Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(F)cc1F)C(=O)O

Procedure:
Analogously to Example 1i), 3.1 g (7.18 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,4-difluorophenyl)methyl]-dihydrofuran-2-(3H)-one in 77 ml of dimethoxyethane and 19 ml of water are hydrolysed with 28.7 ml of 1M lithium hydroxide solution (19 h RT): tRet (I)=14.7 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])(C)[CH3:6].C[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:21](N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[CH:5]([N:8]([CH3:21])[S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1)(=[O:19])=[O:18])[CH3:6]
Reactant: COC(=O)C(C)(C)N
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
methyl-2-amino-2-methylpropanoate hydrochloride (2 g, 13.1 mmol) was dissolved in CH2Cl2 (50 ml), and added with 2-methylbenzene-1-sulfonylchloride (2.74 g, 14.4 mmol) and triethylamine (14 ml, 52.4 mmol), followed by stirring for 12 hours at room temperature. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-(methylphenylsulfonamido)propanoate (3.2 g, 11.7 mmol, 90%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32]I>>[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCCCI
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 90.9 %

Procedure:
Step AAL (1): 2-(4-(Methylthio)phenyl)acetic acid (1.00 g, 5.49 mmol) was deprotonated with NaHMDS 2.0 M in THF (5.49 mL, 11.0 mmol) and reacted with 1-chloro-4-iodobutane (0.672 mL, 5.49 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(methylthio)phenyl)hexanoic acid (1.36 g, 4.99 mmol, 91% yield) as a pale-yellow oil. LC-MS (M−H)− 271.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.95 (1 H, br. s.), 7.12-7.28 (4 H, m), 3.39-3.55 (3 H, m), 2.39-2.50 (3 H, m), 1.97-2.19 (1 H, m), 1.59-1.86 (3 H, m), 1.28-1.51 (2 H, m).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:16][CH3:17])(OC)(=O)=O.C(#N)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH3:4])[C:17](=[O:16])[CH:3]=1
Reactant: COc1cnc(Cl)cc1Br
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cn(C)c(=O)cc1Br
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-chloro-5-methoxypyridine (1 g, 4.5 mmol) in dimethyl sulfate (1.9 mL, 19.5 mmol) was stirred at 120° C. for 16 h in a sealed tube. After cooling, acetonitrile and a saturated aqueous NaHCO3 solution were added and the mixture was stirred at rt over week-end. DCM was added and extracted. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound. tR: 0.57 min (LC-MS 2); ESI-MS: 218.0/220.0 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:13]([F:14])=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:11]([F:20])=[CH:10][C:6]=2[C:7]([OH:9])=O)[CH2:3][CH2:2]1.[C:21]([N:28]1C=CN=C1)(N1C=CN=C1)=[O:22].C(N(CC)CC)C.Cl.[C:41]([O:45]N)([CH3:44])([CH3:43])[CH3:42]>C1COCC1.O>[C:41]([O:45][N:28]1[C:7](=[O:9])[C:6]2[C:5](=[C:13]([F:14])[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[N:4]([CH:1]2[CH2:2][CH2:3]2)[C:21]1=[O:22])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)ON
Reactant: O=C(O)c1cc(F)c(N2CCCC2)c(F)c1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)On1c(=O)c2cc(F)c(N3CCCC3)c(F)c2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 2-cyclopropylamino-3,5-difluoro-4-pyrrolidin-1-yl-benzoic acid (Example T-3, 1.65 g, 5.85 mmol) in THF (20 mL) was reacted with carbonyldiimidazole (1.2 g, 7.31 mmol) and stirred overnight at ambient temperature. The mixture was reacted with triethylamine (1.22 mL, 8.77 mmol) and O-t-butyl hydroxylamine hydrochloride (1.10 g, 8.77 mmol) and allowed to stir for 4 hours. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The resulting residue was dissolved in THF (15 mL), reacted with carbonyldiimidazole (2.44 g, 15.0 mmol), and heated to 100° C. in a sealed tube for 5 days. The mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The organic layer was washed with H2O, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 0.52 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]12[C:9](=NO)[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2.[OH2:12]>C(O)(=O)CCC(C)=O>[CH3:1][C:2]12[C:9](=[O:12])[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2
Reactant: O
Reactant: CC12CCC=CC1CC2=NO
Agent: CC(=O)CCC(=O)O
Product: CC12CCC=CC1CC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 120 mg of 6-methylbicyclo[4.2.0]oct-2-en-7-one oxime, prepared as shown in Preparation 19, in 4 ml of levulinic acid/1N hydrochloric acid (9/1) was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with hexane. The combined hexane extracts were washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Solvent was carefully removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 10% ethyl acetate in hexane, to give 6-methylbicyclo[4.2.0]oct-2-en-7-one, the compound of formula (8).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ICC1CCOCC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl (4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25–1.45 (3H, m), 1.55–1.65 (2H, m), 1.70–1.80 (1H, m), 2.05–2.15 (1H, m), 3.25–3.35 (2H, m), 3.79 (1H, t), 3.90–3.95 (2H, m), 4.10–4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0 M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP—HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].[OH-].[Na+]>O.CCOCC>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: O=C=O
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a stirred, chilled (-70° C.) solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (15.0 g) and ether (500 ml) was added n-butyl lithium (20.5 ml, 2.5M solution in hexanes) over 15 mins., under a nitrogen atmosphere. The mixture was stirred 1.5 hr, and was transferred under nitrogen to a vessel containing a large excess of dry ice and ether (500 ml). The suspension was stirred at room temperature overnight. The mixture was poured into water (1 L) and the mixture was basified with 2.5N sodium hydroxide solution. The organic phase was removed. The aqueous phase was acidified with 10% hydrochloric acid and extracted with dichloromethane. The combined, dried over anhydrous sodium sulfate, organic phase was concentrated, and the residue was recrystallized from toluene to give 7.10 g (52.8%) of product, mp 196°-197° C.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[C:3]([F:8])([F:7])[C:4]([F:6])=[O:5].C(O)(=[O:18])CCC.C(OC(=O)CCC)(=O)CCC>>[F:10][C:9]([F:12])([F:11])[C:2]([F:13])([F:1])[C:3]([F:8])([F:7])[C:4]([OH:18])=[O:5].[C:4]([F:6])(=[O:5])[CH2:3][CH2:2][CH3:9]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCC(=O)O
Agent: CCCC(=O)OC(=O)CCC
Product: CCCC(=O)F
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
The following run illustrates the metathetical reaction of impure heptafluorobutyryl fluoride with butyric acid in the presence of butyric anhydride to give heptafluorobutyric acid and butyryl fluoride and the recovery of products from the reaction mixture by fractional distillation.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[C:18]#[N:19])#[CH:12].N>>[F:21][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(F)c(C#N)c1
Agent: N
Product: N#Cc1cc(-c2cc(-c3cccnc3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and the product of Example 68A (73 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.49 (s, 1H), 7.52-7.68 (m, 2H), 8.28 (ddd, J=8.8, 5.1, 2.4 Hz, 1H), 8.33-8.41 (m, 2H), 8.68 (dd, J=4.9, 1.5 Hz, 1H), 9.09 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: O.C(O)(=O)C.[N+:6]([C:9]1[C:10]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)([O-])=O>[Fe].C(O)C>[F:24][C:21]([F:22])([F:23])[CH2:20][NH:19][C:10]1[C:9]([NH2:6])=[CH:14][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1NCC(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A mixture of an iron powder (2.12 g), ethanol 6 ml), water 4 ml) and acetic acid 0.1 ml) was added dropwise a mixture of (3-nitro-5-trifluoromethylpyridin-2-yl)-(2,2,2-trifluoroethyl)amine (1.83 g) and ethanol (10 ml) at 70° C., and then the mixture was stirred at 70° C. for 1 hour. After allowing to cool, the cooled reaction mixture was filtrated. To the filtrate was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give N2-(2,2,2-trifluoroethyl)-5-trifluoromethylpyridin-2,3-diamine (1.59 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([N:17]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)C(=O)C(F)(F)F)[CH:9]=2)[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([NH:17][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(CO)c(NC3CCOCC3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
500 mg (1.060 mmol) of 4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid dissolved in 5 ml of tetrahydrofuran is added at 0° C. to a suspension of 201 mg (5.30 mmol) of LiAlH4 in 9 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture is cooled at 0° C. and then, drop by drop, 200 μl water, then 200 μl of soda solution (15% by weight) and finally 1 ml of water are added. The reaction mixture is stirred at room temperature for 2 hours and then filtered and rinsed with tetrahydrofuran. The filtrate is concentrated to yield 250 mg (yield=77%) of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol in the form of a white solid.
Reaction SMILES: O.[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:4][CH3:5])[CH3:3].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=1)([CH2:4][CH3:5])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CCC(C)c1ccc(O)cc1
Solvent: O
Solvent: CCOCC
Product: CCC(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 10.0 g of 4-sec-butylphenol was added dropwise, 7.5 ml of 61% nitric acid was added dropwise while cooling with ice. After, the temperature of the mixture was raised to room temperature and the reaction was continued for 4 days. The reaction mixture was extracted with 300 ml of ethyl acetate, washed with a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 14.71 g of 4-sec-butyl-2-nitrophenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.C(Cl)(=O)C(Cl)=O.[CH:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH2:33]([N:32]([CH:29]([CH3:31])[CH3:30])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(Cc1ccccc1)C(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (4.321 g, 14.25 mmol) in CH2Cl2 (100 mL) and DMF (2 drops) was added oxalyl chloride (1.5 mL, 2.21 g, 17.5 mmol) dropwise. Most solids dissolved at first, later a precipitate formed. The suspension was stirred for 1 hour at 0° C., and then allowed to warm to room temperature (all solids dissolved). The solution was concentrated to a dark oil, which crystallized upon standing. The crude acid chloride was taken up in toluene (50 mL, distilled, dried over Na2SO4) and cooled in ice. N-Isopropylbenzylamine (9.5 mL, 8.5 g, 56.8 mmol) was added. The resulting suspension was stirred at room temperature for 90 minutes, washed with water and a saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1). All fractions containing the product were combined and concentrated. Some of the excess amine eluted with the product. A solution of the mixture in CH2Cl2 (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25.mL), and saturated aqueous NaCl solution (25 mL), dried over Na2SO4, and concentrated to give pure 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide as a yellowish foam (5.685 g, 13.08 mmol, 92%).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[CH2:22][OH:23])[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][CH3:18].[CH2:35]([O:53][CH2:54]C(N)CO)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CCCCCCCCCCCC.C(C1C=CC=C2C(NC(=O)C=12)=O)(OCC)=[O:60]>>[CH2:1]([O:19][CH2:20][CH:21]([N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29])[CH2:22][O:23][C:54]([O:53][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:60])[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][CH3:18]
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(N)CO
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)N1C(=O)c2ccccc2C1=O
Product: CCCCCCCCCCCCCCCCCCOCC(COC(=O)Oc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
3-Octadecyloxy-2-phthalimidopropan-1-ol used as the starting material was synthesized by reacting 3-octadecyloxy-2-aminopropane-1-ol as produced in Example 18-(i) with carboethoxyphthalimide.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.O[CH:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:18](SC1C=CC(O)=CC=1)[C:19]([O:21][CH3:22])=[O:20].C[OH:52]>>[OH:52][CH:18]([CH:17]([S:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: Oc1ccc(S)cc1
Reactant: COC(=O)C(Sc1ccc(O)cc1)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(O)C(Sc1ccc(O)cc1)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C

Procedure:
The compound of Example 1(c) (722 mg, 2 mmol) was dissolved in methanol (10 ml) containing 2% triethylamine and the solution was stirred under argon at room temperature. Triethylamine (1.68 ml, 12 mmol) and 4-hydroxythiophenol (428 mg, 3.4 mmol) were dissolved in methanol (15 ml) and added to the reaction mixture which was then stirred overnight at room temperature. The solvent was evaporated and the residue was flash chromatographed on 80 grams of silica gel eluted with 30% ethyl acetate/hexane to give a mixture of the desired product and its regioisomer, methyl 3-hydroxy-2-(4-hydroxyphenylthio)-3[2-(8-phenyloctyl)phenyl]propionate. The mixture of regioisomers was dissolved in methanol (20 ml) and stirred under argon at room temperature. Sodium methoxide, 25 wt. % in methanol, (0-92 ml, 4 mmol) was added dropwise and the mixture-stirred for 2.5 hours. The mixture was cooled in an ice bath and acetic acid (0.3 ml, 5.2 mmol) was added dropwise. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product which was flash chromatographed on 80 grams of silica gel eluted with 25% ethyl acetate/hexane to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N([CH2:20][CH3:21])CC)C>CCO>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C@@H:20]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Temperature: 0 °C
Yield: 41275.6 %

Procedure:
To EtOH (55 ml) cooled to 0° C. was added acetyl bromide (41 ml, 0.6 mol) dropwise, followed by a solution of (S)-4-methyl-dihydro-furan-2-one (Tetrahedron 1983, 39, 3107; 18.6 g, 0.2 mol) in EtOH (20 ml). The ice bath was removed and the reaction allowed to reach RT. After 2 h of stirring the reaction was concentrated, the residue redissolved in CH2Cl2, washed with sat. aq. NaHCO3 solution, dried (Na2SO4) and concentrated affording (S)-4-bromo-3-methyl-butyric acid ethyl ester (33.6 g, quant). This was redissolved in EtOH (100 ml), cooled to 0° C. and N-benzylglycine ethyl ester (28.2 g, 0.14 mol) and triethylamine (22.4 ml, 0.16 mmol) were added. The reaction was then warmed to 75° C. for 4 d after which time the reaction was concentrated, the residue redissolved in CH2Cl2, washed with sat. aq. NaHCO3 solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/heptane 5:95) afforded the titled product as a light gold oil (20.3 g, 43%). MS (ISP)=322.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.N1CCCCC1.[CH2:34]([OH:39])[CH2:35][CH2:36][C:37]#[CH:38].Cl>[Cu]I>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][OH:39])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCCO
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To 3.3 g (7.72 mmol) Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester in 20 ml piperidine 447.0 mg (3.9 mmol) tetrakis(triphenylphosphine)palladium and 73.6 mg (3.9 mmol) CuI were added. At 80° C. 1.43 ml (15.45 mmol) 4-pentyn-1-ol were added slowly, and the solution was stirred for an additional hour. The cooled solution was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 30:1 yielded 2.7 g (96%) 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as orange oil, MS: 361 (M).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-c2ccccn2)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 415 [M+1]+.