Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)[OH:38].[NH4+].[Cl-]>C1COCC1.C(N(CC)CC)C>[OH:38][C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=1)=[O:24]
Reactant: OC(c1ccc2ccccc2c1)(c1ccc2ccccc2c1)[C@@H]1CCCN1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)N2CCC[C@H]2C(O)(c2ccc3ccccc3c2)c2ccc3ccccc3c2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of mesyl chloride (0.1 ml) in 1 ml of dry THF is added dropwise under argon over a period of 15 minutes to a cooled (−20° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (0.38 g) and triethylamine (0.52 ml) in 10 ml of dry THF. The obtained reaction mixture is stirred for 60 min at −20° C. then treated with a solution of (S)-dinaphthalen-2-ylpyrrolidin-2-ylmethanol (0.46 g) in 5 ml of dry THF and further stirred at −20° C. for 2 h. The reaction mixture is then allowed to warm to room temperature, and stirring is continued overnight. The reaction mixture is then poured into 40 ml of saturated NH4Cl solution and extracted with 4×40 ml of diethyl ether and 20 ml of dichloromethane. The combined organic extracts are washed with saturated NaCl solution (2×80 ml), dried over MgSO4, filtered and evaporated to give a brownish residue. This was purified by chromatography over a short silica column (CH2Cl2 / Et2O : 19 / 1 ) to give acrylic acid (S)-6-[4-[2-(hydroxydinaphthalen-2-ylmethyl)pyrrolidine-1-carbonyl]phenoxy]hexyl ester as a white crystalline material. Yield 0.51 g.
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([OH:12])=O)=[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[NH:2][N:1]=[C:5]4[CH2:6][CH2:7][O:8][CH2:9][C:4]=34)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1[nH]nc2c1COCC2
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1COCC2
Yield: 32.5 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid (0.078 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by recrystallization from acetonitrile. Yield 32.5%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 2.79 (t, 2H), 3.89-3.94 (m, 2H), 4.27 (dd, 1H), 4.39 (dd, 1H), 4.48-4.58 (m, 1H), 4.84-4.94 (m, 2H), 6.61 (d, 1H), 7.52 (d, 1H), 7.65 (dd, 1H), 7.69 (d, 1H), 7.80-7.82 (m, 1H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].IC.[Cl-].[NH4+]>C1COCC1.O>[Cl:21][C:22]1[C:29]([CH3:1])=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C#N)c1Cl
Temperature: -5 °C
Yield: 73.8 %

Procedure:
To a solution of diisopropylamine (474 mL, 3.35 mol) in anhydrous THF (5.8 L) at −5° C. under a nitrogen atmosphere is added dropwise 2.5 M n-butyllithium in hexanes (1.24 L, 3.10 mol) over 3 h and the resulting mixture is stirred at −5° C. for one additional hour. The LDA solution is added dropwise to a solution of 2-chloro-4-fluoro-benzonitrile (400 g, 2.58 mol) in anhydrous THF (5.8 L) at −70° C. over 6 h and then stirred at −70° C. overnight. Iodomethane (643 mL, 10.32 mol) is added dropwise over 2.5 h and the temperature is raised to −5° C. for 17 h. Saturated aqueous ammonium chloride (3 L) is added. The solution is diluted with water (3.5 L) and extracted with diethyl ether (2×2 L). The organic phases are separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a black solid. The solid is purified through a silica gel pad eluting with EtOAc/hexanes (1/40) to obtain the title compound (323 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.08 (dd, J=8.6, 8.6 Hz, 1H), 7.54 (dd, J=8.6, 5.6 Hz, 1H), 2.36 (d, J=2.4 Hz, 3H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:19])[CH2:13][O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:10].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:44])[C:28]=1[O:29][CH2:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])[CH:24]=[O:25]>C1COCC1>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:24]([C:23]1[CH:22]=[C:21]([CH3:20])[C:28]([O:29][CH2:30][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[O:35][C:36]=2[CH3:37])=[C:27]([CH3:44])[CH:26]=1)[OH:25])[CH3:10]
Reactant: C=CCCOCC(=O)OCC
Reactant: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCOC(C(=O)OCC)C(O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
To a stirred 2 M solution of LDA in THF (0.38 ml, 0.76 mmol) was added a cooled (−78° C.) solution of but-3-enyloxy-acetic acid ethyl ester (120 mg, 0.76 mmol) in THF (3 ml) at −78° C. (for the preparation of but-3-enyloxy-acetic acid ethyl ester see: A. F. Noels, A. Demonceau, N. Petiniot, A. J. Hubert, P. Teyssié, Tetrahedron 1982, 38, 2733-2739). The solution was stirred for 10 min and then a solution of 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (254 mg, 0.76 mmol, example 117) in THF (3 ml) was added. The reaction mixture was stirred 30 min at −78° C. and then quenched by the addition of sat. NH4Cl at −78° C. The solution was diluted with water and ethyl acetate, the layers were separated and the aqueous phase was extracted two times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil which was purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 160 mg (0.32 mmol, 43%) of the title compound as a mixture of diastereomers as colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>CN(C=O)C.O1CCCC1>[CH3:27][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1)(=[O:24])=[O:25]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)n2nc(C(=O)O)c3ccccc32)c(C)c1
Temperature: 0 °C

Procedure:
NaH (60% in oil, 40 mmol) is washed under argon with petroleum ether and then suspended in 60 ml of anhydrous DMF. An indazole-3-carboxylic acid solution (3.35 g, 20 mmol) in anhydrous DMF (50 ml) is added dropwise to this suspension kept at 0° C. The reaction mixture becomes clear. When the addition is complete, the medium is allowed to react for 30 min at room temperature and then the reaction mixture is again cooled to 0° C. Mesitylenesulphonyl chloride (4.82 g, 22 mmol) in solution in anhydrous tetrahydrofuran (THF) (50 ml) is added. The ice bath is removed and a suspension appears. The medium is allowed to react for 30 min at room temperature. The solvents are evaporated under vacuum and the residue is taken up in 0.1N NaOH solution. The solution obtained is washed with diethyl ether and then acidified with 6N HCl. The compound which separates is filtered, and taken up in AcOEt. The AcOEt solution is dried over Na2SO4 and then evaporated. The residue (6.18 g) is recrystallized from AcOEt/petroleum ether.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([SH:14])[CH2:12][CH3:13].Cl[C:16]1[N:30]=[C:29]([Cl:31])[C:28]([F:32])=[CH:27][C:17]=1[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19]>C1COCC1.CN(C=O)C>[Cl:31][C:29]1[C:28]([F:32])=[CH:27][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[C:16]([S:14][CH2:11][CH2:12][CH3:13])[N:30]=1
Reactant: O=C(NC1CCCCC1)c1cc(F)c(Cl)nc1Cl
Reactant: CCCS
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide (8.24 mL, 8.24 mmol) in THF (1M) was added to a stirred solution of 1-propanethiol (0.622 mL, 6.87 mmol) in DMF (30 mL) at 5° C., over a period of 3 minutes under air. The resulting suspension was stirred at 20° C. for 15 minutes. 2,6-dichloro-N-cyclohexyl-5-fluoronicotinamide (2.0 g, 6.87 mmol) in DMF (10 mL) was added at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].O1CCCC1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC1=CC2=C(CC1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Yield: 65.3 %

Procedure:
3-Methoxyestra-2,5(10)-dien-17β-ol 1 (2.0 g, 6.9 mmol) was added to a solution consisting of tetrahydofuran (15 ml), DMSO (5 ml) and t-BuOK (20.7 mmol). The resultant solution was stirred at ambient temperature for 10 hours at which time the solution was concentrated to Å5 ml and chromatographically filtered with 50% ethylether/petroleum ether (light) through 10 g of silica gel. The subsequent dimethyl sulfoxide (DMSO) free -powder was flash chromatographed affording 4 as white needles (1.30 g, 65% conversion, 91% based on recovered 1), Alternatively, crystallization by selective seeding (ether/methanol) was utilized, thereby circumventing chromatographic purification. 1H NMR (d6-acetone) δ4.629 (s, 1H), 3.505 (t, J=8.09 Hz, 1H), 3.431 (s, 3H), 2.15-0.98 (complex, 20H), 0.644 (s, 3H). 13C NMR (CDCl3) δ156.71, 126.56, 123.88, 96.55, 81.31, 54.19, 50.18, 46.03, 39.91, 37.54, 30.64, 30.58, 30.21, 27.71, 27.17, 25.67, 25.24, 23.22, 11.37.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH2:26]([CH2:28][NH2:29])[OH:27].COC(O)C.[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:29][CH2:28][CH2:26][OH:27])[N:3]=1
Reactant: NCCO
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Nc1nc(NCCO)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A flask charged with (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.53 g, 2.00 mmol) from Example 4, triethylamine (0.92 g, 9.10 mmol), ethanolamine (0.172 g, 2.82 mmol) and methoxyethanol (6 mL) was stirred at reflux for 2 hours. The solution was allowed to cool to room temperature before the addition of 2 mL of 1.0 N NaOH. Concentration of the solution left the crude product which was purified by elution from a silica gel column with 10% methanol chloroform (0.430 g, 74%). Crystallization of such a sample from ethanol-water gave a white powder, m.p. 150-152° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[CH:15]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3-fluorophenylboronic acid.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([C:10]([CH3:12])=O)=[CH2:9].CO.[OH-].[Na+]>C1C=CC=CC=1.O.CCCCCCCC[N+](C)(C)C.[Br-].[Cr]([O-])([O-])=O.[Cu+2]>[CH:2]1[C:3]2[C:4](=[CH:9][CH:8]=[CH:10][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: O=C1CCCCC1
Reactant: C=CC(C)=O
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: CCCCCCCC[N+](C)(C)C
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: Oc1ccc2ccccc2c1
Temperature: 80 °C
Yield: 75 %

Procedure:
Next, the 46 parts by weight of the morpholine enamine of cyclohexanone was admixed with 19 parts by weight of methyl vinyl ketone in 53 parts by weight of benzene solvent and heated at reflux (80°C) for 3 hours. After the 3 hour period, the reaction mixture was cooled and treated with the solution comprising 40 parts by weight of methanol, 25 parts by weight of water and 5 parts by weight of sodium hydroxide to yield a resulting mixture which was then heated at reflux (70°C) for 2 hours and thereafter diluted with approximately 100 parts by weight of water and separated in the 2-phases. The aqueous phase was extracted with ether to yield a phase which was combined with the organic phase and thereafter distilled to obtain a product having a boiling point of from 93°-117°F at 3 millimeters Hg. The product yield comprised 73.5% (based on octalones). A gas liquid chromatographic analysis of this product showed it to include 81.6% octalone, an 8.6 mole % decalone, and 10% other cyclic materials. The resulting mixture was then agitated with 10% of its weight of copper chromite and maintained at a temperature of 250°-350°c for 4 hours to obtain a 75% yield of pure beta-naphthol.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([N+:18]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>C1COCC1.[Pd]>[NH2:18][C:8]1[CH:7]=[C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])[CH:11]=[CH:10][C:9]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CNS(=O)(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c(N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a mixture of N-methyl-4-(4-morpholinyl)-3-nitrobenzenesulfonamide (2.5 g, 8.30 mmol) in THF (100 mL) under nitrogen, Pd/C (0.8 g) was added. The flask was then evacuated and recharged with hydrogen three times. The resulting mixture was allowed to stir under a hydrogen atmosphere at 50° C. overnight. The mixture was then filtered and concentrated to afford 3-amino-N-methyl-4-(4-morpholinyl)benzenesulfonamide (1.98 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ 7.07-7.17 (m, 2H), 7.01 (d, J=8.28 Hz, 1H), 6.94 (dd, J=1.88, 8.16 Hz, 1H), 5.20 (s, 2H), 3.72-3.81 (m, 4H), 2.80-2.89 (m, 4H), 2.38 (d, J=4.77 Hz, 3H); MS (m/z) 272.2 (M+H+)
Reaction SMILES: COC1C=CC(CNC)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([N:24]([CH:34]2CC2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:16]2[N:17]([C:19]([C:22]#[N:23])=[CH:20][N:21]=2)[N:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH3:34])[C:16]2[N:17]([C:19]([C:22]#[N:23])=[CH:20][N:21]=2)[N:18]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)c2cc(Cl)nn3c(C#N)cnc23)cc1

Procedure:
16A was prepared from 1F and 1-(4-methoxyphenyl)-N-methylmethanamine following the procedure employed in the preparation of 1G. HPLC: Rt=3.12 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=328.1 [M+H]+.
Reaction SMILES: COC.[Al+3].[Cl-].[Cl-].[Cl-].[CH:8]([C:17]([O:20]C)(F)[F:18])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10].CF>>[CH:8]([C:17]([F:18])=[O:20])([C:9]([F:11])([F:10])[F:12])[C:13]([F:16])([F:15])[F:14]
Reactant: COC(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: CF
Agent: COC
Agent: [Al+3]
Product: O=C(F)C(C(F)(F)F)C(F)(F)F
Yield: 2.9 %

Procedure:
The above methyl ether, 48.5 g (0.209 mol), and 1 g of AlCl3 were refluxed together for 15 hours and treated as described in Comparative Example 1. An amount of 43.8 g of unreacted (CF3)2CHCF2OCH3 was recovered, together with 1.1 g of (CF3)2CHCOF (2.7% yield) and 0.75 g of CH3F. No improvement in product was obtained when the reactants were heated in a sealed tube at 120° for 4 hours.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[O:11][CH:10]1[C@H:30]([OH:62])[C@@H:31]([C:55]([O:57]C(C)(C)C)=[O:56])[NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:54])[C@H:38]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>O>[O:29]=[C:23]1[NH:24][C:25](=[O:28])[CH:26]=[CH:27][N:22]1[C@@H:12]1[O:11][CH:10]([C@H:30]([OH:62])[C@@H:31]([C:55]([OH:57])=[O:56])[NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:54])[C@H:38]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:9]([OH:8])[C@H:13]1[OH:14]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCN[C@H](C(=O)OC(C)(C)C)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCN[C@H](C(=O)O)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 15.4 %

Procedure:
By using an analogous procedure to that described for Example 47, tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis[tert-butyl(dimethyl)silyl]oxy}-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (123 mg, 0.136 mmol, obtained from Example 6), trifluoroacetic acid (5 ml) and water (6 drops) were stirred for 10 hours at room temperature. The volatiles were removed and the residue was azeotroped with toluene. The resulting residue was purified by preparative HPLC (20×250 mm YMC-ODS column eluted with 10-70% acetonitrile in water containing 0.02% trifluoroacetic acid over 49 minutes) to provide (5S,12S)-12-[(R)-[(3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxy-tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oic acid (13 mg, 15%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:27])[CH:11]=[C:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH2:23][CH2:24][CH:25]=[CH:26][C:15]=2[CH:14]=[CH:13]1.CO.[Li+].[OH-].Cl>O>[CH:22]1[C:17]2[C:16]3[CH2:23][CH2:24][CH:25]=[CH:26][C:15]=3[CH:14]=[CH:13][C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[O:27])[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(2-(10,11-dihydro-5H-dibenzocyclohepten-5-ylidene)acetamido)hexanoic acid methyl ester (377 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (265 mg, 73% yield) as a white solid. LC-MS (m/z) 364 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:14][CH:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[C:29]3[CH2:30][CH2:31][CH2:32][N:17]([C:18]=23)[C:16]1=[O:33]>>[C:1]([NH:8][C@H:9]([C:11]([NH:14][CH:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[C:29]3[CH2:30][CH2:31][CH2:32][N:17]([C:18]=23)[C:16]1=[O:33])=[O:13])[CH3:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: NC1C(=O)N2CCCc3cccc(c32)-c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N2CCCc3cccc(c32)-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-Alanine (Aldrich) and 9-amino-5,6-dihydro-4H-quino[8,1-ab][3]benzazepin-8(9H)-one (from Example 3-AB), the title compound was prepared.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C:5]([CH3:7])([NH:8][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([F:10])([F:22])[F:23])(=[O:20])=[O:19])[CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C)(C)NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
Methyl-2-amino-2-methylpropanoate hydrochloride (1 g, 6.53 mmol) was dissolved in CH2Cl2 (20 ml), and added with 2-(trifluoromethyl)benzene-1-sulfonylchloride (1.76 g, 7.18 mmol) and triethylamine (3.6 ml, 26.1 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(2-(trifluoromethyl)phenylsulfonamido)propanoate (1.98 g, 6.08 mmol, 93%).
Reaction SMILES: [CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15](Br)=[CH:14][C:12]=2[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C[O:25][B:26](OC)[O:27]C.Cl>CCCCCC.O1CCCC1>[CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([B:26]([OH:27])[OH:25])=[CH:14][C:12]=2[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cc2cc(Br)ccc2o1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc2cc(B(O)O)ccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
In a 500 ml-three-necked flask, 19.0 g (61.5 mM) of 2-octyl-5-bromobenzofuran (II) and 190 ml of anhydrous tetrahydrofuran (THF) were placed. To the mixture, 45 ml (72.0 mM) of 1.6M-n-butyllithium solution in hexane was added dropwise under argon stream at −70° C. or below in 30 min., followed by stirring at that temperature for 4 hours. To the resultant mixture, a solution of 17.8 g (171 mM) of trimethylborate in 70 ml of anhydrous THF was added dropwise at −70° C. or below in 20 min., and stirred at that temperature for 2 hours. The system was heated up to room temperature and stirred for 17 hours. To the reaction mixture, 100 ml of 10%-hydrochloric acid was added dropwise, followed by extraction with ether. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain a white crystal of 2-octylbenzofuran-5-boronic acid (III) (Yield: 10.8 g (64.1%)).