Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][C:25](OCC)=[O:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:30][C:31]3[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][CH2:25][OH:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4cccc(Cl)n4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.2 %

Procedure:
Ethyl (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (400 mg) was dissolved in tetrahydrofuran (8 mL), lithium borohydride (43 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 17 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=40:60 to 100:0, volume ratio) to give the title compound (75 mg, yield 20%) as an amorphous solid. The amorphous solid was crystallized from diethyl ether to give pale-yellow crystals. melting point 93-94° C. MS 558 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:29]1([CH:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1]3)=[CH:16][CH:17]=2)[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=c1[nH][nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2[nH]c3ccccc3c2=O)cc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
At 0° C., 170.9 mg (1.27 mmol) of 1,2-dihydro-3H-indazol-3-one were added to 50.9 mg (1.27 mmol, 60% pure) of sodium hydride in 1.8 ml of DMF. The mixture was stirred for 30 min, and 500 mg (1.06 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. The reaction mixture was stirred for a further 30 min, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 217 mg (50.3% of theory) of the target compound.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]([CH3:31])[CH2:12][N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[C:15]2[C:14]1=[O:30]>C(Cl)Cl>[F:7][CH:11]([CH3:31])[CH2:12][N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[C:15]2[C:14]1=[O:30]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)CN1CCn2nc(COc3ccccc3)cc2C1=O
Solvent: ClCCl
Product: CC(F)CN1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
DAST (0.02 mL, 0.15 mmol) was added dropwise to a solution of (rac)-5-(2-hydroxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.1 mmol) in DCM (0.6 mL) at 0° C. The mixture was then allowed to warm to room temperature and stirred at 100° C. for 10 minutes under microwave irradiation. The mixture was quenched with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 100/0). Desired fractions were collected and solvents evaporated in vacuo. The product was repurified by RP HPLC on (C18 XBridge 30×100 5 um). Mobile phase (Gradient from 80% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 20% ACN to 0% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 100% ACN) and triturated with DIPE to yield (rac)-5-(2-fluoro-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (8.3 mg, 29% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (dd, J=24.0, 6.5 Hz, 3H), 3.42 (ddd, J=20.1, 14.6, 7.6 Hz, 1H), 3.80-3.91 (m, 1H), 3.91-4.08 (m, 2H), 4.33-4.46 (m, 2H), 4.83-5.05 (m, 1H), 5.10 (s, 2H), 6.90-6.95 (m, 1H), 6.95-7.03 (m, 3H), 7.27-7.33 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH:26]([CH2:28][CH3:29])[CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][CH:26]([CH2:28][CH3:29])[CH3:27])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCC(C)O/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 79.7 %

Procedure:
To 522 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(sec-butoxyimino)ethyl]-2-(trifluoromethyl)benzamide in 3 ml of acetonitrile, 1 mg of benzophenone was added, and the mixture was irradiated with light for 12 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 416 mg of the desired product as white crystals.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=N1.Cl.[OH-:32].[Na+]>C(O)C>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C:10]3[C:9]4[C:14](=[CH:15][CH:16]=[C:7]([C:4]([OH:5])=[O:32])[CH:8]=4)[N:13]=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)COC(c2ccc3nccc(Cc4ccc(-c5ccccc5)cc4)c3c2)=N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2nccc(Cc3ccc(-c4ccccc4)cc3)c2c1

Procedure:
A mixture of 6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4-(4-phenylbenzyl)-quinoline (132 mg), ethanol (1 ml) and 3N hydrochloric acid (3 ml) was refluxed under heating for 2 hr. Then 6N hydrochloric acid (3 ml) was added and the mixture was refluxed for 4 hr. The mixture was basified with aqueous sodium hydroxide solution, and washed once with chloroform. The aqueous layer was adjusted to pH 4 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give the objective compound (87 mg) as a white powder.
Reaction SMILES: [Br:1]P(Br)Br.O[CH:6]([C:8]1[CH:9]=[C:10]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][C@H:20]([CH3:24])[CH2:19]1)=[CH:14][C:13]2=[O:25])[CH3:7]>ClCCCl.C(OCC)C>[BrH:1].[Br:1][CH:6]([C:8]1[CH:9]=[C:10]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][C@H:20]([CH3:24])[CH2:19]1)=[CH:14][C:13]2=[O:25])[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Solvent: CCOCC
Solvent: ClCCCl
Product: Br
Product: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 225.2 %

Procedure:
A solution of tribromophosphine (0.215 mL, 2.29 mmol) in 1,2-dichloroethane (1 mL) at 10° C. was added dropwise to 8-(1-hydroxyethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (750 mg, 2.08 mmol) suspended in 1,2-dichloroethane (9 mL) under nitrogen. The resulting suspension was stirred at 50° C. for 1 hour. The reaction mixture was allowed to cool to RT under stirring and diluted with diethyl ether (40 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to afford 8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (1.3 g, 124%) as a white solid, which was used without further purification. Mass Spectrum: M+H+ 424.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21](=[CH:26]N(C)C)[C:22](OC)=[O:23])=[C:16]([CH3:30])[CH:15]=1)#[N:13].Cl.C(N(C(C)C)C(C)C)C>O.CC(O)C>[C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:22]=2[OH:23])=[C:16]([CH3:30])[CH:15]=1)#[N:13]
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: COC(=O)C(=CN(C)C)c1cc(F)c(C#N)cc1C
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Combined 6-hydrazinylnicotinic acid (0.73 g, 4.77 mmol), methyl 2-(4-cyano-5-fluoro-2-methylphenyl)-3-(dimethylamino)acrylate (1.375 g, 5.24 mmol), 2-propanol (18 mL), and 0.5M aqueous hydrochloric acid (11.44 mL, 5.72 mmol). After 2 hours, N-ethyl-N-isopropylpropan-2-amine (4.15 mL, 23.83 mmol). After an hour the reaction mixture was diluted with water and washed with IPAc twice. The aqueous phase was acidified to ˜pH=3.5 and stirred for 30 minutes to give a solid which was collected by filtration, washed with water, ethanol, and heptanes, and dried overnight under vacuum to give the title compound (1.20 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H) 7.74 (d, J=7.07 Hz, 1H) 7.91 (d, J=11.62 Hz, 1H) 8.26 (s, 1H) 8.37-8.47 (m, 1H) 8.47-8.56 (m, 1H) 8.96 (dd, J=2.15, 0.88 Hz, 1H). ESI-MS m/z [M+H]+ 339.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([C:18]2[S:26][C:25]3[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=4)=[N:23][CH:22]=[N:21][C:20]=3[CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:8][CH2:9][CH2:10][NH:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:24]2[C:25]3[S:26][C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:19][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Nc2ncnc3cc(-c4ccccc4)sc23)cc1
Reactant: O=CCOCc1ccccc1
Product: c1ccc(COCCNc2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc2)cc1

Procedure:
The title compound was prepared from benzyloxy-acetaldehyde (12 mg, 0.079 mmol) and N-(6-Phenyl-thieno[3,2-d]pyrimidin-4-yl)-benzene-1,4-diamine (150 mg, 0.471 mmol) by a procedure analogous to example 17. RP18-HPLC RT: 7.062 minutes; API MS: 452.58 (M+1) MP: 201-203° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH:30][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: CC(C)(C)CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.196 g, 0.5 mmol), 2,2-dimethylpropan-1-amine (1 ml, 8.5 mmol) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography (EtOAc) gave the title compound. Yield: 0.1 g. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 242° C. MS m/z (rel. intensity, 70 eV) 313 (M+, 6), 298 (32), 257 (14), 256 (bp), 207 (12), 100 (92). [α]=−53° (MeOH).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a suspension of 4-piperidone hydrochloride (3.52 g, 22.9 mmol) in ethanol (40 ml) was added triethylamine (10.8 ml, 91.6 mmol), followed by the addition of 3,4-dichlorobenzyl bromide (5.0 g, 20.8 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Column chromatography with 25% ethyl acetate and 25% dichloromethane in hexanes gave 1-(3,4-dichlorobenzyl)-4-piperidone (4.4 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=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][CH2:16][CH2:17][CH2:18][CH3:19].[NH2-].[Na+].C[N:29](C)C1C=CC=CC=1>O>[NH2:29][C:24]1[CH:25]=[C:20]([CH2:1][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][CH2:16][CH2:17][CH2:18][CH3:19])[CH:21]=[CH:22][N:23]=1
Reactant: CN(C)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCc1ccncc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCc1ccnc(N)c1
Temperature: 150 °C
Yield: 45 %

Procedure:
A mixture of 0.5 molar portion of 4-nonadecylpyridine, 0.59 mole of sodium amide and 1.18 moles of N,N-dimethylaniline was heated at 150° C. for six hours. The reaction mixture, after cooling, was poured into water, and the dimethylaniline layer was separated and dried over anhydrous potassium carbonate. After removal of the solvent in vacuo the residue was stirred in petroleum ether and crystallized from ethyl acetate/ligroin. Yield 45%. Anal. Calcd for C24H44N2: C, 79.93; H, 12.30; N, 7.77. Found: C, 79.63; H, 12.40; N, 7.60. MS (ESIMS): m/z: 360.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3(O)[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[CH:7][C:6]=2[CH:18]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: CN1CCC(O)(c2cc3cc(Cl)ccc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2cc3cc(Cl)ccc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.2 %

Procedure:
To 0.30 gm (1.06 mMol) 5-chloro-2-(1-methyl-4-hydroxy-1,2,3,6-tetrahydropyridin-4-yl)benzothiophene were added 4.0 mL trifluoroacetic acid. The reaction mixture was stirred for two hours at room temperature. The volatiles were removed under reduced pressure and the residue partitioned between aqueous sodium bicarbonate and dichloromethane. The phases were separated and the organic phase dried over sodium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with chloroform containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.336 gm of 5-chloro-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzo-thiophene as an orange powder. A portion of this material was dissolved in ethyl acetate and treated with 1.0 equivalents of oxalic acid. The solution was concentrated under reduced pressure to give the title compound as a rust solid.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][C:6](OC)=[O:7])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1ccc(Cl)cc1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A stirred solution of 10.7 grams (0.045 mole) of methyl 3-cyclopropyl-3-(4-chlorophenyl)propanoate in 45 ml of tetrahydrofuran was cooled to 0° C., and 45 ml of 1.0 M of lithium aluminum hydride in tetrahydrofuran was added slowly during a one hour period. Upon completion of addition, the reaction mixture was stirred at 0° C. for two hours and then was allowed to warm to ambient temperature. The reaction was quenched by the sequential addition of 2 ml of water, 2 ml of aqueous 15% sodium hydroxide, and 6 ml of water. The reaction mixture was taken up in 100 ml of diethyl ether. The solution was filtered, and the filtrate was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 9.3 grams of 3-cyclopropyl-3-(4-chlorophenyl)propan-1-ol.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[O:51]=[C:52]1[NH:1][CH:2]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:31][CH:32]=2)[C:3](=[O:4])[N:5]1[C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8]
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCCCC4)cc3)C2=O)n1
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.16 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (142 μL, 105 mg, 0.81 mmol) and was transferred via cannula to a solution of diphosgene (14 μL, 23 mg, 0.12 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{2,5-dioxo-4-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as a white solid (26 mg, 27%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33](N(OC)C)=[O:34])=[CH:31][CH:30]=1.[Cl-].[NH4+]>C1COCC1.O>[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33]([CH:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[O:34])=[CH:31][CH:30]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Into a 2 L 3-necked round bottom flask fitted with a thermometer, dry nitrogen gas inlet, addition funnel and mechanical stirrer was added diisopropylamine (65 mL, 0.46 mol) in THF (120 mL). Cooled to -20° C. with a isopropyl alcohol/dry ice bath and added a solution of n-butyllithium in hexanes (210 mL of a 2.5M solution, 0.53 mol). Stirred at -15° C. for 30 min, then cooled to -20° C. Added 4-t-butydimethylsilyloxymethylpyridine from Step A (98.2 g, 0.44 mol) neat over a 30 min period. Let stir for 45 min at -20° C. To this mixture was added a solution of 4-fluoro-N-methoxy-N-methyl-benzamide (84.5 g, 0.46 mol) in THF (90 mL) over a 30 min period. The dark solution was stirred at 0° C. for 1 h, then warmed slowly to room temperature for 30 min. The reaction was poured into water (500 mL) containing ammonium chloride (100 g). After stirring for 10 min at room temperature, the solution was extracted with ethyl acetate (3 times). The combined organic extracts were washed successively with water and saturated salt solution. The combined aqueous layers were extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 15-50% ethyl acetate in hexanes (17 L in total). The solvent was removed by rotoevaporation to yield the tide compound as an amber oil (120.4 g, 74% yield).
Reaction SMILES: [C:1]([CH:4]([CH2:21][CH2:22][CH2:23][CH:24]([OH:34])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])(=[O:3])[CH3:2].C(C(CCCC(O)COC1C=CC(F)=CC=1)CCCCCCC(O)=O)(=O)C>>[C:1]([CH:4]([CH2:21][CH2:22][CH2:23][CH:24]([OH:34])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)C(CCCCCCC(=O)OCc1ccccc1)CCCC(O)COCc1ccccc1
Agent: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COCc1ccccc1

Procedure:
The synthesis of this compound is carried out by the hydrolytic procedure of Example 1, Step F, except that an equivalent quantity of benzyl 8-acetyl-12-hydroxy-13-benzyloxytridecanoate is substituted for the ethyl 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoate of Example 1, Step F. The title compound is purified by chromatography on silica gel with 3% methanol in chloroform as eluant.