Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of N-Boc-3-hydroxymorphinan 2 (20 mg, 0.058 mmol) and triethylamine (9 μL, 0.064 mmol) in dry CH2Cl2 (1 mL) was slowly added pivaloyl chloride (8 μL, 0.064 mmol) at 0° C. and the mixture stirred for 1 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (5:1 n-Hexane/EtOAc) to give a colorless oil (23 mg, 92% yield): 1H NMR (300 MHz, CDCl3) 0.9˜1.7 (m, 29H); 2.34 (d, J=9.9 Hz, 1H); 2.52˜2.73 (m, 2H); 3.09˜3.17 (m, 1H); 3.73˜3.84 (m, 1H); 6.83˜6.87 (m, 1H); 6.95 (s, 1H); 7.09˜7.12 (m, 1H).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and glycine benzylester p-toluene sulfonic acid salt (1.0 g, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was dropwise added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling, and next, overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give oily dibenzylphosphoryl-L-alanyl-L-prolyl-glycine benzylester-(1.5 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.Cl>CCOCC>[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:18][CH2:17]2
Reactant: Cc1ccc2c(c1)CCCC2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 6.1 h
Yield: 85.1 %

Procedure:
Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in ether (50 mL) and treated with a sodium methoxide solution (25% in methanol, 9.92 g, 45.9 mmol) followed by 6-methyltetralone (5.94 g, 37.1 mmol). The reaction was stirred at room temperature for 6.1 hours then treated with 1N HCl (20 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (8.09 g) that was used in the next step without further purification.
Reaction SMILES: [Mg].[CH3:2][Si:3]([CH3:16])([CH3:15])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=O.Cl.S(=O)(=O)(O)O>CCOCC.C(O)(=O)C.C1COCC1>[CH3:2][Si:3]([CH3:16])([CH3:15])[C:4]1[CH:5]=[C:6]([C:18]2[CH2:17][C:25]3[C:20]([CH:19]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1
Reactant: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[Si](C)(C)c1cc(C2=Cc3ccccc3C2)cc([Si](C)(C)C)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Magnesium turnings (6.8 g, 0.28 mol) and anhydrous THF (100 mL) were placed in a three-necked flack under argon. A solution of 3,5-bis(trimethylsilyl)bromobenzene (85.2 g, 0.28 mol) in of THF (100 mL) was added incrementally to the THF and magnesium mixture keeping the temperature near reflux. The Grignard reaction started immediately after the addition of the first increment. The remaining solution was added over a one hour period. The resulting slurry was refluxed for an additional 30 minutes. The solution was cooled to 20° C. and a solution of 2-indanone (36.7 g, 0.28 mol) in ether (100 mL) was added dropwise over a 1 hour period. The solution was then stirred at room temperature overnight. The solution was neutralized with 1N HCl. The aqueous layer was separated and washed three times with 100 mL of ether. The organics were combined and dried over magnesium sulfate. The solvents were evaporated to yield a tan solid of the crude alcohol. This solid was taken up in acetic acid (200 mL) and cooled to 15° C. A solution of sulfuric acid (40 g) and of acetic acid (200 mL) was added slowly, keeping the temperature of the mixture near 15° C. The product separated as and oil. The acetic acid layer was diluted with 1L of ice water and extracted with toluene. The organic layer was separated and washed twice with sodium bicarbonate solution and dried over magnesium sulfate. The solvents were evaporated. The product was then taken up in a minimal amount of hexanes and passed through a short silica gel column to remove very polar material. Attempts to crystallize the product failed and the product was distilled to yield 20.5 g (22% yield), b.p. 175-180° C. @ 0.3 mm Hg. This procedure was repeated to yield an additional 22.3 grams of material. 1H NMR (C6D6): δ 7.45 (2H, s), 7.26 (1H, s), 7.13 (2H, dd), 6.94 (1H, m), 6.85 (2H, m), 3.51 (2H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([Cl:28])[CH:25]=1)[CH2:21][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[CH:4]=1)(=[O:11])=[O:10]
Reactant: NCc1cccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 3-(aminomethyl)-N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)benzenesulfonamide (290 mg, 0.64 mmol) in CH2Cl2 (6 mL) was added 4-fluorobenzaldehyde (0.07 mL, 0.64 mmol). The resulting mixture was stirred at rt. for 1 h. To the mixture was added sodium triacetoxyborohydride (217 mg, 1.02 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 20 h. To the reaction mixture was added saturated aq NaHCO3 solution and the mixture was stirred for 20 minutes. The mixture was concentrated. The residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was washed with brine and dried over MgSO4. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel eluting with 100% CH2Cl2 to 25% ethyl acetate in CH2Cl2 to obtain the desired product as a colorless oil (0.16 g, 45%). 1H NMR (CDCl3): δ 7.86 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.33-7.29 (m, 2H), 7.16-7.15 (m, 1H), 7.09-6.99 (m, 4H), 6.94-6.89 (m, 2H), 6.85-6.84 (m, 2H), 4.32 (s, 2H), 4.25 (s, 2H), 3.89 (s, 2H), 3.78 (s, 2H), 1.77 (bs, 1H); MS (ESI): [M+H]+=561.0.
Reaction SMILES: [BH-](O[C:11]([CH3:13])=[O:12])(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][C:21]1[CH:28]=C(O)[CH:26]=[CH:25][C:22]=1C=O.Cl>C(Cl)Cl>[CH3:26][C:25]1[CH:22]=[C:21]([CH2:28][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:20]=[CH:13][C:11]=1[OH:12]
Reactant: C1CCNC1
Reactant: Cc1cc(O)ccc1C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CN2CCCC2)ccc1O
Yield: 85.6 %

Procedure:
NaB(OAc)3H (11.8 g, 0.056 mol) was added in portions for 15 min to a mixture of pyrrolidine (3.3 mL, 0.041 mol) and 2-methyl-4-hydroxybenzaldehyde (5 g, 0.037 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (10 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with K2CO3 to pH 9 (30 mL) and extracted with EtOAc (4×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (6.06 g, 86%) was obtained as white crystals. H-NMR (400 MHz)-data (DMSO-d6, J, Hz): 9.18 (br s, 1H, OH); 6.83 (s, 2H, ArH); 3.79 (s, 3H, CH3); 3.44 (s, 2H, CH2Ar); 2.36-2.44 (m, 4H, CH2CH2CH2CH2,); 1.65-1.72 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=1[F:12].[CH2:14]([NH2:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[F:12][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][NH:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1cc(C=O)ccc1F
Reactant: CCCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCNCc1ccc(F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.7 %

Procedure:
To solution of 2-fluoro-5-formylbenzoic acid methyl ester (1.0 g; 5.49 mmol) in anhydrous DCE (50 mL) were added hexylamine (Aldrich, 0.87 mL; 6.59 mmol), triacetoxyborohydride (1.74 g; 8.24 mmol) and acetic acid (0.47 mL; 8.24 mmol). The resulting mixture was stirred at room temperature under N2 atmosphere for 5 hours. The mixture was poured into a saturated solution of NaHCO3 and extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (DCM/MeOH/NH4OH, 98:2:0.1) gave 920 mg (63%) of the title compound as a yellow cream. HPLC, Rt: 2.34 min (purity=94.9%), LC/MS: M+(ESI): 268.1, 1H NMR (CDCl3) δ: 7.8 (dd, J=2.2, 8.2 Hz, 1H), 7.42 (m, 1H), 7.00 (dd, J=8.2, 2.2 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 2H), 2.58 (t, J=7.1 Hz, 2H), 1.46 (qt, J=6.7 Hz, 2H), 1.22 (m, 6H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCCCCCC>C1COCC1>[CH3:5][C:4]([CH3:6])([CH:3]=[CH2:2])[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:14]
Reactant: CC(C)=CCCl
Reactant: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCCCCC
Product: C=CC(C)(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
4-Chloro-2-methyl-2-butene (3.2 mmol) was weighed into a vial and sealed with a septum. Using a freeze-pump-thaw technique, air was removed and replaced with argon. THF (4 ml) was added to the vial and then cooled to -78° C. The allyl chloride was then cannulated to the active coppersolution (8.00 mmol) at -108° C. The solution was stirred at -108° C. for 10 minutes and then warmed to -78° C. Benzaldehyde (1.60 mmol) and decane (3.20 mmol) were admixed with 4 ml of THF in a vial, cooled to -78° C. and then cannulated to the organocopper solution at -78° C. and stirred for 30 minutes. The solution was then quenched with saturated NH4Cl(aq), extracted with ether (3×20 ml), washed with brine (3×50 ml), and the organic layer dried over MgSO4. Flash silica gel chromatography usinggradient mixtures of hexanes/EtOAc afforded 2,2-dimethyl-1-phenyl-3-butene-1-ol (1.28 mmol), for an 80% yield: IR (neat) 3451, 3083, 3062, 3029, 2964, 2929, 2869, 1637, 1452, 1413, 1378, 1361, 1187, 1024, 998, 730, 701. 1H NMR (300 MHz) 7.24-7.28 (m, 5H),5.84-5.93 (dd, J1 =17.41 Hz, J2 =10.73 Hz, 1H), 5.00-5.12 (m, 2H), 4.37 (s, 1H), 2.23 (s, 1H), 0.98 (s, 3H), 0.93 (s, 3H). 13C NMR(300 MHz) 144.9, 140.6, 127.7, 127.3, 113.6, 80.4, 42.0, 24.2, 20.9.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11]C)=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[C-]#N.[K+].C(Cl)Cl>CS(C)=O>[NH2:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1
Reactant: COc1cccc2c1C(N)=NS2(=O)=O
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC1=NS(=O)(=O)c2cccc(O)c21
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5 gm of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide and 1.63 gm of potassium cyanide in 15 ml of dimethyl-sulfoxide was heated to 130°-140° C. (bath temperature 160° C.) and kept at this temperature for 1.5 hours. After cooling, the reaction mixture was stirred into 250 ml of methylene chloride, and the resulting precipitate was filtered off, dried and dissolved in 30 ml of water. At 60° C. the solution was treated with charcoal and filtered while hot. The hot filtrate was adjusted to pH 1 with concentrated aqueous hydrochloric acid. After cooling, the resulting crystals were suction-filtered off, washed with a little ice water and dried in vacuo.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CS(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:12]1[C:13]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:30]
Reactant: c1ccc2c3c([nH]c2c1)CCCC3
Reactant: CCOC(=O)CCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCn1c2c(c3ccccc31)CCCC2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
A RB flask fitted with reflux condenser containing tetrahydrocarbazole (1.71 g, 10.0 mol) was dissolved in DMSO (30 mL), treated with potassium tert-butoxide (1M solution in THF, 12 mL) and stirred at 110° C. for 20 min. Ethyl 6-bromohexanoate (1.67 mL, 10.0 mmol) was added and the mixture stirred at 110° C. for 60 min. The reaction was quenched with a 1:1 brine:water solution (120 mL) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by column chromatography (25% ethyl acetate in hexane) afforded the title compound (1.01 g, 32%). 1H NMR (400 MHz, CDCl3): δ 7.52 (m, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 7.12 (m, 1H), 4.18 (q, 2H, J=7.1 Hz), 4.04 (t, 2H, J=7.4 Hz), 2.78-2.73 (m, 4H), 2.33 (t, 2H, J=7.5 Hz), 2.00-1.92 (m, 4H), 1.80-1.75 (m, 2H), 1.72-1.66 (m, 2H), 1.42 (m, 2H), 1.30 (t, 3H, J=6.9 Hz). ESI-HRMS (m/z): [M+H]+ calcd. for C20H27NO2, 314.2115. found, 314.2103.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[CH2:10]2)(=[O:3])[CH3:2].C1N=C[N:35](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH2:35])=[O:19])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 73.9 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide was prepared by the procedure of example 6 from 3-[7-(acetylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.6 g, 1.3 mmol), CDI (0.3 g, 2 mmol) and NH4OH (0.20 ml, 2.6 mmol) in THF (30 ml) to give 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide as white solid (0.43 g, 72%): mp 129-131° C.; 1HNMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.97 (dd, J=5, 15 Hz, 1H, CH2), 3.42 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.40 (broad, 1H, NH2), 5.56 (m, 1H, CHN), 6.01 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.95 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.47 (d, J=7.5 Hz, 1H, Ar), 10.25 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 3.2, 14.4, 16.2, 24.4, 37.7, 46.7, 51.7, 64.2, 93.9, 113.0, 116.6, 117.2, 117.5, 119.2, 121.3, 132.8, 137.0, 138.2, 139.0, 142.2, 149.8, 168.0, 168.5, 171.0; Anal. Calcd. for C22H23F2N3O5: C, 59.06; H, 5.18; N, 9.39. Found: C, 58.48; H, 5.12; N, 9.65.
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([O:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][CH:11]=1)[CH3:8].[CH2:36]([Si:41]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:46][CH2:45][CH:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH2:37][CH2:38][CH2:39][CH3:40]>CCCCCC.O.O1CCCC1>[CH2:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:47][CH:44]2[CH2:43][CH2:42][Si:41]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:46][CH2:45]2)=[CH:34][CH:35]=1)[CH3:8]
Reactant: CCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=O)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(OCC)cc2)CC1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
65 ml of an n-hexane solution of 1.60 moles of n-butyl lithium was added to a mixture of 48.0 g of p-ethoxybenzyltriphenylphosphonium bromide and 200 ml of tetrahydrofuran to obtain a ylide solution. 27.4 g of 4-n-pentyl-4-phenyl-4-silacyclohexane carbaldehyde was dropped in the solution. After agitation at room temperature for 2 hours, the resultant solution was charged into iced water and extracted with ethyl acetate. The extract was subjected to ordinary washing and concentrating operations to obtain a residue, to which n-hexane was added. The resultant crystals of triphenylphosphine oxide were removed by filtration and the flitrate was concentrated. The resultant residue was purified through silica gel column chromatography to obtain 38.0 g (yield: 97%) of 4-(2-(4-ethoxyphenyl)ethenyl)-1-n-pentyl-1-phenyl-1-silacyclohexane.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [O-][n+]1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1cccc[n+]1[O-]
Reaction time: 47 h
Yield: 89.3 %

Procedure:
A mixture of mono-Boc-1,2-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, 43.67 mmole), NaHCO3 (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture was cooled, diluted with CH2Cl2 (100 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene. Silica gel chromatography (10% MeOH/CHCl3) gave impure title compound (8.23 g, 89%) as a yellow solid which was used without further purification: TLC (10% MeOH/CHCl3) Rf 0.42; 1H NMR (250, CDCl3) δ 8.16 (dd, J=6.5, 1.3 Hz, 1H), 7.05-7.30 (m, 2H), 6.68 (br d, J=8.6 Hz, 1H), 6.50-6.65 (m, 1H), 5.70-5.95 (m, 1H), 3.25-3.60 (m, 4H), 1.44 (s, 9H); MS (ES) m/e 254 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[C:11](Cl)(Cl)=[O:12].C(N(CC)CC)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH3:9])[C:11](=[O:12])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CNc1ccc(Br)cc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-N1-methylbenzene-1,2-diamine (581 mg, 2.89 mmol) in methylene chloride (50 mL) was cooled to 0° C. in an ice/water bath and treated dropwise with a solution of 20% phosgene in toluene (1.52 mL). When the addition was complete, triethylamine (585 mg, 5.78 mmol) was added and the reaction stirred at 0° C. for 30 min. After this time, the reaction was poured into 1 M hydrochloric acid (80 mL) and extracted with methylene chloride. The combined organic layers were washed with water and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by trituration with ethyl acetate to afford 5-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (bs, 1H), 7.17 (dd, J=8.4, 1.6 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 3.26 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[OH:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[CH:37][C:38]=1[OH:39]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (34 mg, 0.200 mmol) to afford the desired product (39 mg, 72%) as an off-white solid: ESI MS m/z 538 [C30H36ClN3O4+H]+.