Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:26]1([CH3:34])[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1>>[O:15]([C:4]1[N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[CH3:34])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc(Oc2ccccc2)nc(Oc2ccccc2)n1
Reactant: Cc1cc(C)cc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(-c2nc(Oc3ccccc3)nc(Oc3ccccc3)n2)c(C)c1

Procedure:
A 250-mL reaction flask fitted with a magnetic stirrer and a condenser is charged with 21.0 g (0.070 mol) of the product of Example 15, 100 mL of mesitylene and 9.30 g (0.070 mol) of aluminum chloride. The mixture is refluxed for three days. The mixture is then poured onto ice and the phases are separated. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to give a brown resin. The crude resin is recrystallized from ligroin to give 7.9 g of the title compound as a white powder melting at 135-143° C.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([CH3:56])[NH2:55]>CN(C=O)C>[CH3:53][N:54]([CH3:56])[NH:55][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NN(C)C)s1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (90 mg, 0.29 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (104 mg, 0.32 mmol), N,N-diisopropyl ethyl amine (250 μL, 1.47 mmol) and 1,1-dimethylhydrazine (0.03 mL, 0.39 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 0 to 2% methanol in dichloromethane) afforded the title compound (45 mg, 44%) as a white solid. MS: m/e=349.3 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.P(Br)(Br)[Br:16].O>ClCCl>[Br:16][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1
Reactant: BrP(Br)Br
Reactant: COc1ccc2c(c1)C(CCO)CC2
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CCBr)CC2
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-6-methoxyindan (4.95 g, 25.7 mmol) in dichloromethane (100 ml) was added dropwise at −5° C. phosphorus tribromide (0.86 ml, 2084 27.0 mmol). The mixture was stirred for 30 minutes. To the reaction mixture was added water, which was subjected to extraction with chloroform. The extract solution was washed with brine and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 7:3→1:1) to give 1.80 g (yield 27%) of the above-titled compound as an oily product.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)(=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:20][N:21]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:22]1=[O:36]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:20][N:21]1[CH2:25][CH2:24][C:23]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)([CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:22]1=[O:36]
Reactant: COc1ccc(COS(C)(=O)=O)cc1
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)C2=O)cc(OC)c1OC
Product: COc1ccc(CC2(CCO[Si](C)(C)C(C)(C)C)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1

Procedure:
Prepare by the method of Example 17.3 using 4-methoxybenzyl mesylate and 1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine to give the title compound: Rf=0.15 (silica gel, 1/4 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([C:5]1([CH2:36][CH2:37][CH2:38][CH3:39])[C:17]2[CH:16]=[C:15]([C:18]#[C:19][C:20]3[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([C:27]#[C:28][C:29]1[S:33][C:32]([CH:34]=O)=[CH:31][CH:30]=1)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[I-].[CH2:41]([N:47]([CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:50][CH:49]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(O[K])(C)(C)C>C(Cl)Cl>[CH2:74]([N:47]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:48]1[CH:49]=[CH:50][C:51](/[CH:54]=[CH:34]/[C:32]2[S:33][C:29]([C:28]#[C:27][C:8]3[CH:7]=[C:6]4[C:11]([C:12]5[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]6[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=6)=[CH:16][C:17]=5[C:5]4([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)=[CH:52][CH:53]=1)[CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: CCCCCCN(CCCCCC)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC1(CCCC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Agent: CC(C)(C)O[K]
Agent: [I-]
Solvent: ClCCl
Product: CCCCCCN(CCCCCC)c1ccc(/C=C/c2ccc(C#Cc3ccc4c(c3)C(CCCC)(CCCC)c3cc(C#Cc5ccc(C=O)s5)ccc3-4)s2)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a solution of 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis-2-thiophenecarboxaldehyde (1.14 g, 2.085 mmol) and [[4-(dihexylamino)phenyl]methyl]triphenylphosphonium iodide (1.66 g, 2.501 mmol) in anhydrous CH2Cl2 (40 mL), was added tBuOK (0.352 g, 3.137 mmol). The mixture was stirred at 20° C. for 16 h, then filtered through a short pad of silica gel. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (heptane/CH2Cl2 gradient from 70:30 to 30:70) to yield 701 mg (42%) of 5-[[7-[[5-[(1E)-2-[4-(dihexylamino)phenyl]ethenyl]thien-2-yl]ethynyl]-9,9-dibutyl-9H-fluorene-2-yl]ethynyl]thiophene-2-carboxaldehyde; 1H NMR (300.13 MHz, CDCl3) δ 9.88 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.69 and 7.35 (AX, JAX=3.9 Hz, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.56-7.49 (m, 4H), 7.33 and 6.61 (AA′XX′, JAX=8.9 Hz, 4H), 7.17 and 6.87 (AX, JAX=3.8 Hz, 2H), 6.95 (d, J=16.0 Hz, 1H), 6.86 (d, J=16.0 Hz, 1H), 3.28 (m, 4H), 2.00 (m, 4H), 1.60 (m, 4H), 1.33 (m, 12H), 1.11 (m, 4H), 0.91 (t, J=6.8 Hz, 6H), 0.69 (t, J=7.3 Hz, 6H), 0.59 (m, 4H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:14][C:15]([OH:19])([C:17]#[CH:18])[CH3:16]>COCCOC.[Cu]I.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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:18]#[C:17][C:15]([CH3:16])([OH:19])[CH3:14]
Reactant: Brc1nccs1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1nccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,3-thiazole (6.0 g, 37 mmol) and CuI (1.3 g, 7.3 mmol) were combined in DME (150 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (25 mL, 180 mmol) and PdCl2(PPh3)2 (2.5 g, 3.7 mmol) were added and 2-methyl-3-butyne-2-ol (4.6 g, 55 mmol) was added dropwise. After stirring at ambient temperature for 16 h, GC/MS showed the reaction was not complete. The reaction was heated to reflux for 2 h. The mixture was filtered through Celite™, the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (600 mL), washed with water (600 mL), brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 7:3 hexane:ethyl acetate to afford 4-(2-thiazolyl)-2-methyl-3-butyn-2-ol contaminated with 2,7-dimethyl-but-3,5-diyne-2,7-diol. (The dimer of 2-methyl-3-butyne-2-ol) The product was crystallized from boiling hexane to afford 2-methyl-4-(1,3-thiazol-2-yl)-3-butyn-2-ol (2.18 g, 36% yield) as off white crystals that were contaminated with a small amount of 2,7-dimethyl-but-3,5-diyne-2,7-diol. M.p. 69-70° C. 1H NMR (CDCl3, 300 MHz) δ 7.80 (d, J=3.0 Hz, 1H), 7.34 (d, J=3.0 Hz, 1H), 4.40 (s, 1H), 1.65 (s, 6H). MS (ESI) 168.1 (M++H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][NH:57][CH3:58])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.CN(C=O)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:57]([C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH3:58])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
To a stirred solution of 4-cyanobenzoic acid (322 mg, 2.19 mmol) in CH2Cl2 (10 mL) was added TBTU (702 mg, 2.19 mmol) and N,N-diisopropylethylamine (1.14 mL, 6.54 mmol) and the reaction mixture stirred at RT for 10 min. 4-Methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.19 mmol) in DMF (4 mL) was added and the reaction mixture was stirred at RT for 2 h. The crude material was concentrated in vacuo and purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 100% EtOAc to afford 4-{[(4-cyano-benzoyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a orange solid (700 mg, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@@H](CO)c2nc3cc(Br)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:13]1CCCC1.C(O[CH:21]=[CH:22][C:23](=O)[C:24]([F:27])([F:26])[F:25])C.C([O-])(=O)C.[NH4+]>O1CCOCC1.O.C1(C)C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[C:23]1[CH:22]=[CH:21][C:3]2[CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=2[N:13]=1
Reactant: C1CCNC1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCc2nc(C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.3 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (3.0 g, 17 mmol), pyrrolidine (3.6 mL, 43 mmol, 2.5 equiv.) and toluene (50 mL) was heated to reflux with azeotropic removal of water. After 17 h the reaction was judged complete, and the cooled mixture was concentrated. The residue was taken up in ether (100 mL), dried (MgSO4), filtered and concentrated to afford crude enamine as an oil (3.97 g). The crude enamine (assumed 17 mmol) was dissolved in 1,4-dioxane (50 mL), and the solution cooled to 10° C., before a solution of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (3.5 g, 21 mmol) in 1,4-dioxane (10 mL) was added dropwise over 10 min to the yellow suspension, which rapidly clarified and darkened to a deep red-brown. The mixture was allowed to warm to room temperature overnight. After 18 h ammonium acetate (2.7 g, 35 mmol, 2 equiv.) was added, and the mixture heated to reflux for 2.5 h. The mixture was concentrated to an oil. Chromatography on silica (0-20% EtOAc/hexane) afforded the desired trifluoromethylpyridine as an oil (1.27 g, 27%). 1H NMR (400 MHz, CDCl3) [δ] 7.57 (d, J=7.9 Hz, 1JH), 7.44 (d, J=7.9 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.18-2.96 (m, 4H), 2.85-2.76 (m, 1H), 2.48-2.39 (M, 1H), 2.09-1.97 (m, 1H), 1.29 (t, J=7.2 Hz, 3H); m/z=274.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[K].O.C[C:29](OC(C)=O)=[O:30]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:14][C:29](=[O:30])[C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: O=COC(=O)c1ccccc1
Agent: [K]
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)OC2=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 21.4 g (0.10 mol) of 4-(methylsulfonyl) phenylacetic acid [Forrest, et al., J. Chem. Soc. (1948), 1501-1506] and 18.8 g (0.10 mol) of potassium benzoyl formate in 200 mL of Ac2O is stirred and refluxed for 2 h. The reaction mixture is cooled to r.t. and poured into 1L of H2O and stirred until the Ac2O dissolves (ca. 2h). The precipitate is filtered and dried to obtain the title compound. If desired, it is recrystallized from HOAc or acetone.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH3:8])[C:3]1=[O:16].[F:17][C:18]1([F:31])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>>[F:31][C:18]1([F:17])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]([CH:2]2[CH2:6][CH2:5][N:4]([C@H:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH3:8])[C:3]2=[O:16])[CH2:19]1
Reactant: Oc1ccc(C2CCNCC2(F)F)cc1
Reactant: C[C@@H](c1ccc(F)cc1)N1CCC(Br)C1=O
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(F)cc1)N1CCC(N2CCC(c3ccc(O)cc3)C(F)(F)C2)C1=O
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (from Example 50, step B) (0.145 g, 0.51 mmol), 4-(3,3-difluoropiperidin-4-yl)phenol (0.06 g, 0.28 mmol, E-2a from Example 56 step B) and 0.2 mL of triethylamine (1.4 mmol) was heated at 120° C. for 1 h. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, and then it was dried over Na2SO4, filtered, and concentrated to afford 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one as a pair of diastereomers. These diastereomers were separated via preparative HPLC (method B) to yield 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one homochiral Examples 56 P-1 (10.7 mg) and P-2 (5.5 mg). The relative and absolute configurations of Examples 56 P-1 and P-2 were not determined and are arbitrarily named P-1 and P-2 based on the order of elution during the HPLC purification. Data for P-1: pale yellow solid; LCMS (method O) RT 1.21 min (95.8% AP) m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (m, 3H) 1.78-1.90 (m, 1H), 1.90-2.01 (M, 1H), 2.1-2.2 (m, 1H), 2.21-2.35 (m, 1H), 2.49 (m, 1H), 2.80-2.99 (m, 1H), 3.01-3.10 (m, 4H), 3.33-3.38 (m, 3H), 3.63 (t, 1H), 5.40 (m, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.38-7.41 (m, 2H); 19F NMR δ ppm-76.948, -102.623, -103.262, -115.103, -115.743, -117.043. Data for P-2: solid; LCMS (methods N, O) 99% AP; 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=7.03 Hz, 3H) 1.79-1.90 (m, 1H) 2.01-2.23 (m, 3H) 2.62-2.72 (m, 1H) 2.86-3.19 (m, 5H) 3.40-3.74 (m, 2H) 4.36-4.56 (m, 1H) 5.28-5.48 (m, 1H) 6.76 (d, J=9.04 Hz, 2H) 7.08-7.19 (m, 4H) 7.30-7.42 (m, 2H); 19F NMR δ ppm-76.938, -102.480, -012.630, -103.120, -103.146, -103.269, -114.559, -115.124, -115.199, -115.763, -116.990, -117.049.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 80% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[O:26][CH3:27])=[CH:5][CH:4]=1)[CH3:2].[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].C(OCC)(=O)C>C(O)C>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][NH:17][CH2:16]3)=[CH:11][C:10]=2[O:26][CH3:27])=[CH:28][CH:29]=1)[CH3:2]
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2OC)cc1
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1ccc(COc2ccc(C3CNC3)cc2OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carboxylate (32.4 g) prepared in (2) in ethanol (160 mL) was added methanesulfonic acid (6.3 mL). The reaction mixture was stirred at 80° C. for 3 hr. Ethyl acetate (320 mL) was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (24.3 g, 77%).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:12]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3]>[Pd].C(O)C>[C:23]([O:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:8]([OH:9])[CH2:7][NH:6][C:2]([CH3:3])([CH3:5])[CH3:4])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)CCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCC(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)CCC
Reaction time: 8 h

Procedure:
A mixture of 30 g. of 3,4-bis(butyryloxy)phenyl N-tert-butylaminomethyl ketone hydrochloride, 200 ml. of 90 percent ethyl alcohol, and 2 g. of 10 percent palladium-on-charcoal hydrogenation catalyst was hydrogenated for two hours at 50° C. under an initial hydrogen pressure of 50 pounds per square inch. The hydrogenation mixture was filtered to remove the catalyst. The solvent was evaporated from the filtrate under reduced pressure and the resulting residue was taken up in 50 ml. of isopropyl alcohol, allowed to stand overnight at 5° C., and filtered to remove 3 g. of solid. The filtrate was evaporated under reduced pressure, the residue thus obtained was dissolved in 50 ml. of isopropyl acetate, and this solution was filtered to remove a small amount of insoluble solid. When the filtrate was diluted with anhydrous diethyl ether, a solid separated from solution. This solid was collected on a filter. There was thus obtained 20 g. of crude 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. This salt was dissolved in water and then ammonium hydroxide was added, resulting in precipitation of the free base, 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol. This precipitate was collected on a filter and washed well first with water and then with n-hexane. This base, which melted at 97°-99° C. (uncorr.), was dissolved in isopropyl alcohol and this solution was concentrated under reduced pressure. The resulting residue was dissolved in 30 ml. of isopropyl acetate and there was added ethereal hydrogen chloride solution in an amount affording a slight excess of the required amount of hydrogen chloride for conversion of the base to the hydrochloride. The mixture was cooled and the inside of the container was scratched to induce crystallization. The mixture was diluted with 100 ml. of diethyl ether and the solid precipitate was collected on a filter and washed with anhydrous diethyl ether and dried at 70° C. There was thus obtained 11 g. of 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 136°-138° C. (uncorr.). This salt was soluble in water to the extent of at least 20 percent. The pH of a 1 percent aqueous solution of this salt was 6.0; and a precipitate formed when the pH of this solution was raised to 7.0 by addition of N/10 sodium hydroxide solution.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](/[CH:14]=[C:15](\[S:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])/[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:17])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:36]I.[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](/[CH:14]=[C:15](\[S:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])/[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:17])=[CH:10][N:11]2[CH3:36])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)/C(=C/c2c[nH]c3cc(NC(C)=O)ccc23)SCC(O)CO)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)/C(=C/c2cn(C)c3cc(NC(C)=O)ccc23)SCC(O)CO)cc(OC)c1OC
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Compound 125 (300.0 mg) obtained in Example 125 was dissolved in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), and methyl iodide (93.6 mg) and then sodium hydride (26.4 mg, 60% mineral oil dispersion) were added thereto, followed by stirring for 1.5 hours. The reaction solution was subjected to partitioning between chloroform and water, and the organic layer was successively washed with water and a saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude crystals were washed with chloroform and recrystallized from a mixed solvent of ethanol, N,N-dimethylformamide, and water to give Compound 126 (249.7 mg).