Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[O:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C>[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:41][N:40]=2)=[O:43])[CH2:55]1
Reactant: Fc1ccc(F)c(OC2CCNC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)C1)c1cc(-c2ccccc2)on1
Reaction time: 0.03 h
Yield: 35.4 %

Procedure:
DIPEA (153.5 mg, 1.2 mmol) followed by HOBt (44.1 mg, 0.32 mmol) and EDCI (113.8 mg, 0.59 mmol) were added to a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (73.4 mg, 0.29 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(2,5-difluoro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (70 mg, 0.29 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 50% EtOAc in hexane) afforded 45 mg (35.4% Yield) of 5-phenyl-isoxazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 428, 91.77%. 1H NMR (300 MHz, DMSO-d6): δ 8.8-8.68 (m, 1H), 8.0-7.9 (m, 2H), 7.6-7.5 (m, 3H), 7.4 (s, 1H), 7.34-7.2 (m, 2H), 6.9-6.75 (m, 1H), 5.3-5.0 (m, 2H), 4.2-4.0 (m, 2H), 3.9 (m, 1H), 3.8-3.7 (m, 1H), 3.7-3.5 (m, 2H), 2.3-2.2 (m, 1H), 2.1 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[C:31]([CH3:33])[C:30](Br)=[CH:29][CH:28]=1>>[CH3:33][C:31]1[N:32]=[C:27]([NH2:26])[CH:28]=[CH:29][C:30]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)ccc1Br
Product: Cc1nc(N)ccc1C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 6-amino-3-bromo-2-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (90 mg, 19%). MS (ISP) 462.2 [(M+H)+]; mp 251–254° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCOc1ccccc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCOc1ccccc1

Procedure:
4-Phenoxy-1-butanol (4 g), 1,6-dibromohexane (6.7 ml), TAB (0.8 g) and sodium hydroxide (9.4 g in 18 ml water) were stirred at room temperature under nitrogen for 20 h. Water (80 ml) was added and the mixture extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried and evaporated to give a colourless liquid. This was applied to an FCC column and eluted with cyclohexane (2 l) and then with System A (1:40). The resulting oil was distilled to give the title compound (3.4 g) as a colourless oil b.p. 150°/3.5 mmHg T.l.c. (System A 1:6) Rf 0.3.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(F)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1 g), 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (0.67 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.9 g, 64%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@@H:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[CH2:12][NH:11]C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][NH:9][C@@H:13]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[CH2:12][NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC[C@H](COc2ccc(Br)cc2)N1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC[C@H](COc1ccc(Br)cc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 3F in ethanol (300 mL) was treated with a solution of 30% (w/w) KOH in water (100 mL), heated to reflux, stirred for 8 hours, treated with additional 30% KOH in water (5 mL), stirred for 40 minutes, cooled to room temperature, concentrated to a slurry, and extracted with toluene. The extract was washed with 1M NaOH and brine, dried (Na2SO4), filtered, and concentrated to provide 48.6 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ7.45 (m, 2H), 7.33 (m, 5H), 6.90 (m, 2H), 6.67 (d, 1H, J=5 Hz), 4.63 (s, 2H), 3.95 (m, 2H), 3.08 (m, 1H), 2.73 (m, 1H), 2.62 (m, 1H), 1.40 (br s, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C(Cl)(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][C@H:23]([O:25][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4R)-tert-Butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (300 mg) obtained in Step 1 above was dissolved in chloroform (3.0 ml). Triethylamine (137 μl) and methanesulfonyl chloride (56 μl) were added to the solution at 0° C. After stirring at room temperature for 2.0 hours, chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (389 mg). Physical properties: m/z[M+H]+ 534.1
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][C:39](=[O:41])[CH3:40])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CCC[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of Trans (racemic) 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (8.84 g, 21.2 mmol) dissolved in DCM (5 ml) was added N,N-diisopropylethylamine (3.88 ml, 22.28 mmol), followed by 4-Dimethylamino pyridine (420.3 mg, 3.44 mmol) at room temperature. To this was added Acetyl chloride (6.04 ml, 84.90 mmol) dropwise with stirring at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated under reduced pressure to give an oil, which was used, as is, for the next step. LCMS (Method M, ESI): RT=3.07 min, m+H=459.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1CCNCC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1N1CCCCC1

Procedure:
5-Bromo-2-fluorobenzonitrile and piperidine were heated at 80° C. in DMSO in the presence of cesium carbonate to obtain 5-bromo-2-piperidin-1-ylbenzonitrile. F: 265.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[S:40])[CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 149.8 %

Procedure:
Compound 17a (293 mg) was dissolved in toluene (8.34 ml), and Lawesson's reagent (189 mg) was added thereto in a nitrogen atmosphere. The obtained mixture was stirred while refluxing under heating for 2 hours. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (10% ethyl acetate/n-hexane) to obtain Compound 17b (319 mg, 76%) as a yellow foam material.
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:23]=2)[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([CH3:35])[N:26]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH3:35][C:27]1[N:26]=[C:25]([N:19]2[CH2:18][C:17]3[CH:23]=[C:13]([C:11]4[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:3]([O-:5])=[O:4])[CH:12]=4)[CH:14]=[CH:15][C:16]=3[O:22][CH2:21][CH2:20]2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCOc3ccc(-c4ccc(N)c([N+](=O)[O-])c4)cc3C2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A solution of 2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline dihydrochloride (323 mg, 1.0 mmol), 4-chloro-2-methylquinazoline (179 mg, 1.0 mmol), and diisopropylethylamine (700 uL, 4.0 mmol) in NMP (11 mL) was heated to 90° C. and stirred for 40 min. After cooling to rt, water was added to the reaction mixture. The orange precipitate formed was collected by filtration and then dried to provide 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-2-nitroaniline (380 mg, 0.89 mmol, 89% yield) as a bright orange powder. MS (EI) for C24H21N5O3: 428 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11](=O)[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][C:15](OC)=[O:16].C([O-])(=O)C.[NH4+].[BH3-]C#[N:29].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:29][C:15](=[O:16])[CH2:14][C:13]([CH3:20])([CH3:19])[CH2:12]1
Reactant: COC(=O)CC(C)(C)CC(=O)c1c(OC)cccc1OC
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(OC)c1C1CC(C)(C)CC(=O)N1
Temperature: 80 °C

Procedure:
A sealed tube containing a mixture of methyl 5-(2,6-dimethoxyphenyl)-3,3-dimethyl-5-oxopentanoate (474 mg; 1.61 mmol), ammonium acetate (1.241 g; 16.10 mmol), and NaBH3CN (106 mg; 1.61 mmol) in anh. MeOH (8 ml) was heated to 80° C. for 48 h. After cooling to rt, 2 M aq. HCl (7.5 ml) was added, and the volatiles were removed under reduced pressure. The resulting aq. layer was extracted with DCM (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded 6-(2,6-dimethoxyphenyl)-4,4-dimethylpiperidin-2-one as a yellow solid. LC-MS (conditions D): tR=0.91 min.; [M+H]+: 264.22 g/mol.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.[CH3:28][C:29]1[S:30][C:31](=[S:34])[NH:32][N:33]=1.Cl>O.C(=O)(O)[O-].[Na+]>[C:25]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:34][C:31]1[S:30][C:29]([CH3:28])=[N:33][N:32]=1)[CH:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]1[S:18][C:19](=[O:22])[S:20][CH:21]=1)[C:9]2=[O:24])([OH:27])=[O:26]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: Cc1n[nH]c(=S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
3-Acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (8.8 g.) is dissolved in distilled water (100 cc.) and sodium bicarbonate (1.72 g.). A solution of 2-methyl-5-thioxo-1,3,4-thiadiazoline (2.7 g.) in distilled water (100 cc.) and sodium bicarbonate (1.72 g.) is added and the resulting solution is heated to 60° C. for 6 hours. After cooling, it is acidified to pH= 5.5 by adding 4 N hydrochloric acid and the extracted twice with ethyl acetate (100 cc.). The organic extracts are discarded. The acidification is continued in the presence of ethyl acetate (200 cc.) until the pH is 2. After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.). The organic extracts are washed twice with water (200 cc.), dried over magnesium sulphate, treated with decolourising charcoal and then filtered and concentrated under reduced pressure (20 mm.Hg) to a final volume of 25 cc. The solid compound formed is removed by filtration and washed twice with isopropyl ether (25 cc.). After drying under reduced pressure (0.5 mm.Hg), 2-carboxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.5 g.) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:16]=[C:15]([CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[NH2:17]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 4-(2-(2-fluoro-4-nitrophenoxy)ethyl)morpholine (1.3 g, 4.81 mmol) and Pd/C (0.4 g, 10%) in THF (12 mL) under H2 was stirred at rt overnight. The mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound as yellow oil (1.00 g, 86%), the crude product was used for next step without further purification.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.Cl.N([O-])=O.[Na+].[I:32]I>CC(C)=O.O.CCOC(C)=O>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([I:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reaction time: 0.5 h

Procedure:
Compound 494 (0.62 g, 1.66 mmol) was dissolved in acetone (14 mL). Concentrated HCl (37%, 0.69 mL, 8.3 mmol) was added and the solution was cooled on an ice bath. NaNO2 (0.14 g, 1.99 mmol) was dissolved in H2O (1 mL) and added to the above solution during 15 minutes. The internal temperature was kept at 0° C.-2° C. during the addition. The suspension was stirred on an ice bath for 0.5 h, after which a solution of KI (0.41 g, 2.45 mmol) and I2 (0.31 g, 1.22 mmol) in H2O (4 mL) was added drop wise during 5 minutes. The mixture was stirred at 0° C. for 2 h. H2O (20 mL) and EtOAc (20 mL) was added and stirred and the phases were separated. The organic phase was washed with aqueous NaHSO3, then with aqueous Na2CO3, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:5 to afford the title compound as a slightly coloured crystalline compound.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]([CH:4]=[CH:3][C:2](=[O:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)O)o1
Product: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OC)o1
Temperature: 0 °C
Yield: 79 %

Procedure:
II (2.52 g, 0.00755 mole), methanol (30 ml), and ethyl ether-borontrifluoride complex (0.24 g) were stirred and heated under reflux for 1 hour. After cooling, the reaction mixture was poured into ice-water (150 ml) and extracted with two 80-ml portions of ether. The combined ethereal extracts were washed with cold 10% sodium carbonate (50 ml) and then with two 50-ml portions of cold water. The ethereal solution was dried over magnesium sulfate and evaporated to dryness from a water bath (60°C), at last under 15 mm Hg. Distillation under nitrogen of the residual oil (2.46 g) gave 2.07 g (79%) of III, b0.3 202°-204°C, nD25 1.5262.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]P(=O)(OC)OC.O.[OH-].[Li+].[C:18]([O:21][C@@H:22]1[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:25]([CH:37]=O)[C@H:24]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:23]1)(=[O:20])[CH3:19]>COC(C)(C)C.O>[C:18]([O:21][C@@H:22]1[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:25](/[CH:37]=[CH:3]/[C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@H:24]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:23]1)(=[O:20])[CH3:19]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCC(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.178 g, 0.801 mmol) in t-butyl methyl ether (2 ml), lithium hydroxide monohydrate (32.5 mg, 0.775 mmol) was added and the mixture was stirred for two hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.213 g, 0.535 mmol) in t-butyl methyl ether (2 ml) and water (0.12 ml) were added thereto, and the mixed solution was stirred for one hour at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane=3:7), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (13) (0.255 g; 0.516 mmol; yield: 96.4%) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 3 neck 3 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (130 g, 870 mmol, obtained by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-octadecanol (351.2 g, 1.30 mol), sodium hydrogen sulfate (2.10 g, 17 mmol), and toluene (1000 mL). The reaction was heated to reflux with removal of water (21.5 mL) during the course of about 4 hours. The reaction was cooled to room temperature overnight and the mixture was filtered. The filtrate was washed with saturated NaHCO3 (1×500 mL), DI water (1×500 mL) and brine (1×500 mL), dried over sodium sulfate, filtered and evaporated to give light brown semi-solid (319.4 g). The semi-solid was treated with hexanes (750 mL) and the resulting mixture was filtered. The solid was washed with hexanes (250 mL) and the combined filtrate was evaporated to give an oil which solidified upon standing (278.8 g). The solid was purified by kugelrohr at 175° C. and 0.1 mm Hg vacuum to give a waxy solid remaining in the distillation pot (214.0 g, 61%). m/z 425 (MNa+).