Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2/[CH:23]=[CH:24]/[CH:25]([OH:34])[CH2:26][C:27](=[O:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:21])[CH3:22])[C:9]=2/[CH:23]=[CH:24]/[C@@H:25]([OH:34])[CH2:26][C@@H:27]([OH:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A solution of (E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (357 mg, 0.77 mmol) in THF (12 ml) was treated with triethylborane (1.0M in THF, 1.62 ml, 1.62 mmol). Twenty five milliliters of air was bubbled through the solution and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to -78° C. and treated with NaBH4 (29.4 mg, 0.78 mmol) followed by dropwise addition of dry methanol (1.90 ml). After stirring at -78° C. for 1.5 hours, the mixture was quenched with 30% H2 O2 (3.5 ml) in H2O (11 ml). The mixture was kept at -78° C. for 15 minutes, then warmed to room temperature and stirred for 30 minutes. The solution was poured into 50% saturated NaHCO3 and extracted with Et2O (3×). The Et2O extracts were combined, washed with H2O, saturated NaHCO3 and brine, then dried (Na2SO4). Filtration and removal of the solvent gave a yellow oil which was chromatographed (Flash, Merck SiO2, 40% EtOAc in hexane) to afford (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, methyl ester (320 mg, 89%) as a colorless oily foam.
Reaction SMILES: Cl.[F:2][C:3]([F:36])([F:35])[C:4]1[CH:34]=[CH:33][C:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49](=[O:53])[C:50](Cl)=[O:51])[CH3:47]>C(Cl)Cl>[O:51]=[C:50]([N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:35])[F:36])=[CH:34][CH:33]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=2)=[CH:15][CH:16]=1)[C:49]([O:48][CH2:46][CH3:47])=[O:53]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a cold (0° C.) solution of N-[4-(trifluoromethyl)benzyl]-N-[4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzyl]amine hydrochloride (45 mg, 0.09 mmol) and DIEA (24 mg, 0.19 mmol) in anhydrous DCM (1 mL) was added dropwise the chloro-oxo-acetic acid ethyl ester (24 mg, 0.19 mmol). The reaction mixture was stirred at 0° C. for 3 h. Evaporation of the solvents under vacuum gave an orange oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/9) to give the title compound as a colorless oil (38 mg, 75%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, J=8.3 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.39-7.21 (m, 4H), 4.50 (s, 2H), 4.37 (s, 2H), 4.29 (dq, J1=7.1 Hz, J2=2.3 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 1.85-1.65 (m, 2H), 1.41-1.05 (m, 19H), 0.89 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 7.5 min (HPLC purity: 88.8%).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16])(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:17]([C:6]1[C:5]([OH:4])=[C:15]([CH3:16])[C:9]2[CH2:10][C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[CH:7]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(O)c(C(C)(C)C)cc2c1CC(C)(C)O2
Temperature: 25 °C
Yield: 45.4 %

Procedure:
Under argon atmosphere, 65 mg of 5-acetoxy-6-t-butyl-2,2,4-trimethyl-2,3-dihydrobenzofuran was dissolved in 1.5 ml of anhydrous tetrahydrofuran, a solution of 22 mg of lithium aluminium hydride in 1 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature for a whole day and night. After cooling to 0° C, the reaction was quenched with water and then the reaction solution was combined with 10% hydrochloric acid and extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was recrystallized from hexane to give 25 mg of 6-t-butyl-5-hydroxy-2,2,4-trimethyl-2,3-dihydrobenzofuran as a white solid (yield 45%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]1COCC1>>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then Mel (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: [BH4-].[Na+].[C:3]1([NH:9][C:10]2([CH:23]=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([NH:9][C:10]2([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Sodium borohydride (2 g) was added portionwise to a stirred solution of 4-(N-phenylamino)-1-phenylmethyl-piperidine-4-carboxaldehyde (2 g) in methanol at room temperature. After stirring at room temperature for 2 hours the mixture was diluted with water, extracted with chloroform and the combined extracts washed and dried. After removal of the solvent, the crude product was purified by chromatography on silica gel, using chloroform/methanol (38:1) as eluant, to give the title compound (1.53 g) 4-(N-phenylamino)--1-phenylmethyl-4-piperidinylmethanol is then converted to sufentanil following the method described in U.S. Pat. No. 4,179,469 and as illustrated by FIG. 2.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:19])[C:9]2=[O:20])(=[O:5])=[O:4].[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:14][CH:13]=2)[C:9](=[O:20])[C:10]1=[O:19]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A mixture of crude 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetic acid (0.178 g, 0.57 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.274 g, 1.428 mmol) and DMAP (0.029 g, 0.238 mmol) in dry DCM (10 ml) was stirred at room temperature overnight. The mixture was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude was purified by silica gel flash chromatography (DCM:MeOH from 99.5:0.5 to 98:2) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.128 g, 0.179 mmol, 37% yield). This product was further purified by crystallization from ethyl acetate/hexane 1/1 to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N,N-dimethyl sulfamoyl)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.052 g, 0.179 mmol, 15% yield). MS/ESI+ 714.11 [MH]+; [αD]=−37.09, c=0.488; MeOH; 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.15 (s, 2H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.19 (d, 1H), 6.83-7.01 (m, 2H), 6.74 (d, 1H), 6.67 (t, 1H), 6.13 (dd, 1H), 4.53 (d, 2H), 3.91 (d, 2H), 3.58 (dd, 1H), 3.28 (dd, 1H), 2.79 (s, 6H), 1.09-1.43 (m, 1H), 0.55-0.84 (m, 2H), 0.18-0.52 (m, 2H)
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)#[CH:2]
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C=C(Br)Br)CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@H]1CC[C@H](c2ccc(CCCCC)cc2)CC1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
A solution of 480 mg of 1-[trans-4-(2,2-dibromovinyl)cyclohexyl]-4-pentylbenzene in 60 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 3 minutes with 3.2 ml of a 0.1N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -78° C. for a further 2.5 hours, then poured into 150 ml of water and extracted three times with 150 ml of petroleum ether each time. The organic phases were washed with 100 ml of water, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (310 mg) on silica gel with hexane gave 255 mg (83.5%) of 1-(trans-4-ethynylcyclohexyl)-4-pentylbenzene as a colourless oil (purity 95.9%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17].Br[CH2:24][C:25]([CH3:27])=[CH2:26]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:26][C:25](=[CH2:24])[CH2:27][C@H:15]([C@H:14]([OH:13])[CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCC[C@@H](O)CC(=O)OC
Reactant: C=C(C)CBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)C[C@@H](C(=O)OC)[C@H](O)CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred solution of diisopropylamine (19.4 mL, 139 mmol) in 70 mL of THF at −78° C. is added dropwise 86.6 mL (139 mmol) of 1.6 M n-butyllithium in hexanes over 15 min. After 1 h, a solution of methyl (3R)-3-hydroxyhexanoate (9.2 g, 63 mmol) in 10 mL of THF is added dropwise over several minutes. The reaction mixture is stirred 1 h, then treated with a solution of 3-bromo-2-methyl-1-propene (7.6 mL, 75.6 mmol) in 10 mL of HMPA and is allowed to stand at −20° C. overnight. The reaction mixture is poured into ice-cold 1 N hydrochloric acid (300 mL) and extracted with two 200-mL portions of EtOAc. The combined organic layers are washed with two 100-mL portions of saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. The solvents are removed under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc-hexanes affords 7 g (55%) of methyl (2R,3R)-2-(2-methyl-2-propene-1-yl)-3-hydroxyhexanoate as an oil.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C([O-])(O)=O.[Na+]>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2([CH3:16])[CH2:7][C:6]3[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=3[O:4]2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(Cc3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 4-benzylpiperidine (1.1 g), and triethylamine (1.3 mL) was stirred under nitrogen gas at 180° C. for 15 hours. This reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethanol=10:1) and crystallized from hexane to provide 0.86 g of the title compound. Yield 78%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CC(O)C.C(=O)=O.C([Li])CCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:42])N(OC)C)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:42])[C:7]2[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[CH:3][C:2]=2[F:1])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(C(F)(F)F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
A solution of 4-fluorobenzotrifluoride (25 g, 0.152M) in anhydrous THF (300 mi) was cooled to −60° C. (IPA/CO2 bath) and treated with n-butyl lithium (84 mL of a 2.0M solution in Hexane, 0.168M-1.1 eq) with a maximum rate so not to exceed 60° C. The reaction was stirred for 3 hours (temperature maintained) and then treated with a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (51.86 g, 0.190M-1.25 eq, in 130 mL of anhydrous THF) with a maximum rate so as not to exceed −55° C. The mixture was stirred for a further two hours before allowing to warm to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution (75 mL) and the THF removed under reduced pressure. The residue was dissolved in ethylacetate (800 mL), washed with 1N Hydrochloric acid (400 ml), 5% aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively. The organics were dried over MgSO4, filtered and concentrated to give a brown oil, which on triturating in ethyl acetate gave a white solid 27.6 g (48%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.[OH-].[Na+].CO>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[O:18][CH2:17][CH2:16][N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid ethyl ester using the procedure described in Step B of Example 1 with 2N NaOH. Purification by flash chromatography (1% MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t, 2H), 1.61 (m, 4H), 1.33 (m, 4H); MS 411 (M−1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A mixture of 160b (120 mg, 0.21 mmol) and lithium hydroxide monohydrate (88 mg, 2.1 mmol) in THF/i-propanol (4:2, 6 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (10 mL). It was then extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 160 (50 mg, 45%) as a white solid. MS-ESI: [M+H]+ 527.8. 1H NMR (500 MHz, CHCl3) δ 8.78 (d, J=2.5 Hz, 1H), 8.71 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.59 (s, 1H), 7.56-7.55 (m, 2H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:8]=1[CH3:9].N1C(C)=CC(C)=CC=1C.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]1[CH2:39][C:40]1[O:44][C:43]([C:45](O)=[O:46])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:10][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([CH2:2][NH:1][C:45]([C:43]2[O:44][C:40]([CH2:39][N:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:28])=[CH:41][CH:42]=2)=[O:46])=[C:4]([CH3:18])[CH:5]=1
Reactant: O=C(O)c1ccc(Cn2ccc3ccccc3c2=O)o1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: Cc1cc(N)nc(C)c1CNC(=O)c1ccc(Cn2ccc3ccccc3c2=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (41.1 mg, 0.163 mmol) in THF (5 ml) were added collidine (0.022 ml, 0.163 mmol), 5-((1-oxoisoquinolin-2(1H)-yl)methyl)furan-2-carboxylic acid (44.0 mg, 0.163 mmol) and HATU (81.0 mg, 0.212 mmol). After stirring for 18 h at rt, all volatiles were removed in vacuo. The crude intermediate was purified by column chromatography (CombiFlash Companion, 12 g SiO2, heptane to EA), dissolved in DCM (1 ml) and TFA (1 ml), kept for 1 h at rt, and concentrated. Purification by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×19 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 6-36% B in 10 min, 30 ml/min, rt) afforded the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.37 (s, 3H), 4.28 (d, 2H), 5.23 (s, 2H), 6.45 (d, 1H), 6.62 (s, 1H), 6.68 (d, 1H), 7.06 (d, 1H), 7.49-7.59 (m, 4H), 7.65-7.76 (m, 2H), 8.21 (d, 1H), 8.52 (t, 1H), 13.33 (s, 1H). LCMS RtM=1.50 min, [M+H]+=403.3.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH3:15])[CH2:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1.CO.Cl>O.C(Cl)(Cl)Cl>[OH:11][C:12]1[CH:13]=[C:4]([OH:3])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:15])[CH2:9][C:10]([OH:1])=[O:14]
Reactant: CC1CC(=O)Oc2cc(O)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(CC(=O)O)c1ccc(O)cc1O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium hydroxide (5.0 M, 27 ml, 135 mmol) was added to a suspension of 7-hydroxy-3,4-dihydro-4-methylcoumarin (Compound of formula B1) (8.0 g, 45 mmol) in water (40 ml) at room temperature and the resulting solution stirred for 20 min. At this time, TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was cooled to 5° C. and carefully acidified with concentrated HCl to pH less than about 1, keeping the temperature at less than about 15° C. throughout the addition. The solution was extracted with ethyl ether (4×100 ml), the organic layers washed with saturated NaCl (4×50 ml), combined, dried (Na2SO4), filtered and the solvent removed to give a pale orange oil. Further purification by filtering through a short pad of silica gel and eluting with ethyl acetate afforded pure product as a white solid (8.3 g, 94%): m.p. 92-94° C.; 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.33 (dd, JJ=15.0, 8.9, 1H), 2.52 (dd, JJ=15.5, 7.3, 1H), 3.32 (m, 1H), 6.16 (dd, JJ=8.2, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 9.08 (s, 1H), 9.59 (s, 1H), 11.87 (s, 1H); 13C NMR (DMSO-d6) d 20.39, 28.97, 41.0, 102.58, 106.01, 122.55, 127.27, 155.19, 156.18, 173.74; m/z (EI; TMS derivatized; M+) 412; IR (neat; cm1) 3360.1, 2974.1, 2935.1, 2876.4, 1748.0, 1713.8, 1625.9, 1606.3, 1518.4, 1459.8, 1381.6, 1347.4, 1283.9, 1254.6, 1239.9, 1156.9, 1117.8, 1025.0, 981.0, 937.1, 849.1, 810.1.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29][CH2:30]O)[CH3:27].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH2:27][CH2:26][O:28][CH2:29][CH3:30])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOCCO
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OCCOCC)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.