Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][CH2:33]SC)[C:13]([NH:15][C@H:16]1[CH2:22][CH2:21][C@@H:20]2[CH2:23][C@H:17]1[C:18](=[O:31])[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:32][CH2:33][N:15]([C@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][C@H:17]2[C:18](=[O:31])[N:19]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H]2C[C@H]1C(=O)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
Preparation A3, Step 3: (1R,2S,5R)-Tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (5.1 g) was dissolved in iodomethane (40 mL). The resulting solution was stirred at rt for 12 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. This material was dissolved in DMF (30 mL) and the solution was charged with Cs2CO3 (6.6 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.0 g). MS found: (M+H)+=458.6.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Cl:16][C:17]1[C:18]([O:35][CH3:36])=[C:19]([C:32](=O)[CH3:33])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:31])[CH3:30]>>[Cl:16][C:17]1[C:18]([O:35][CH3:36])=[C:19](/[C:32](/[CH3:33])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: COc1c(C(C)=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.2 mL, 1.07 mmol) and 1-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 144, 930 mg, 2.88 mmol) were reacted to give the title compound as a light yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: Br[CH:2]=[CH:3]Br.[O:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH2:13])[CH2:7][CH2:6]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@H:21]2[C@@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:2][CH2:3][NH:13][CH2:12][CH2:11][N:8]4[CH2:9][CH2:10][O:5][CH2:6][CH2:7]4)[C:24]3=[O:32])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: NCCN1CCOCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: BrC=CBr
Product: O=C1N(CCNCCN2CCOCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 81 starting from dibromo ethylene, 2-morpholinoethanamine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H28ClN3O2: 425, observed (M+H)+: 426.2 1HNMR (400 MHz, MeOD-d4) δppm 2.09-2.34 (m, 3 H) 3.02 (br. s., 4 H) 3.17 (t, J=6.19 Hz, 2 H) 3.27 (t, J=8.72 Hz, 1 H) 3.44-3.61 (m, 4 H) 3.87 (t, J=4.67 Hz, 4 H) 4.12-4.45 (m, 2 H) 6.11 (d, J=7.83 Hz, 1 H) 6.80 (t, J=7.58 Hz, 1 H) 7.10-7.18 (m, 1 H) 7.20-7.27 (m, 3 H) 7.29-7.40 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([F:26])[CH:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][NH:16][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[CH:19][C:20]=1[F:26])#[N:23]
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)cc1F
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)c(F)c2)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 15.1) was coupled with 4-aminomethyl-2-fluorobenzonitrile (CAS 368426-73-7) according to general procedure B to give (RS)-N-(4-cyano-3-fluoro-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light yellow solid. MS 347.3 ([M+H]+)
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:39][NH2:40])=[O:38])[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>O1CCCC1>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]4[O:38][C:41](=[O:42])[NH:40][N:39]=4)[CH2:19][CH2:20][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[C:26]=4[F:35])[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)n1nccc1Nc1cccc(CC2(C(=O)NN)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Solvent: C1CCOC1
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 68.5 mg of 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(2-fluoro-3-(trifluoromethyl)benzoyl)piperidine-4-carbohydrazide in 5 ml of tetrahydrofuran was added 23.7 mg of 1,1′-carbonyldiimidazole at room temperature. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1 to ethyl acetate) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3]C(C)(C)C)=O.[CH2:20]([NH:27][CH2:28]C(OCC)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:20]([N:27]1[CH2:28][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C1CN(Cc2ccccc2)C(=O)[C@H](Cc2ccccc2)N1
Yield: 88.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using Boc-L-phenylalanine (12.8 g, 48.2 mmol), ethyl N-benzylglycinate (9.32 g, 48.2 mmol) and dicyclohexylcarbodiimide (96.5 mL 0.5M in dichloromethane, 48.2 mmol). The crude diketopiperazine was triturated with hexane to give the title compound as a white powder (12.5 g). NMR (300 MHz, CD3OD) δ 7.0-7.4 (10H, m), 4.61 (1H, d, J=16 Hz), 4.37 (1H, t, J=5 Hz), 4.24 (1H, d, J=16 Hz), 3.42 (1H, d, J=18 Hz), 3.28 (1H, dd, J=4, 16 Hz), 2.96 (1H, dd, J=6, 16 Hz), 2.55 (1H, d, J=18 Hz).
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1.[CH:23]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[ClH:32].CCO>CC(O)C>[ClH:32].[OH:1][CH:2]([CH2:22][NH:31][CH:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[C:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1
Reactant: O=c1c(-c2ccccc2)coc2cc(OCC3CO3)ccc12
Reactant: NC1CCCCCCC1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)coc2cc(OCC(O)CNC3CCCCCCC3)ccc12

Procedure:
Using Method B, the reaction of 7-(2,3-epoxypropoxy)isoflavone with cyclooctylamine followed by acidification of the resulted free base with HCl/EtOH gave the hydrochloride as light yellow prisms, m.p. 185°-186° (iPrOH).
Reaction SMILES: [NH3:1].[C:2]([CH2:4][CH2:5][N:6]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][C:8]([OH:10])=[O:9])#[N:3]>>[C:2]([CH2:4][CH2:5][N:6]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][C:8]([O-:10])=[O:9])#[N:3].[NH4+:1]
Reactant: N
Reactant: CCCCCCCCCCCC(=O)N(CCC#N)CC(=O)O
Product: CCCCCCCCCCCC(=O)N(CCC#N)CC(=O)[O-]
Product: [NH4+]

Procedure:
28% aqueous ammonia was gradually added to the N-cyanoethyl-N-dodecanoylglycine obtained in Example 2 to thereby adjust the pH of the system to 6.5. Thus, an aqueous solution of ammonium N-cyanoethyl-N-dodecanoylglycinate was obtained.
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][O:14][C:9]2=[CH:8][CH:7]=1.[Br:15][C:16]1[C:17]([O:25][CH3:26])=[C:18]([C:21]([F:24])=[CH:22][CH:23]=1)[CH:19]=[O:20].[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[O:14]1[C:13]([CH:19]([C:18]2[C:21]([F:24])=[CH:22][CH:23]=[C:16]([Br:15])[C:17]=2[O:25][CH3:26])[OH:20])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: COc1c(Br)ccc(F)c1C=O
Reactant: c1ccc2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)ccc(F)c1C(O)c1cc2ccccc2o1
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 1.12 g of 2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 10 minutes, the mixture was stirred under ice-cooling for 15 minutes and was then stirred at −78° C. for 8 minutes. Then, a solution of 2 g of 3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride solution was added at the same temperature. Water was added at room temperature and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 2 g of the title compound as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(C[O:46][S:47]([CH3:50])(=O)=O)=CC(C2C=CC(S(C)=O)=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:47]([CH3:50])=[O:46])=[CH:23][CH:22]=2)=[N:17]1)[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(S(C)=O)cc2)cc(COS(C)(=O)=O)c1=O
Agent: CN1CCNCC1
Product: Cc1c(-c2ccc(S(C)=O)cc2)nn(CC(C)C)c(=O)c1N1CCN(C)CC1
Yield: 61.8 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13]C(OCC=C)=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CO>[NH3:7].[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)N[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N)C1
Product: N
Yield: 0 %
Yield: 56 %

Procedure:
Following the procedure for ((1R,3R)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester the title compound was prepared from ((1R,3S)-3-allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester with further purification by column chromatography on silica gel (gradient: 0 to 5% methanol in DCM then 0 to 10% 2M NH3 in methanol solution in DCM) to afford 300 mg (56%) of ((1R,3S)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester. LCMS (Method I, ESI): RT=0.32 min, m+H-Boc=101.2; 1H NMR (400 MHz, DMSO) δ: 6.84 (s, 1H), 3.77-3.69 (m, 1H), 3.21 (m, 2H), 2.00 (m, 1H), 1.78-1.63 (m, 2H), 1.50 (m, 1H), 1.37 (s, 9H), 1.17 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1OC2(CCCN(Cc3ccccc3)C2)c2ccccc21
Product: c1ccc(CN2CCCC3(C2)OC(c2ccccc2)(c2ccccc2)c2ccccc23)cc1

Procedure:
Reaction of 1'-benzyl-1,3-dihydrospiro[isobenzofuran-1,3'-piperidine]-3-one with a large excess of phenyllithium by the method described in Example 1 provides off-white crystals, m.p. 144°-146°.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:14][CH:13]=4)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
A stirred mixture of 4-ethylsulfonylbenzoic acid (0.64 g, 3.00 mmol) and CDI (0.51 g, 3.15 mmol) in N,N-dimethylformamide (34 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (150 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient). The product fractions were combined and concentrated to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethanesulfonyl-benzamide as a white solid (0.63 g, 44% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.66 min (97.99%); mp: 182-184° C.; 1H NMR (DMSO-d6) δ 1.11 (t, J=7.4 Hz, 3H), 2.00-2.18 (m, 1H), 2.54-2.68 (m, 2H), 2.80-2.99 (m, 1H), 3.35 (q, J=7.4 Hz, 2H), 4.68 (d, J=5.7 Hz, 2H), 5.15 (dd, J=5.3, 12.8 Hz, 1H), 7.77-7.97 (m, 3H), 7.98-8.07 (m, 2H), 8.08-8.25 (m, 2H), 9.49 (t, J=5.8 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 7.06, 21.99, 30.93, 42.77, 49.02, 122.08, 123.58, 128.03, 128.32, 129.90, 131.63, 133.53, 138.50, 140.85, 147.11, 165.24, 166.96, 167.10, 169.82, 172.75; LCMS: MH=484; Anal Calcd for C23H21N3O7S+0.45H2O: C, 56.19; H, 4.49; N, 8.55. Found: C, 55.87; H, 4.47; N, 8.28.
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Se](=O)=[O:22]>>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Yield: 70.6 %

Procedure:
Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (0.3 g.) and selenium dioxide (0.11 g.) were treated according to a similar manner to that of Preparation 6-4) to give brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].C1(=O)C=CC(=O)C=C1.CCOCC>C(O)C>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[S:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Solvent: CCOCC
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccccc4s3)cc2)S1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a suspension of 5-(4-formylbenzylidene)-2,4-thiazolidinedione (50 mg, 0.21 mmol) and 2-aminothiophenol (0.025 mL, 0.23 mmol) in ethanol (7 mL) was heated to reflux for 10 h. 1,4-Benzoquinone (24 mg, 0.22 mmol) was added, and the mixture was heated additional 1 h. The mixture was cooled to room temperature, ether (3 mL) was added, and the precipitated product was collected by filtration to afford 2-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]benzothiazole (53 mg, 75%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][O:31][CH:28]([CH3:30])[CH3:29])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CC(C)O
Product: CC(C)OCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 21 except starting with N-(1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-2-bromoacetamide and isopropanol, the title compound was obtained as a white solid (39%), mp 134.5°-5.5° C.; MS(CI): 405 (M+H); NMR (300 MHz,DMSO-d6): 1.10(d, 6H, J=6.0 Hz), 1.52-1.61(br m, 4H), 2.28(br m, 2H), 2.46(s, 2H), 2.95(br m, 2H), 3.35(s, 2H), 3.58(septet, 1H, J=5.7 Hz), 3.65(br s, 1H), 3.78(s, 2H), 4.31(s, 1H), 6.92(br m, 4H), 7.19(d, 2H, J=7.0 Hz), 7.27(d, 2H, J=6.5 Hz), 7.34(d, 1H, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[OH-].[Na+].Cl>ClCCl.C1COCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:16])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)C1CCCCC1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of 4-aminophenol (5.00 g, 45.8 mmol) in dichloromethane (50 ml) were added cyclohexanecarbonyl chloride (6.72 g, 45.8 mmol) and pyridine (3.70 ml, 45.8 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. Water (100 ml) was added, the dichloromethane was removed by evaporation and the resulting solution was extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with water (2×200 ml), dried, filtered and evaporated, yielding an off-white solid. The crude product was purified by flash column chromatography (SiO2, ethyl acetate/heptane (2:3)), yielding a mixture of two compounds, which were dissolved in THF. 6N NaOH (aq, 32 ml) was added and the mixture was stirred at room temperature for 2.5 h. The solution was acidified with concentrated hydrochloric acid. The THF was removed by evaporation. The solid material was collected by filtration, dried in vacuo and recrystallised (ethyl acetate/heptane), yielding the title compound (4.20 g, 41%, off-white solid).
Reaction SMILES: [CH2:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[O:13]C)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[C:22]1[CH:31]=[CH:30][CH:29]=C[C:23]=1[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.O.[Cu]I>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:31][CH:30]=[CH:29][C:12]=1[O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:13])[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(OC)cccc1OC
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1c(O)cccc1Oc1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 13 %

Procedure:
2-Butyl-1,3-dimethoxybenzene (14.98 g, 77.6 mmol) was de-methylated as described above for the preparation of Example 10(B) to provide 19 g crude product as a brown oil. A solution of 15 g of this material and potassium tert-butoxide (9.70 g, 86.5 mmol) in pyridine (150 mL) was added to a second solution of methyl 2-iodobenzoate (11.9 g, 180 mmol) and copper(I) iodide (17.3 g, 91.0 mmol) in pyridine (150 mL). The resulting mixture was refluxed for 36 hours. The mixture was cooled to room temperature, diluted with water, and extracted three times with diethyl ether. The combined ether fractions were filtered through a mat of Celite®, washed once with 5N aqueous hydrochloric acid, once with 2N aqueous sodium hydroxide, and filtered again through a mat of Celite®. The resulting solution was dried over magnesium sulfate, filtered, and evaporated in vacuo. Silica gel chromatography (ethyl acetate/hexane) provided 3.02 g (11%) of the title intermediate product as an orange oil: NMR (CDCl3) 7.91 (d, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.14 (t, J=8 Hz, 1H), 6.97 (t, J=9 Hz, 1H), 6.83 (d, J=8 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.39 (d, J=8 Hz, 1H), 5.04 (bs, 1H, —OH), 3.83 (s, 3H), 2.66 (t, J=9 Hz, 2H), 1.54 (quintet, J=5 Hz, 2H), 1.35 (hextet, J=5 Hz, 2H), 0.91 (t, J=8 Hz, 3H); MS-EI m/e 300 (p, 34), 225 (100), 213 (42), 197 (53), 107 (38); IR (mull, cm−1) 3410, 2926, 1709, 1600, 1463, 1234, 1107, 1090, 992.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:30])[CH2:27][CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][CH2:27][N:26]([CH3:30])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: CN(CCO)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CN(CCO)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-[(5-amino-pyridin-2-yl)-methyl-amino]-ethanol. LCMS calcd for C19H17F3N4O3 (m/e) 406, obsd 407 (M+H).