Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)ccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.4 %

Procedure:
To a solution of of 4-bromo-3-methylbenzonitrile (1.0 g, 5.0 mmol) in carbon tetrachloride (7.5 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) followed by of benzoylperoxide (50 mg 0.2 mmol) and the mixture was refluxed. After 10 hours, the reaction was cooled to rt, filtered, and the filtrate was washed with 10% NaHSO3 (5 mL) followed by water (5 mL). The organic layer was dried (Na2SO4), filtered, volatiles removed, and the residue was purified by flash chromatography on silica gel. Elution with 10% Ethyl acetate in hexanes gave the title compound (0.5 g, 36%) as a white solid. 1H NMR (270 MHz, CDCl3) δ4.55 (s, 2 H), 7.38-7.42 (m, 1 H), 7.65-7.77 (m, 2H).
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[OH:6][CH2:7][CH2:8][O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1>CO>[OH:6][CH2:7][CH2:8][O:9][C:10]1[N:11]=[N:12][C:13]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:14][CH:15]=1
Reactant: OCCOc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCO)nn1

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 1.00 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.75 g(0.01 mol) of 3-(2-hydroxyethoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:11][N:10]=1.OO.[OH-].[Na+].C(OCC)(=[O:33])C.C(OCC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N+:11]([O-:33])[N:10]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[n+]([O-])c(-n3cncn3)c2c1
Reaction time: 48 h
Yield: 41 %

Procedure:
Under N2 at 0° C. a solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-4-[1,2,4]triazol-1-yl-phthalazine (5.1 g, 13.2 mmoles), prepared as described in example 51, in trifluoroacetic acid (25 ml), was dropwise added with H2O2 (1.35 ml, 13.5 mmoles). The temperature was left to rise to the room value and, after 48 hours, the pH was adjusted with NaOH. After further 24 hours under stirring, the mixture was dried, taken up in CH2Cl2. The organic phase was washed with water, anhydrified and dried to give a foam which was flash chromatographed (eluent: ethyl acetate/ethyl ether 6:4, then 8:2) to give 2.2 g of the title compound (yield: 41%). m.p.: 218-220° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17]>>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)[CH2:14][CH2:15][CH2:16][Cl:17]
Reactant: ClCCCBr
Reactant: COC(=O)Cc1ccc(Br)cn1
Product: COC(=O)C(CCCCl)c1ccc(Br)cn1

Procedure:
Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[OH:14][CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a stirred solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1.21 g, 5.6 mmol) in THF (30 mL) at 0° C. was added borane THF (1.0 M, 17 mL, 16.9 mmol) dropwise. The resulting mixture was warmed to rt over 30 min and then heated at 45° C. for 1 h, then at 55° C. for 90 min. The reaction mixture was then cooled to 0° C. and quenched carefully with 3N HCl (30 mL). The resulting mixture was stirred at rt for 20 min before it was extracted with Et2O (50 mL). The organic layer was washed with sat. NaHCO3 (20 mL) brine (20 mL), dried over NaSO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.1 g, 91%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([C:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.Cl.[C:23]([O-:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([O-:28])=[O:27].C(O)(=O)/C=C/C(O)=O>O1CCOCC1.CCOCC>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][NH:2][C:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12]1
Reactant: CN(C(=O)OC(C)(C)C)C1(CCOc2cccnc2)CC1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC1(CCOc2cccnc2)CC1

Procedure:
A solution of 1.2 g of the product obtained in Step 1 dissolved in 5 ml of dioxane and 4 ml of 4N hydrochloric acid in dioxan is stirred for 20 hours at ambient temperature and then 10 ml of ether are added. The precipitate formed is separated off, taken up in 15 ml of water and made alkaline by the addition of potassium carbonate. The aqueous phase is then extracted with dichloromethane. The organic phases are subjected to customary treatment which, after concentration under reduced pressure, allows the expected product to be obtained, which is converted into its fumarate form by treatment with an ethanolic solution of fumaric acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([C:21]2[O:25][N:24]=[C:23]([CH2:26]Cl)[N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:26][C:23]1[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:29])([F:13])[F:28])[CH:16]=3)[O:25][N:24]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1

Procedure:
Synthesized as described in Example 4 using 5-nitro-1H-indazole and 5-[3(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole to afford a mixture of regioisomers. The following data are for the title regioisomer: 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=1.7 Hz, 1H), 8.34 (m, 2H), 8.27 (m, 2H), 7.84 (d, J=7.8 Hz, 1H), 7.65 (m, 2H), 5.83 (s, 2H); MS (ES) m/z 389 (M+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][NH:38][CH2:39]2>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:37][CH:36]5[N:35]([CH3:34])[CH:40]([CH2:41][CH2:42]5)[CH2:39]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN1C2CCC1CNC2
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1C2CCC1CN(C1=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S1)C2

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:38]1[CH:42]=[CH:41][CH2:40][CH2:39]1>O1CCOCC1>[Si:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][CH:39]1[CH2:40][CH2:41][CH2:42][O:38]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)CO[Si](C)(C)C(C)(C)C
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)OC1CCCO1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
In dioxane was dissolved 3.45 g (11 mmol) of 1,3-O-di-(t-butyldimethylsilyl)glycerol followed by addition of 3.03 g (12 mmol) of pyridinium p-toluenesulfonate. To this suspension was added 16.5 ml (22 mmol) of dihydrofuran gradually under ice-cooling and the mixture was stirred for 1 hour. After return to ambient temperature, the mixture was allowed to react overnight. After completion of the reaction, the solvent was distilled off and the residue was treated with methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The methylene chloride layer was washed with water, dried, and concentrated to provide 4.25 g (100%) of 1,3-O-di-(t-butyldimethylsilyl)-2-O-tetrahydrofuranylglycerol.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)([OH:35])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=3)[OH:21])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[CH3:42][C:39]1[CH:38]=[CH:37][C:36]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)([OH:35])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:24][CH:23]=3)[OH:21])[CH2:13][CH2:12]2)=[CH:41][CH:40]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccc(C)cc3)c3ccc(C)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCN(CCCC(O)c3ccc(C(C)(C)C(=O)O)cc3)CC2)cc1

Procedure:
To 350 mL of methanol in a 1 L round bottom flask equipped with a mechanical stirrer is added 5.3 g (9.8 mmol) of methyl 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate, prepared in accordance with Example 10, 5.1 g (0.13 mol) of solid sodium hydroxide, and 100 mL of water. The mixture is heated to reflux for 3 hr. After cooling, the methanol is removed in vacuo, and 6 N hydrochloric acid is added dropwise until the solution was no longer basic (pH=7). The solution is extracted three times with ethyl acetate. The organic layers are combined, and precipitation is induced. The solid is washed with ether to provide 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid, as the dihydrate.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\CCCC(O)=O)[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C.C([N:36](CC)CC)C>>[OH:23][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH2:36])=[O:24]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Product: NC(=O)c1ccccc1O

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2 α , 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.299 g. of o-hydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone-water (25:75:1). The residue obtained by concentration of selected fractions, 0.296 g., is crystallized from ethyl acetate diluted with 1.5 volumes of hexane as the title compound, white free-flowing crystals, m.p., 98.5°-100.1° C. having Rf 0.55 (TLC on silica gel in ethyl acetate-acetone (1:3)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:5]2[C:4]=1O)#[N:2].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[C:5]2[N:6]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=2)[N:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Temperature: 75 °C
Yield: 48 %

Procedure:
To a round bottom flask was added POCl3 (200 mL) and ethyl 3-cyano-4-hydroxypyrrolo[1,2-b]pyridazine-6-carboxylate (20 g, 80 mmol). The reaction was heated under nitrogen at 75° C. for 2 hours. The reaction was cooled to room temperature and POCl3 was removed under vacuum. The residue was poured onto ice-water. The aqueous solution was extracted with CH2Cl2. The organic layer was washed with saturated sodium carbonate solution, dried and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 10 g (48%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm: 8.33 (1H, d, J=1.3 Hz), 8.11 (1H, s), 7.41 (1H, d, J=1.6 Hz), 4.41 (2H, q, J=6.8 Hz), 1.41 (3H, t, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([CH3:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles), 4methylphthalic anhydride (1.76 gm, 10.8 mmoles) and dicyclohexylcarbodiimide (2 gm, 1,0 mmoles) in dichloromethane (DCM 100 ml) was stirred at room temperature for 2 hr. The insolubles were filtered off. The DCM solution was concentrated to a crude solid. This was purified on at flash chromatography column (35 gm, SiO3, Sorbsil-C-30; eluted with 1% CH3OH in 99% DCM). The material thus purified weighed 1.0 gm (26%) as a white solid. Recrystallization from hot ethanol gave 665 mg of crystals, m.p.=138°-140°]C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:51])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([O:36]C2CCCCO2)[C:27]([CH2:34]C)([CH2:32]C)[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([O:43]C2CCCCO2)[CH2:21][C@@H:20]1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:51])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:36])[C:27]([CH3:34])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([OH:43])[CH2:21][C@H:20]1[F:7]
Reactant: CCCCC(CC)(CC)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](F)C[C@H]1O
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
0.56 ml of diethylaminosulfur trifluoride (DAST) is instilled in a solution of 2.05 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-diethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 43 ml of methylene chloride and 1.1 ml of pyridine at -70° C. and stirred for 3.5 hours at -70° C. Then it is added to 200 ml of 5% sodium bicarbonate solution cooled to 0° C. and allowed to stir vigorously for 10 minutes. Then it is extracted several times with methylene chloride, the extract is washed with water, dried over MgSO4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 20° C. with 60 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10), concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. 306 mg of the title compound is obtained as oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][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][CH3:27])[CH2:4][NH2:5].[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(N(CC)CC)C>[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][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][CH3:27])(=[O:35])=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 74082.7 %

Procedure:
To a solution of 1.018 g (2.95 mM) of 3-hexadecylthio-2-methoxypropylamine IV a2 in 15 ml of dichloromethane and 0.534 ml (3.83 mM) of triethylamine is added 0.563 mg (3.24 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at 0° C. for 3 hours. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 1.275 g (2.62 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane III a2 as a colorless powder in 89% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([N:21]([CH3:32])[C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c(N(C)C(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.51 mmol) synthesized in Example 1 in DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid paraffin, 24 mg, 0.6 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (78 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The extracts were washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 25 mg (yield: 12%) of the desired product having low polarity, of two rotational isomers of the title compound. Melting point: 122-123° C. (petroleum ether).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][C@H:6]1[CH2:30][OH:31])(=[O:4])=[O:3].Br[CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH3:1][S:2]([N:5]1[C@H:6]([CH2:30][O:31][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][C@@H:8]([SH:10])[CH2:9]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: BrCC=Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1COCCCc1ccccc1

Procedure:
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol with 3-bromo-1-phenyl-1-propene, followed by hydrogenation (17 h) and TFA/triethylsilane deprotection (Method 3) gave (3R,5S)-1-methanesulfonyl-5-(3-phenyl-propoxymethyl)-pyrrolidine-3-thiol, MS: 329 (M).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].[Li+].[CH3:18][CH:19]([N-]C(C)C)[CH3:20].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:20][CH:19]=[CH2:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 2 (see Example 1, Step 1) (4.58 g, 20 mmol) was dissolved in THF (100 mL) and cooled down to −78° C. in a dry ice-acetone bath. LDA (12 mL, 2.0 M, 24 mmol) was then added dropwise. The mixture was stirred at −78° C. for 1 hr. Allyl bromide (5.3 mL, 61 mmol) was added in neat. The reaction was allowed to warm to rt naturally and stirred for 24 hrs. It was then quenched with sat. NH4Cl solution, extracted with ethyl acetate 2×150 mL. The organic layer was washed with brine, dried (MgSO4) and concentrated. The crude was purified on silica gel column using 4:1 hexanes/ethyl acetate to get the title compound (3.6 g) as a yellow oil. MS (292, MNa).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:33]=[CH:32][C:27](C(OC)=O)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].BrC1C=CC([C:44](OC)=[O:45])=CC=1>>[CH3:44][O:45][C:25]1[CH:26]=[CH:27][CH:32]=[CH:33][C:24]=1[N:21]1[CH2:20][CH2:19][CH:18]([N:15]2[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:37])([F:38])[F:1])[CH:4]=3)[CH2:14]2)[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Product: COc1ccccc1N1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was synthesized in similar fashion to methyl 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoate, substituting bromo-2-methoxybenzene for methyl 4-bromobenzoate, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.50-2.20 (m, 5H), 2.25-2.40 (m, 1H), 2.50-2.70 (m, 3H), 2.82 (dd, J=11.1, 6.9 Hz, 1H), 3.13-3.20 (m, 1H), 3.30-3.40 (m, 1H), 3.49-3.51 (m, 2H), 3.84 (s, 3H), 4.00-4.21 (m, 2H), 4.60-4.71 (m, 1H), 6.81-6.90 (m, 2H), 6.93-7.02 (m, 1H), 7.10-7.28 (m, 4H), 7.56 (t, J=8.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.25 (s, 1H). MS m/z: 505 (M+1).