanol and 5 ml. of tetrahydrofuran. The mixture is stirred for 1 hour at -40°, then combined with 0.5 ml. of glacial acetic acid, concentrated under vacuum, the residue mixed with methylene chloride, and the organic extract is shaken with 4% sodium bicarbonate solution and then washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. After chromatography of the residue on silica gel with ether/pentane (6+4), 110 mg. of the β-configured compound and 150 mg. of the title compound are obtained in the form of an oil.