Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CCC(O)C.CCOC(C)=O.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]>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:5]3=[N:6][CH:7]=[C:2]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)[N:3]=[C:4]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCC(C)O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cccnc3)cnc2s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A mixture of 24 (30 mg, 0.061 mmol), pyridine-3-boronic acid (11.2 mg, 0.092 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.8 mg, 3.06 μmol), potassium phosphate, tribasic (26 mg, 0.122 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2.92 mg, 6.12 μmol) in butanol-2-ol was stirred at 100° C. for 30 min. Diluted with EtOAc and washed with water, brine, dried and evaporated. Triturating with acetonitrile gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(pyridin-3-yl)thieno[2,3-b]pyrazine-6-carboxamide 25h (9 mg, 27.6%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.29 (s, 3H), 7.33 (d, J=8.2 Hz, 1H), 7.58-7.69 (m, 3H), 7.76 (d, J=7.8 Hz, 1H), 7.90 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.62 (m, 2H), 8.76 (d, J=4.7 Hz, 1H), 9.45 (m, 2H), 10.38 (s, 1H), 10.55 (s, 1H). (m/z)=533 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][OH:12].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][OH:12]
Reactant: OCCCl
Reactant: Oc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCOc1cccc(Cl)c1
Yield: 49.5 %

Procedure:
A mixture of 51.4 g (0.4 mole) of 3-chlorophenol (Aldrich Chem. Co.), 34.7 g (0.43 mole) of 2-chloroethanol (Aldrich) and 16.1 g (0.4 mole) of sodium hydroxide pellets in 500 ml of 95% ethanol was stirred and heated at reflux for 16 hr. The mixture was filtered and the filtrate was evaporated under reduced pressure to yield a semisolid residue. The residue was partitioned between methylene chloride and a 15% sodium hydroxide solution (300 ml of each). The organic layer was washed with two 300 ml portions of water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 34.2 g (50%) of the title compound as a viscous oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
A solution of 3-iodo-1H-indole-5-carboxylic acid (3.70 g, 12.89 mmol) in DMF (9.5 mL) at 0° C. was treated with NaH (60% in mineral oil) (1.289 g, 32.2 mmol). After 15 min at 0° C., p-toluenesulfonyl chloride (2.95 g, 15.47 mmol) was added in 1 g portions at 0° C. every 15 min and the reaction was warmed slowly in the ice bath to 10° C. After 2 h, the mixture was dumped into H2O and the mixture was acidified with 5 M HCl. The precipitate was collected by filtration, washed with water and dried to afford crude 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (5.72 g) as a tan solid. MS (ESI, pos. ion) m/z: 442 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, s), 8.03-8.09 (1H, m), 7.93-8.02 (3H, m), 7.91 (1H, s), 7.42 (2H, d, J=8.0 Hz), 2.33 (3H, s)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.C([Li])(CC)C.[C:21](=[O:23])=[O:22]>C(OCC)C>[CH2:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:21]([OH:23])=[O:22])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C=O
Reactant: CCCCc1nccc2ccc(Br)cc12
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCCCc1nccc2ccc(C(=O)O)cc12
Temperature: 25 °C

Procedure:
To a −60° C. solution of 7-bromo-1-butylisoquinoline prepared in step 1 (940 mg, 3.55 mmol) in diethyl ether (15 mL) was added sec-butyl lithium (3.0 nL, 1.3 M cyclohexanes, 3.90 mmol) to yield a dark green solution. The reaction mixture was stirred at −60° C. for an additional 15 minutes at which time carbon dioxide gas was bubbled through the solution for 20 minutes with the aid of a gas dispersion tube. The resulting solution was then allowed to warm to room temperature and concentrated under reduced pressure to yield a pink solid. The residue was partitioned between ethyl acetate and water and then acidified to pH 7 with 1 N hydrochloric acid. The aqueous phase was extracted again with ethyl acetate and the combined organic phases were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield 1-butylisoquinoline-7-carboxylic acid (299 mg). ESI MS m/z 230 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1.CO>C(#N)C.C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]2[N:31]([CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(CCN2CCOCC2)c2nc(Br)cnc2N1
Temperature: 45 °C
Yield: 56.4 %

Procedure:
N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (0.5 g, 1.188 mmol), diisopropylethylamine (0.415 mL, 2.376 mmol) and 2-morpholinoethanamine (0.162 g, 1.248 mmol) were combined in acetonitrile (5 mL). The solution was heated to 45° C. for 1 h. Solution was condensed and diluted with 75% ethyl acetate in hexanes. The resulting solid was filtered and the filtrate collected and condensed followed by purification via Biotage chromatography (0-75% ethyl acetate in hexanes then 0-10% methanol in ethyl acetate) to afford the title compound (0.228 g, 0.67 mmol, 56% yield). MS (ESI) m/z 342.4 [M]+, 344.4 [M+2]+.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:10]([CH2:11][O:12]S(C)(=O)=O)[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=O)=O.[OH-].[Na+].Cl>O>[C@@H:8]1([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[O:9][C@@H:10]2[CH2:11][O:12][C@H:6]2[CH2:7]1
Reactant: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cn([C@H]2C[C@@H]3OC[C@H]3O2)c(=O)[nH]c1=O
Temperature: 50 °C
Yield: 75.2 %

Procedure:
A two liter, four-necked flask was equipped with an overhead stirrer and paddle, a pH probe connected to an automatic titrator, and a thermocouple probe connected to a temperature controller and a heating mantle. Water (350 mL) was added to the flask and about a 20-25% portion of 3',5'-di-O-methanesulfonylthymidine (500 g total, 1.255 moles) was added with stirring. The pH was adjusted to 10.5 with 30% aq. sodium hydroxide and the temperature was raised to 50° C. While maintaining the temperature at 50°-55° C. and the pH at 10.5-11.0, the remaining 3',5'-di-O-methanesulfonylthymidine was added slowly as material dissolved, maintaining a stirrable slurry. A total of 502 g (3.765 moles) of 30% aq. NaOH is added. The reaction mixture is then heated at 70° C. for one hour, then cooled to 10°-15° C. The pH was adjusted to 9.7-9.8 with 12N HCl using cooling to maintain the temperature at 10°-15° C. while crystallization occurred. Finally, the slurry was adjusted to pH 6.0-6.5 with 12N HCI and cooled to 0°-5° C. and filtered. The collected solids were washed with cold (0°-5° C.) water (200 mL) and air dried to give 211.6 g (75.2%) of the title compound, which assays 99.8% (by weight) purity.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=O)[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]1)[CH3:2].O.CCOC(C)=O.CCCCCC>C(#N)C>[CH2:1]([C@H:3]1[CH2:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC[C@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: CC#N
Solvent: O
Solvent: CCCCCC
Product: CC[C@H]1Cc2ccccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of enone 55 (0.35 g, 1.17 mmol) in acetonitrile (10 mL) was added a CuBr2 (0.31 g, 1.4 mmol) and stirred overnight at room temperature. Water was added until disappearance of the green color, and the acetonitrile was removed under reduced pressure. The residue was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and the combined organic layers were washed with water; brine, dried over anhydrous MgSO4, filtered, and concentrated to afford a gum. Chromatography (20% EtOAc/hexane) yielded estrone 56 as a yellow solid (0.28 g, 80%): The major 7α-ethyl isomer of 56: 1H NMR (300 MHz, CDCl3) δ0.91 (s, 3, CH3), 0.95 (t, J=7.3 Hz, 3, CH2CH3), 6.59 (d, J=2.5 Hz, 1, ArH), 6.65 (dd, J=2.5, 8.4 Hz, 1, ArH), 7.13(d, J=8.4 Hz, 1, ArH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:35]6[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
(11β,16α,17β)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (10 g, 20.3 mmol), 3-pyridinylboronic acid (3.7 g, 30.4 mmol), potassium phosphate (5.2 g, 24.3 mmol), bis(triphenylphosphine)palladium(II) chloride (442 mg, 0.61 mmol) and triphenylarsine (426 mg, 1.4 mmol) were dissolved in a mixture of dioxane (240 mL) and water (30 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours at 100° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to dryness. Purification by column chromatography (SiO2, heptane/ethyl acetate, gradient 2/1 to 1/2) gave crude product (8.3 g, 16.9 mmol) which was crystallized from acetonitrile/water to give (11β,16α,17β)-17-cyclopropylcarbon-yl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (5.5 g, 11.2 mmol, 55% yield), mp. 206° C. 1H NMR (400 MHz, CDCl3): δ 0.35 (s, 3H), 0.86-2.86 (m, 24H), 4.46 (d, J=8 Hz, 1H), 5.80 (s, 1H), 7.26-7.29 (m, 2H), 7.35 (dd, J=10 and 6 Hz, 1H), 7.49-7.53 (m, 2H), 7.86 (dt, J=10 and 4 Hz, 1H), 8.57 (dd, J=6 and 4 Hz, 1H), 8.84 (d, J=4 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>O1CCCC1>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]([CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([CH2:25][CH2:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]1)[C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=C(N(C[C@H]1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-((S)-pyrrolidin-3-ylmethyl)acetamide (140 mg, 0.448 mmol) in tetrahydrofuran (3 mL) were added tert-butyl acrylate (0.085 mL, 0.583 mmol) and triethylamine (0.094 mL, 0.672 mmol), and the mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 110 mg of product as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH2:18][CH3:19])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(CC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.4 g, 6.8 mmol) and allowed to stir for 10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.28 g, 2.04 mmol) was added and stirred for further at 100 deg C. for 18 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.025 g, 10% yield). 8-Chloro-5-[2-(6-ethyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.07 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.07 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 32% yield).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:10]=1)C1C=CC=CC=1.Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:26][S:23]([C:11]1[C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([OH:8])[CH:10]=1)(=[O:25])=[O:24]
Reactant: COc1cc(-c2noc(C)n2)c(S(C)(=O)=O)cc1OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(S(C)(=O)=O)cc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-(4-benzyloxy-2-methanesulfonyl-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole and methylene chloride (20 mL) was added titanium(IV) chloride (0.472 g). After stirring at room temperature for 15 minutes, 2 mol/L hydrochloric acid and methylene chloride were added to the mixture. The separated organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10%-100% ethylacetate/hexane, gradient elution) to give the title compound (112 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[C:18]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[S:10][CH:11]=1)(=[O:20])[CH3:19]
Reactant: OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (21 mL) of the compound (5.4 g, 21 mmol) obtained in Example 64b in tetrahydrofuran were added acetyl chloride (2.0 g, 25 mmol) and triethylamine (3.8 mL, 27 mmol), and the mixture was stirred at room temperature for 30 min. The resulting salt was removed and the solvent was evaporated under reduced pressure to give a crude title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:30](OC)([O:33]C)[O:31]C>C(OCC)C>[CH:14]1([CH2:13][C:4]2[C:5]3[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=3[CH:12]=[C:2]([B:30]([OH:33])[OH:31])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C)COc2c(CC3CCCCC3)cc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC1(C)COc2c(CC3CCCCC3)cc(B(O)O)cc21

Procedure:
Following General Procedure A and using 5-bromo-7-cyclohexylmethyl-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 46, 0.58 g, 1.79 mmol),15 mL of anhydrous diethyl ether, 1.7M solution of t-butyllithium in n-pentane (2.21 mL, 3.77 mmol) and trimethyl borate (0.42 mL, 3.77 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][NH:15][C:14]1=[O:22])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])[C:14]1=[O:22])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC1CNC(=O)C1CN(C=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1CN(C(=O)c2ccccc2)C(=O)C1CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a solution of (+/−)-(3RS,4SR)-N-benzyloxy-N-(4-butyl-2-oxopyrrolidin-3-yl-methyl)formamide (0.18 g, 0.59 mmol) in dry THF (3 mL) at −78° C. under argon was added dropwise lithium bis(trimethylsilyl)amide in THF (1 M, 0.71 mL). After 20 min, benzoyl chloride (0.077 mL, 0.89 mmol) was added dropwise and stirring continued for 2 h. The reaction was warmed up to 0° C., quenched with saturated aq. NH4Cl (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic solution was dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:1) to afford (+/−)-(3RS,4SR)-N-benzyloxy-N-[4-butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-methyl)formamide as a white solid (0.12 g, 50%). MS(ES) m/e 409 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:5]([CH3:9])[C:6]([OH:8])=O.[C:19]([O-])(=[O:21])[CH3:20].[Na+]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:9])=[C:6]([O:8][C:19](=[O:21])[CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=1)=[O:18]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of crude 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (approximately 49 g, 0.196 mol) in acetic anhydride (490 mL) was added sodium acetate (32.15 g, 0.392 mol) in one portion. The reaction mixture was stirred at 150° C. for 3 hours. After this time, the reaction mixture was cooled to room temperature, then stirred overnight. Acetic anhydride was removed in vacuo, providing a viscous brown oil. This crude product was dissolved in ethyl acetate. The resulting solution was washed with a saturated, aqueous ammonium chloride solution. The organic phase was dried over Na2SO4, filtered, and concentrated. Flash chromatography (Analogix SuperFlash™ 10% ethyl acetate in hexane) gave 18.4 g (34%) of 4-acetoxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]([O:20][CH:21]1[CH2:24][N:23](C(=O)C)[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[OH-].[Na+].C(OCC)(=O)C.[ClH:36]>CO.C(OCC)(=O)C>[ClH:36].[C:1]([O:20][CH:21]1[CH2:22][NH:23][CH2:24]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(C(OC2CNC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In 88 mL of methanol was suspended 22.0 g of 1-[3-(trityloxy)-1-azetidinyl]-1-ethanone, followed by adding thereto 66 mL of a 5 mol/L aqueous sodium hydroxide solution, and the resulting mixture was refluxed for 9 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and 110 mL of water and 220 mL of ethyl acetate were added to the residue, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The oil thus obtained was dissolved in 154 mL of ethyl acetate, and to the resulting solution was added 25 mL of a 2.95 mol/L dried hydrogen chloride-ethyl acetate solution, after which the resulting mixture was stirred at room temperature. The crystals precipitated were collected by filtration to obtain 13.7 g of 3-(trityloxy)azetidine hydrochloride as colorless crystals.