Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (445 mg) in DMF (3 mL) were added potassium carbonate (471 mg) and (bromomethyl)cyclopropane (0.331 mL), and the mixture was stirred with heating at 60° C. for 7 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate), and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (439 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](O)=[O:9])[C:4]([C:11]([F:14])([F:13])[F:12])=[N:3]1.S(Cl)([Cl:17])=O>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([Cl:17])=[O:9])[C:4]([C:11]([F:14])([F:13])[F:12])=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)c(C(F)(F)F)nn1C
Product: Cc1c(C(=O)Cl)c(C(F)(F)F)nn1C

Procedure:
1,5-Dimethyl-3-trifluoromethylpyrazole-4-carboxylic acid (2.09 g, 10 mmol) was dissolved in thionyl chloride, and the mixture was heated under reflux for 3 hr. The mixture was concentrated under reduced pressure to give 1,5-dimethyl-3-trifluoromethylpyrazole-4-carbonyl chloride. This was added to a solution of 3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (3.29 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in tetrahydrofuran (30 ml), and the mixture was heated under reflux for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired compound (3.64 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1I.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][C:21]=1[F:30].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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.C1(C)C=CC=CC=1.O.C(O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)=[CH:3][C:2]=2[F:1])=[CH:22][C:21]=1[F:30]
Reactant: Fc1cc(-c2ccc3ccccc3c2)ccc1I
Reactant: OB(O)Oc1ccc(Cl)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccc(-c3ccc4ccccc4c3)cc2F)ccc1Cl
Reaction time: 44 h

Procedure:
A mixture of 6.66 g (19.13 mmol) of the above-obtained 2-(3-fluoro-4-iodophenyl)naphthalene, 4.00 g (22.94 mmol) of 4-chloro-3-fluorophenylboric acid, 3.97 g (=28.72 mmol) of potassium carbonate, 1.54 g (=4.78 mmol) of tetrabutylammonium bromide, 0.40 g (=0.57 mmol) of dichlorobis(triphenylphosphine)palladium(II), 0.31 g (=1.16 mmol) of triphenylphosphine and a 60 ml mixed solvent of toluene/water/ethanol in a ratio of 1:1:1 was stirred for 44 hours with reflux. The reaction mixture obtained was extracted twice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellowish solid of 9.66 g was purified with silica gel chromatography using heptane/toluene in a ratio of 5:1 as the eluent to obtain a white solid of 7.11 g, which was recrystallized with a mixed solvent of heptane/toluene in a ratio of 8:1 to obtain a product in an amount of 4.79 g, which was characterized as the target compound based on results of various instrumental analyses. The phase transitions of the product are notated as “C 121.9 N 128.7 I”.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:16]([O:18]C)=[O:17])=[C:12]([CH2:31][CH2:32][CH3:33])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].Cl>CO.ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:16]([OH:18])=[O:17])=[C:12]([CH2:31][CH2:32][CH3:33])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a solution of 3.20 g (6.78 mmol) of the product of Step B dissolved in 10 mL of methanol and 3 mL of dichloromethane was added 1.42 mL (7.12 mmol) of a 5.0N aqueous solution of sodium hydroxide and the reaction mixture was magnetically stirred at room temperature. After 4 hours TLC analysis (CHCl3 --MeOH--NH4OH 80:15:1) indicated complete hydrolysis and the reaction mixture was adjusted to pH=4 with 1.0N HCl. The reaction mixture was then completely evaporated and dried in vacuo to afford the crude product which was used directly in the next step.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:22](=[O:24])[C@H:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][CH3:13])[CH3:25])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 1 h
Yield: 29 %

Procedure:
0.37 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.41 g of (S)-2-(2-methoxyphenyl)propionic acid in 15 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.75 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride is added. The reaction mixture is stirred at room temperature for 20 hours and then then washed twice with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.6 cm, height 37 cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetate and cyclohexane mixture (50/50 by volume) and collecting fractions of 50 cm3. Fractions 21 to 41 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in isopropyl oxide and then dried. 0.3 g of (3aR,4S,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol is obtained in the form of a white meringue.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[CH2:18]1)=[O:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)C1CCCC(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)C1
Yield: 69.4 %

Procedure:
Using General Procedure A with 5.6 g (23.2 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (11.6 mmol) cyclohexane-1,3-dicarboxylic acid afforded, after flash chromatography (EtOAc), 4.4 g (70%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F-].[Cs+].[CH2:14](B1OC(C)(C)C(C)(C)O1)[CH:15]=[CH2:16].O>C1COCC1>[CH2:16]([C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:15]=[CH2:14]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
5-Bromo-1,3-dimethoxybenzene (2.13 g, 9.8 mmol), CsF (2.88 g, 19.0 mmol), and Pd(Ph3)4 (0.57-1.13 g, 0.5-1.0 mmol) were weighed into a flame-dried Schlenk flask and put under a flow of argon. THF (80 mL) was added to the flask via syringe, and the resulting suspension was stirred for 30 min at room temperature. Allyl boronic acid pinacol ester (2.96 g, 17.6 mmol) in THF (40 ml) was added and the resulting mixture was heated to reflux for 30 h. Another portion of CsF (2.88 g, 19.0 mmol) and Pd(Ph3)4 (0.57-1.13 g, 0.5-1.0 mmol) were added and the reaction was continued to reflux for 24 h. The reaction mixture was diluted with petroleum ether (100 ml) followed by H2O (100 ml). The layers were separated and the aqueous layer was extracted with petroleum ether (2×80 ml). The combined organic layers were washed with H2O (100 ml), and brine (100 ml). The solution was dried over MgSO4 and evaporated to dryness. The crude product was purified by column chromatography (silica, eluent: hexanes/benzene=3:2) to give 1.60 g (92%) of 5-Allyl-1,3-dimethoxybenzene. 1H NMR (CDCl3): δ 3.33 (d, J=6.7 Hz, 2H, CH2CH═CH2), 3.77 (s, 6H, OCH3), 5.02-5.11 (m, 2H, CH2CH═CH2), 5.89-5.99 (m, 1H, CH2CH═CH2), 6.33-6.38 (m, 3H).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]([C:8]([C:10]1[N:19]=[C:18]2[N:12]([CH2:13][CH2:14][O:15][C:16]3[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:17]=32)[CH:11]=1)=[O:9])[NH2:7])([CH3:5])[CH3:4].[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[CH:3]([N:6]([C:8]([C:10]1[N:19]=[C:18]2[N:12]([CH2:13][CH2:14][O:15][C:16]3[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:17]=32)[CH:11]=1)=[O:9])[NH:7][C:28](=[O:29])[CH2:27][O:26][CH3:25])([CH3:5])[CH3:4]
Reactant: COCC(=O)Cl
Reactant: CC(C)N(N)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: ClCCl
Product: COCC(=O)NN(C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)C(C)C
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 85.9 %

Procedure:
A suspension of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-hydrazide dihydrochloride (2.69 g, 6.1 mmol) in DCM (61 mL) was treated with TEA (3.84 mL, 27.6 mmol). The resultant solution was cooled to 0° C. before methoxyacetyl chloride (1.12 mL, 12.3 mmol) was added dropwise and the reaction stirred at 0° C. for 1.75 h. The reaction was quenched with saturated sodium bicarbonate solution and the phases separated. The aqueous phase was extracted with DCM (×2) before the combined organic phases were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution and brine. The organic solution was dried (Na2SO4), concentrated in vacuo and the resultant solid was triturated with diethyl ether to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide as an off-white solid (2.29 g, 5.24 mmol, 86%). LCMS RT=4.29 min, [M+H]+=437/439. 1H NMR 400 MHz (DMSO-d) δ: 9.61 (1 H, s), 8.29 (1 H, d, J=8.63 Hz), 7.71 (1 H, s), 7.27 (1 H, dd, J=8.64, 2.06 Hz), 7.21 (1 H, d, J=2.06 Hz), 4.84 (1H, t, J=6.91 Hz), 4.45 (4 H, s), 3.92 (2 H, s), 3.33 (3 H, s), 1.15 (6 H, d, J=6.66 Hz)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][P:14]([CH3:21])(=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[F:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[N+:31]([O-:33])=[O:32])=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[CH2:13][P:14]([CH3:21])(=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:27][CH:28]=1
Reactant: CC(C)COP(C)(C)=O
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 8.1 g of diisopropylamine in 50 ml of dry tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 50.0 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 10.0 g of isobutyl P,P-dimethyl-phosphinate is added. This mixture is stirred at -78° C. for a period of 1 hour, after which time a solution of 11.1 g of trans-1-(4-fluorophenyl)-2-nitro-ethene in 50 ml of tetrahydrofuran is added. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product purified by chromatography on silica gel using 5 parts ethyl acetate to 1 part ethanol as eluent. The fractions containing product are combined and concentrated under reduced pressure to give isobutyl 2-(4-fluorophenyl)-3-nitro-propyl-(methyl)phosphinate as a viscous oil, 31P-N.M.R. spectrum: δ=+51.0 and +50.6 ppm (CDCl3).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:34])[NH:9][C:10]2[C:11]3[N:12]([CH:31]=[CH:32][N:33]=3)[N:13]=[C:14]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:14]2[CH:15]=[C:10]([NH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:34])[C:11]3[N:12]([CH:31]=[CH:32][N:33]=3)[N:13]=2)[CH2:18][CH2:19]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(NC(=O)Nc3ccccc3)c3nccn3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2cc(NC(=O)Nc3ccccc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl(trans)-4-(8-(3-phenylureido)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (6.3 mg, 0.135 mmol) from 1a in dichloromethane (2 mL) was added TFA (1 mL). After stirring at RT for 2 hours, the reaction solution was concentrated in vacuo. The residue was purified by SCX column (300 mg, eluting with 2M ammonia in methanol) to give the title compound as a TFA salt 3.2 mgs (64%). 1H NMR (500 MHz, MeOH) δ ppm 7.64 (1H, s), 7.47 (2H, m), 7.31 (2H, m), 7.06 (2H, m), 6.71 (2H, m), 3.63 (1H, m), 2.71 (1H, m), 2.15 (2H, m), 1.91 (2H, m), 1.28-1.33 (4H, t). LC/MS, m/e 366.27 (M+1). HPLC Rt, 2.18 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14]([C:16]1[C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:30][CH:31]=[CH:32][C:33]=3[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:25][CH:24]=2)=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)=[O:15].[CH:41]([S:44](Cl)(=[O:46])=[O:45])([CH3:43])[CH3:42]>ClCCl>[CH3:12][O:13][C:14]([C:16]1[C:17]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[S:30][CH:31]=[CH:32][C:33]=3[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:27][CH:28]=2)=[C:18]([NH:22][S:44]([CH:41]([CH3:43])[CH3:42])(=[O:46])=[O:45])[CH:19]=[CH:20][CH:21]=1)=[O:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)c1cccc(N)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)C(C)C)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Yield: 19.4 %

Procedure:
Add 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) drop wise (0.51 mL, 3.6 mmol) to a suspension of 6-amino-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (208 mg 0.48 mmol) in dichloromethane (9 ml) at 0° C., followed by drop wise addition of isopropylsulfonyl chloride (0.21 mL, 0.9 mmol) and stir the reaction at room temperature overnight. Remove solvent under reduced pressure. Purify with flash chromatography (Silica gel-hexane/EtOAc). Concentrate the desired fractions to provide 6-(propane-2-sulfonylamino)-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (50 mg). MS (m/e): 535.1(M−1).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][CH2:8][C:9]1([CH2:26][CH2:27][CH3:28])[C:14]2[NH:15][C:16]3[C:17]([F:25])=[CH:18][CH:19]=[C:20]([C:22]([OH:24])=O)[C:21]=3[C:13]=2[CH2:12][CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>CN(C=O)C.O>[C:1]([Si:5]([CH3:29])([CH3:30])[O:6][CH2:7][CH2:8][C:9]1([CH2:26][CH2:27][CH3:28])[C:14]2[NH:15][C:16]3[C:21]([C:13]=2[CH2:12][CH2:11][O:10]1)=[C:20]([C:22]([N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[O:24])[CH:19]=[CH:18][C:17]=3[F:25])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(C(=O)O)c21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-5-carboxylic acid (6) (400 mg, 0.918 mmol), EDCI (211 mg, 1.10 mmol) and HOBt (186 mg, 1.38 mmol) in DMF ( 5 mL) was added diisopropylethylamine (0.80 mL, 4.59 mmol) at room temperature. Morpholine (0.12 mL, 1.38 mmol) was added to the mixture and the mixture was stirred overnight at room temperature. The solution was diluted with H2O (10 mL) and extracted with EtOAc (3×15 mL). The organic solution was brine washed (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 415 mg (90%) of title compound as a colorless oil. 1H NMR (CDCl3): 300 MHz δ 9.38 (s, 1H), 6.77 (m, 2H), 3.86–3.20 (m, 12 H), 2.67 (m, 2H), 1.97–1.15 (m, 6H), 0.81 (s, 9H), 0.76 (t, J=7.34 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][S:25][C:24]([CH3:29])([CH3:28])[C@@H:23]2[C:30]([NH:32][OH:33])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=O)C.[OH-].[NH4+]>CO>[OH:33][NH:32][C:30]([C@H:23]1[C:24]([CH3:28])([CH3:29])[S:25][CH2:26][CH2:27][N:22]1[S:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]#[C:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[O:31]
Reactant: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)NO)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCCCO)cc2)[C@H]1C(=O)NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
A mixture of 0.152 g (0.305 mmol) of 7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfonyl)phenoxy]-5-heptynyl acetate, 3 mL of aqueous ammonium hydroxide and 3 mL of methanol was stirred at room temperature for 18 h and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% methanol/dichloromethane to provide 0.09 g (65%) of (3S)-N-hydroxy-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxamide as a white solid. Electrospray Mass Spec: 457.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]([N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36])(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=2)[C:32]1=[O:36])(=[O:30])[CH3:29]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(S(C)(=O)=O)c2)C1=O
Yield: 79.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.36 g) described in Preparation Example 112 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.20 g) was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]([O:20][CH3:21])=[O:19].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1>[OH:26][CH:22]([C:14]1([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16][CH2:17][O:13]1)[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)C1CCCO1
Reactant: CC(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(O)C(C)C)CCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
This procedure was adapted from J. Chem. Soc. Perkin Trans. I. 1997, p 771. To a solution of N,N-diisopropylamine (1 mL, 7.69 mmol) in THBF (13 mL) at 0° C. as added n-butyllithium (4.2 mL, 8.46 mmol, 2 M in hexanes). After stirring the mixture for 30 min, it was cooled to −78° C. and 2-tetrahydrofuroic acid, methyl ester (1 g, 7.69 mmol) in THF (13 mL) was added. The reaction mixture was stirred at the same temperature for 15 min and then warmed to −40° C. Isobutyraldehyde (1 mL, 11.5 mmol) was added and stirring was continued for 1 hr and −40° C. The reaction mixture was then warmed to 0° C. and stirred for 1 hr before it was quenched HCl (30 mL, 1M). Extracted with 2×50 mL of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate. Filtration and evaporation gave the crude product 2.63 g as an oil. Flash column chromatography on silica gel eluted with 15:85 ethyl acetate/hexane gave the desired product (688 mg, 44% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Reactant: O=C(O)C1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 86b) and cyclohexanecarboxylic acid as brown solid (31%). MS 414 (MH+).