Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:27]([Si:29]([CH2:33][CH3:34])([CH2:31][CH3:32])Cl)[CH3:28]>C1COCC1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([Si:29]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:27][CH3:28])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A dry flask is charged with 1.256 g (5 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) and 15 ml dry THF. To the resulting clear solution, 2.02 g (20 mmol) triethylamine is added followed by 904 mg (6 mmol) triethylchlorosilane (TES-Cl). The reaction mixture is stirred at room temperature for 4 h and then quenched on addition of 5 ml saturated NaHCO3 solution, 10 ml water and 10 ml isopropyl acetate. The layers are separated and the aqueous layer extracted with 10 ml isopropyl acetate. The combined organic layers are dried over MgSO4, filtered and evaporated. The resulting residue is purified by column chromatography (dichloromethane+1% v/v triethylamine) to give (S)-5-Biphenyl-4-ylmethyl-1-triethylsilanyl-pyrrolidin-2-one (1-a, R1=TES) as a yellow oil. NMR (300 MHz, DMSO-d6, /ppm): 7.63 (m, 4H); 7.55 (m, 2H); 7.32 (m, 3H); 3.80 (m, 1H); 2.85 (m, 1H), 2.70 (m, 1H), 2.10-1.70 (m, 4H), 1.02-0.80 (m, 15H). MS (ESI, m/e) 366 [M+H]+; 731 [2M+H]+. IR (solution in CH2Cl2, /cm−1): 3426; 3047; 2957; 1698; 1672; 1487; 1378; 1242; 1114; 1008.
Reaction SMILES: C[O-].[Na+].[I-:4].[Na+].CC(C)(C([O-])=O)C([O-])=O.[Na+].[Na+].[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC.CC(C)=O>[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][I:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCCc1ccccc1
Reactant: [I-]
Agent: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(C)=O
Product: ICCCCc1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
R=Me Dimethyl malonate (5.7 mL, 50.0 mmol) was added in one portion to a solution of sodium methoxide (6.6 g, 50.0 mmol) in DME (45 mL) at rt and stirred for 15 min. In a separate reaction vessel, 4(4'-chlorophenyl)-a-bromoacetophenone (14.0 g, 45.0 mmol) was dissolved in DME (136 mL) along with sodium iodide (6.7 g, 45.0 mmol). The NaI solution was allowed to stir for 15 min at rt. The sodium dimethylmalonate solution was transferred via cannula dropwise into the 4(4'-chlorophenyl)-a-bromoacetophenone solution; stirring continued 1 hr at rt. The solvent was removed in vacuo and the resulting oil dissolved in 1:1 methylene chloride:diethyl ether (700 mL). The organic phase was washed with water (250 mL), and saturated sodium chloride solution (250 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was recrystallized using 4:1 chloroform:methanol with hexane to precipitate the methyl 2-carbomethoxy-4[4'-(4"-chloro phenyl)phenyl]-4-oxobutanoate (10.43 g, 64%). 1H NMR (DMSO) d 8.06 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.95 (t, J=7.0 Hz, 1H), 3.70 (s, J=7.0 Hz, 6H), 3.66 (s, 2H). ##STR178## Step 2 (A)--Preparation of 4-phenyl-1-iodobutane. Sodium iodide (8.9 g, 59.2 mol) and 4-phenyl-1-chlorobutane (5.0 g, 29.6 mol) were added to acetone (29.6 mL) at rt. The mixture was heated to 70° C. for 12 h. The resulting solution was gravity filtered to remove salts. The solvent was removed under reduced pressure and excess salts were dissolved in water (100 mL). Hexane (100 mL) was added to the aqueous mixture. The phases were separated and the organic phase was washed with saturated sodium bisulfite solution (3×50 mL), treated with decolorizing carbon, and gravity filtered. The organic layer was then dried (MgSO4), filtered, and concentrated in vacuo to afford 4-phenyl-1-iodobutane (6.94 g, 90%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C@H:5]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)=[CH:17][CH:16]=1)[C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:6]=O.N1C=CC=CC=1>O>[OH:3][N:2]=[CH:4][C@@H:5]([N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH3:6]
Reactant: NO
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=NO
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
Hydroxylamine hydrochloride (25.4 mg, 0.4 mmol) was added to a solution of intermediate (5c) (174 mg, 0.3 mmol), pyridine (3 mL, 37 mmol) and water (1.5 mL, 83 mmol) at room temperature. After 15 minutes, water (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated aqueous NaCl (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5d) as a white solid (148 mg).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([NH:9][O:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)ON[C@H]1CCCNC1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)ON[C@H]1CCCN(Cc2ccccc2)C1

Procedure:
a method, wherein the amino group of L-aspartic acid is protected, the carboxy group is reduced, the resulting hydroxyl group is converted into a leaving group, the resultant is reacted with ammonia to produce (S)-3-(tert-butoxycarbonyloxyamino) piperidine, the piperidine is reacted with benzylamine instead of ammonia to obtain (S)-1-benzyl-3-(tert-butoxycarbonyloxyamino) piperidine, and deprotection is carried out using trifluoroacetic acid to produce (S)-1-benzyl-3-aminopiperidine (Non-patent Document 3).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:18].[CH2:19](B1OC(C)(C)C(C)(C)O1)[CH:20]=[CH2:21]>CO>[CH2:19]([C:13]1([NH2:18])[CH2:14][CH2:15][CH2:16][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11][CH2:12]1)[CH:20]=[CH2:21]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Reactant: N
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Solvent: CO
Product: C=CCC1(N)CCCC(O[Si](C)(C)C(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a solution of 1.5 g (5.85 mmol) of 5-(tert-butyldimethylsilyloxy)cyclooctanone in 8.4 mL (58.5 mmol) of 7N ammonia in methanol, previously stirred for 15 min at room temperature, were added dropwise 1.7 mL (9.36 mmol) of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane. The reaction mixture was stirred for 18 h at room temperature. The volatiles were removed in vacuo and the residue redissolved in 100 mL of diethyl ether. Then, 100 mL of 1 N aqueous HCl were added dropwise and the resultant biphasic mixture was stirred for 30 min. The layers were separated, the aqueous layer was washed with diethyl ether and the pH adjusted to pH9 by the addition of sodium hydroxide. The suspension was then extracted with a 3:1 mixture of dichloromethane and 2-propanol and the combined organic extracts were concentrated in vacuo to afford 0.89 g of the title compound as mixture of diastereomers. Rt=0.44 min, 0.49 min (Method C). Detected mass: 184.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[S:7][C:6]([C:8](=O)[CH3:9])=[N:5][CH:4]=1.[CH3:12]NC.BrC1SC(C(=O)C)=NC=1.[N+]([O-])([O-])=O.[CH3:28][C:29]1[CH:30]=[C:31]([NH:36][C:37]([NH2:39])=[NH2+:38])[CH:32]=[C:33]([CH3:35])[CH:34]=1>>[CH3:1][N:2]([CH3:11])[C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:12][N:39]=[C:37]([NH:36][C:31]3[CH:30]=[C:29]([CH3:28])[CH:34]=[C:33]([CH3:35])[CH:32]=3)[N:38]=2)=[N:5][CH:4]=1
Reactant: CNC
Reactant: CC(=O)c1ncc(N(C)C)s1
Reactant: Cc1cc(C)cc(NC(N)=[NH2+])c1
Agent: CC(=O)c1ncc(Br)s1
Agent: O=[N+]([O-])[O-]
Product: Cc1cc(C)cc(Nc2nccc(-c3ncc(N(C)C)s3)n2)c1

Procedure:
This compound was prepared from 1-(5-Dimethylamino-thiazol-2-yl)-ethanone (prepared from dimethylamine and 1-(5-Bromo-thiazol-2-yl)-ethanone in a procedure similar to that described in method I) and N-(3,5 dimethylphenyl) guanidinium nitrate (prepared using a procedure similar to that described in WO9719065) using procedures similar to those described in methods E-F. The product was isolated as a yellow solid (40% last step); IR (solid) 1738, 1365, 1217, cm−1; 1H NMR (400 Mhz, CDCl3) δ 2.35 (6H, s), 3.1 (6H, s), 6.75 (1H, s), 7.00 (1H, s), 7.37 (1H, s), 7.4 (2H, s), 8.45 (1H, d);); MS (ES+) 326.2 (M+1), (ES−) 324.2 (M−1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.S(=O)(O)[O-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3ccccc3c2)cc1
Yield: 70.4 %

Procedure:
A mixture of 1.00 g (6.94 mmol, Aldrich) of 2-naphthol, 1.01 g (9.26 mmol, Aldrich) of 4-aminophenol, and 5.2 g (50 mmol, Aldrich) of sodium bisulfite in 30 ml of H2O was refluxed for 36 hours. The reaction mixture was cooled, added to 50 ml of H2O and extracted with 50 ml of hot ethyl acetate. The organic layer was separated, washed with an additional 50 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (15×5.0 cm, 1:4 EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 1.15 g (71%) of title compound as pale purple flakes, m.p. 134°-135° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C([Li])CCC.[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][CH:20]=O.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][CH:20]1[O:6][C:4](=[O:5])[CH2:3][CH2:2]1
Reactant: O=CCC1CC2C=CC1C2
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCC(CC2CC3C=CC2C3)O1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
In 80 g of dry tetrahydrofuran was dissolved 10.0 g of 3-bromopropionic acid. In a nitrogen atmosphere, 85.0 g of a hexane solution of 1.6M n-butyllithium was added to the solution at −78° C., followed by 30 minutes of stirring. Then a solution of 8.92 g 2-(5-norbornen-2-yl)acetaldehyde in 20 g hexamethylphosphoric triamide was added dropwise to the solution at the same temperature. With stirring, the temperature of the solution was gradually raised to 20° C. over 2 hours. Next, 80 g of 5% hydrochloric acid was added to the solution, which was stirred for one hour for lactonization. The organic layer was separated, washed with aqueous saturated sodium bicarbonate solution, washed with water, and concentrated in vacuum. Purification by silica gel column chromatography yielded 8.17 g (yield 65%) of γ-(5-norbornen-2-yl)methyl-γ-butyrolactone. The analytical properties of this compound were substantially identical with the data of Synthesis Example 1.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[Br:36]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[Br:36][C:19]1[C:20]([CH3:35])=[CH:21][C:22]([NH:24][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=2)=[CH:23][C:18]=1[C:15]1[S:14][C:13]([C@@:2]2([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]2)=[N:17][CH:16]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.4 %

Procedure:
To a suspension of (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (example 42(1), 50 mg, 0.099 mmol) in chloroform (800 μL) was added N-bromosuccinamide (21 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 minutes, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage 10 G, eluting with 1:99 to 10:90 methanol:dichloromethane) to give (1S,4R)-4-[5-(2-bromo-3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (22 mg, 0.038 mmol, 38% yield) as a pale yellow solid. ESI: [M+H]+ m/z 587.1. 1H NMR (500 MHz, CD3OD) δ 8.70 (d, J=4.9, 1H), 7.86 (d, J=2.6, 1H), 7.78-7.64 (m, 2H), 7.13 (d, J=4.9, 1H), 2.46 (s, 3H), 2.35 (dd, J=2.9, 12.8, 1H), 2.22 (ddd, J=6.1, 13.2, 24.2, 1H), 2.01 (dd, J=6.7, 14.5, 3H), 1.79 (d, J=14.4, 1H), 1.72 (dd, J=3.2, 13.5, 1H), 1.22 (s, 3H), 1.11 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:6]=2[CH:27]=1.[CH2:28]([N:30]([CH2:39][CH3:40])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([CH3:38])[CH:32]=1)[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH2:39][CH3:40])[CH2:28][CH3:29])=[CH:32][C:33]=3[CH3:38])=[S:16])[N:8]=[C:7]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:6]=2[CH:27]=1
Reactant: CCN(CC)c1ccc(N)c(C)c1
Reactant: COc1ncc(C2=NC(N=C=S)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Product: CCN(CC)c1ccc(NC(=S)NC2N=C(c3cnc(OC)nc3OC)c3cc(Cl)ccc3N(C)C2=O)c(C)c1
Temperature: 70 °C
Yield: 87.1 %

Procedure:
As illustrated in the scheme above, a solution of 7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-3-isothiocyanato-1-methyl-2H-1,4-benzodiazepin-2-one (0.069 g, 0.146 mmol) and N4,N4-diethyl-2-methyl-1,4benzenediamine (0.029 g, 0.161 mmol) in (CH2Cl)2 (5.0 mL) was heated at 70° C. for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (7:3 CH2Cl2:EtOAc) to provide the title compound as a light orange solid (0.074 g, 87%). 1H-NMR (CDCl3): δ 8.64 (s, 1H), 7.52 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.17-7.13 (m, 1H), 6.54-6.51 (m, 2H), 6.06 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.74 (s, 3H), 3.42 (s, 3H), 3.40-3.27 (m, 4H), 2.30 (s, 3H), 1.17 (t, J=7.1 Hz, 6H). HRMS calculated for (C28H32ClN7O3S+H) (M+H)+: 582.2054. Found (ESI): 582.2076.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([Li])CCC.[CH:21]([C:24]1[N:25]=[C:26]([CH2:29][CH2:30][C:31]2[CH:49]=[CH:48][N:34]3[C:35](=[O:47])[C:36]([CH:45]=O)=[C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:38]=[C:33]3[CH:32]=2)[S:27][CH:28]=1)([CH3:23])[CH3:22]>O1CCCC1>[CH:21]([C:24]1[N:25]=[C:26]([CH2:29][CH2:30][C:31]2[CH:49]=[CH:48][N:34]3[C:35](=[O:47])[C:36](/[CH:45]=[C:6](\[CH3:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:38]=[C:33]3[CH:32]=2)[S:27][CH:28]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
Under nitrogen atmosphere, triethyl 2-phosphonopropionate (155 mg, 0.65 mmol) was dissolved in tetrahydrofuran (2 ml), added with n-butyl lithium (1 M, 0.65 ml) at −78° C., and stirred at the same temperature for 20 minutes. The reaction mixture was added with a solution of 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (50 mg) dissolved in tetrahydrofuran (1 ml). The cooling bath was removed, and the reaction mixture was warmed to room temperature and stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (14 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].Cl[CH2:20][C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:21](=[O:22])[CH2:20][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=C(O)CCl
Reactant: CC(C)CN
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(=O)N1CC(C)C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin4-one.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:21]=3[CH2:22][N:23]([CH2:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:29][CH2:28]3)[CH2:24][CH3:25])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].CO>CCO.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[CH:39][C:21]=3[CH2:22][N:23]([CH2:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][CH2:32]3)[CH2:24][CH3:25])[C@H:14]2[CH3:47])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)Cc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCN(Cc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)C[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzyl](ethyl)amino]methyl}cyclohexyl)acetate (51 mg, 0.0718 mmol) in EtOH (3 mL) and water (2 mL) was added 4 M KOH (500 μL). The mixture was stirred at room temperature for 30 minutes and then water (1 mL) and MeOH (100 μL) were added. After an additional hour, the reaction was quenched with 1 N HCl (5 mL), diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (50% EtOAc/hexanes with 1% AcOH) was followed by azeotroping of the product with toluene to afford (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzyl](ethyl)amino]methyl}cyclohexyl)acetic acid. Rf=0.13 (50% EtOAc/hexanes with 1% AcOH). LCMS=683.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.79 (s, 2H), 7.61-7.53 (m, 2H), 7.48 (s, 1H), 5.74 (d, J=7.8 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.44 (d, J=16.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.72-3.61 (m, 2H), 2.54-2.53 (m, 2H), 2.23-2.19 (m, 4H), 1.82-1.76 (m, 4H), 1.72-1.64 (m, 1H), 1.39-1.38 (m, 1H), 1.04 (t, J=6.8 Hz, 3H), 0.99-0.78 (m, 4H), 0.76 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Yield: 84.9 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with p-anisaldehyde (0.117 g, 0.87 mmol) in 2 mL of 4% KOH in EtOH at room temperature overnight to afford 0.248 g (84%) of the title compound, mp 132-133° C.: APCI-MS m/e 375 (M+ +1).
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:15]=1.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][N:22]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:15]=1
Reactant: BrCCCOC1CCCCO1
Reactant: c1cncc(CCNCc2ccncc2)c1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cncc(CCN(CCCOC2CCCCO2)Cc2ccncc2)c1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
Sodium iodide (1.5 g) was added to a DMF solution (20 ml) of 2-(3-bromopropoxy)tetrahydropyran (0.85 ml). The mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature. (2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (1.28 g), and N-ethyldiisopropylamine (1.3 ml) were added thereto. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (236 mg) as a colorless oily matter.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[CH:20])=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[C:21](=[O:23])=[O:22].C(OCC)(=O)C>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]([OH:23])=[O:22])=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=C=O
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: -8 °C
Reaction time: 0.08 h

Procedure:
1.6 mL (2.46 mmol) of butyllithium solution (1.6M in hexane) are added dropwise at −10° C. to a solution of 0.5 g (2.34 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine in 30 mL of absolute THF and the mixture is stirred for five minutes at −8° C. stirred. The reaction mixture is combined with dry ice batchwise at −70° C., stirred for 1 hour at ambient temperature, and evaporated down. The residue is suspended in 5 mL of water and combined with 1.6 mL of 1N hydrochloric acid, whereupon a precipitate is formed. Then ethyl acetate is added and the suspension is filtered. The solid is dried in the vacuum drying chamber at 70° C. Yield: 0.25 g (41.5% of theory); melting point: 210° C.; C14H8ClNO2 (M=257.67); calc.: molecular ion peak (M+H)+: 258/260; found: molecular ion peak (M+H)+: 258/260.