Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:21])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonylpyroglutamate (11.5 g, 40 mmol) in THF (200 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in THF (42 mL, 42 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (3.11 mL, 50 mmol) was added. After an additional 2 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed with 1:1 ethylacetate/hexanes to give Boc-PyroGlu(4-methyl)-OtBu (10.6 grams, 35.4 mmol, 88%) as a mixture of isomers (2:1 cis to trans).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:18])[NH:6][C:7](=[O:17])[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)(=[O:3])[CH3:2].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:6]2[C:5](=[O:18])[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][N:8]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]2=[O:17])=[CH:22][CH:21]=1
Reactant: CC(=O)c1cn(Cc2ccccc2)c(=O)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccc(F)cc2)c1=O
Yield: 93.7 %

Procedure:
The title compound was synthesized in 93.7% yield by benzylation of 5-acetyl-1-benzyluracil (2e) with 2 equiv of 4-fluorobenzyl bromide and 2 equiv of potassium carbonate in DMF. Mp. 106-108° C. 1HNMR (CDCl3): 8.23 (s, 1H), 7.30-7.50 (m, 7H), 7.00 (m, 2H), 5.12 (s, 2H), 5.01 (s, 2H), 2.61 (s, 3H). 13CNMR (CDCl3): 194.3, 162.4 (d, J=246.4 Hz), 160.7, 151.0, 148.4, 134.4, 132.1 (d, J=3.4 Hz), 131.1 (d, J=8.2 Hz), 129.2, 128.9, 128.2, 115.3 (d, J=21.6 Hz), 112.3, 53.4, 44.2, 30.6. FAB-HRMS: [M+H]+ calcd. for C20H18FN2O3 353.1301, found 353.1310.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].C(O)C.C(=O)([O-])[O-].[NH4+:39].[NH4+]>ClCCl.C(O)C>[ClH:31].[CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26](=[NH:39])[NH2:27])=[CH:24][CH:25]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Yield: 63 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 63% of theory, C24H24N6O (412.5) Rf value: 0.76 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =413
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]1([CH3:37])[CH2:36][CH2:35]1)[CH:29]=O.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]1([CH3:37])[CH2:36][CH2:35]1)[CH2:29][NH:48][CH2:47][CH2:46][C:41]1[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=1
Reactant: CC1(c2ccc(C=O)cc2Cl)CC1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2Cl)CC1
Yield: 99 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 3-chloro-4-(1-methylcyclopropyl)-benzaldehyde (prepared as described in example S105) (90 mg, 0.46 mmol), 2-(3,4-dichlorophenyl)-ethylamine (88 mg, 0.46 mmol) and sodium borohydride (26 mg, 0.70 mmol). The desired product (168 mg, 99%) was isolated without further purification as a colorless oil. MS (ISP) 370.1 (M+H)+.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH3:21][O:22][C:23]1[N:28]=[C:27](C=CC#N)[CH:26]=[CH:25][CH:24]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:20]([C:26]3[CH:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:16]=[C:14]([NH2:13])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: COc1cccc(C=CC#N)n1
Product: COc1ccc(-c2cc(N)n3nc(-c4ccco4)nc3c2)cn1

Procedure:
The title compound, MS m/e (%): 307 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(6-methoxy-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][CH2:28][N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: CN(C)C=O
Product: CN(CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O)S(C)(=O)=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(2-aminoethyl)-N-methylmethanesulfonamide employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.93 (1H, br s), 10.91 (1H, br s), 9.99 (1H, br s), 8.10 (1H, br s), 7.35-7.25 (3H, m), 7.18-7.08 (2H, m), 3.98 (2H, br s), 3.46 (2H, br s), 3.21 (2H, br s), 2.85 (3H, s), 2.81 (3H, s); HRMS calcd for C20H21FN4O5S+H+: 449.1295. Found 449.1292.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CO
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxyphenylacetyl chloride, the title compound was synthesized according to Example 1b. Yield: 74%. Melting point: 171-173° C. (Methanol)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH3:1][C:2]1[C:3]2[O:9][CH2:18][CH2:17][O:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1OCCO2
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
In 300 ml of dry dimethylformamide, was dissolved 30 g of 3-methylcatechol and then 100 g of potassium carbonate was added to the solution. This solution was heated to 120 to 130° C. and 136 g of 1,2-dibromoethane was added dropwise in ten and several portions. After stirring for 30 minutes under the same conditions, the mixture was cooled and solid materials were removed by filtration. To the filtrate, was added diethyl ether, and the mixture was washed successively with a 3% sodium hydroxide aqueous solution, water and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting oily material was purified by silica gel column chromatography to obtain 29.7 g of the titled 5-methyl-1,4-benzodioxane (yield: 82%) .
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Br[CH2:22][C:23]1[C:24]([CH3:35])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:27][CH:28]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[C:24]([CH3:35])=[N:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:27][CH:28]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: Cc1nc(-c2ccccc2)ncc1CBr
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1nc(-c2ccccc2)ncc1CN1CCN(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise over 30 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 3.05 g of 95% strength 5-bromomethyl-4-methyl-2-phenylpyrimidine (=11 mmol) and 80 ml of absolute 1,2-dimethoxyethane at 45° C. The mixture was stirred for a further 1 hour at 45° C. and 3 hours at 80° C., the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 water and neutralized to pH 6-7, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (3.7 g) was recrystallized from methanol. 2.35 g (65% of theory) of pure 4-(4-hydroxyphenyl)-1-(4 -methyl-2-phenylpyrimidin-5-ylmethyl)piperazine, melting point 201°-202° C., were obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.N1CCCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:32]1([C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH2:7][CH2:8]2)=[O:13])=[CH:22][CH:21]=3)=[O:24])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:35][CH2:36]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C1CCCNCC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCCCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), azepane (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Solvent: ClCCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CCl)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2′-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (203 mg, 0.64 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (761 mg, 6.40 mmol) and the resulting mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted further with CH2Cl2 (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=336 (M+1).
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[CH3:4][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2][CH2:1][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of 2.47 g of the above farnesyl bromide in 20 ml of dry dimethyformamide (DMF) at room temperature under argon was treated with 1.83 g (9.9 mmol, 1.1 eq.) of potassium phthalimide and stirred for 3 hours at room temperature. The solvent was removed under reduced pressure, the residue was triturated with 150 ml of ethyl ether, and the precipitate was filtered off. The ethereal solution was washed with 50 ml of H 0 and 50 ml of brine, dried over MgSO4 and evaporated to yield 2.96 g of crude title compound as a milky oil. Purification by flash chromatography on 300 g of Merck 9385 silica, eluted with 7:93 ethyl acetate:petroleum ether afforded 2.56 g (81%) of the desired product as a colorless oil.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32](SC)=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32]([N:5]([OH:6])[CH:2]([CH3:4])[CH3:3])=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:13])[CH3:15]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Reactant: CC(C)NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)N(O)C1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of N-isopropylhydroxylamine hydrochloride (5.5 g, 0.049 mole), potassium-t-butoxide (4.83 g, 0.043 mole), and ethanol (500 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is then added and the mixture is refluxed with stirring for six hours. After removal of the solvent under reduced pressure, the cooled reaction mixture is poured into a mixture of ice-water containing 1N hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent is evaporated to give 7.7 g of a residue. The residue is flash chromatographed on silica gel (202 g), eluting first with methylene chloride and then with methylene chloride-methanol (9:1) to give 7.0 g purified product. It is recrystallized from methylene chloride-ethyl acetate-ether to give 4.2 g (54%) of pure 5-[[3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2[hydroxy(1-methylethyl)amino]-4(5H)-thiazolidinone, (Z)-, mp 208° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15].[CH3:17][OH:18]>>[CH3:17][O:18][C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:15]
Reactant: CO
Reactant: O=C(Cl)c1cnoc1-c1ccc(Cl)cc1Cl
Product: COC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 63.1 %

Procedure:
5-(2',4'-Dichlorophenyl)-4-isoxazolecarbonyl chloride (2.0 g.; 0.007 mol.) was covered with methanol and the solution was heated on a steam cone for 2 hours. The excess methanol was then removed under reduced pressure and the resulting residue was dissolved in hot pentane. The product crystallized from the pentane solution to yield methyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (1.2 g.; 63.1% yield) having a melting point of 83°-84° C. and the following analysis:
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH2:20].C(O)(=O)C>CO>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[N:20][NH:19][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NN=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a stirred solution of 1-(diphenylmethyl)azetidin-3-one (Preparation 693, 11.4 g, 48 mmol) and tert-butyl hydrazinecarboxylate (6.3 g, 48 mmol) in methanol (110 ml) at 0° C. was added acetic acid (5.56 ml, 96 mmol) dropwise and stirred at room temperature for 18 hours. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (500 ml). The organic layer was washed with 1M aqueous sodium hydroxide solution (2×150 ml), water (3×150 ml), saturated aqueous sodium chloride solution (150 ml), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was triturated with diethyl ether to get 15.8 g (94%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][CH2:28][C:29]([CH2:31][C:32](OC)=[O:33])=[O:30]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:32](=[O:33])[CH2:31][C:29](=[O:30])[CH2:28][CH3:27])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: CCC(=O)CC(=O)OC
Solvent: Cc1ccccc1C
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(=O)CC
Temperature: 135 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 303-2 and 3-keto-n-valeric acid methyl ester (1.46 g) were dissolved in xylene (10 mL), and the mixture was stirred at 135° C. for 8 hr. After cooling to room temperature, the solution was directly packed and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give 2-[(4-{2-[heptyl(3-oxopentanoyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.6 g) as a colorless oil. The present compound was used in the next step without particular purification. The title compound was obtained by an operation similar to that of Example 446 for the steps after cyclization reaction using hydrazine monohydrate.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:12]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 33.93 g of ethyl glycolate, 62.7 g of t-butyldimethylchlorosilane and 58.5 g of imidazole in 150 ml of dimethylformamide is stirred at room temperature for 15 h. The mixture is diluted with ether and washed with water (2×100 ml), brine, dried (MgSO4) and evaporated. The residue is distilled to give ethyl t-butyldimethylsilyloxyacetate, b.p. 100°-105° C. (14 mm/Hg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([OH:19])=O)(=[O:11])=[O:10].ClC(OCC)=O.[CH2:29]([N:31]1[CH2:35][CH:34]([NH2:36])[CH2:33][N:32]1[CH2:37][CH3:38])[CH3:30]>C(Cl)Cl>[CH2:29]([N:31]1[CH2:35][CH:34]([NH:36][C:17](=[O:19])[C:16]2[CH:20]=[C:12]([S:9]([CH3:8])(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])[CH2:33][N:32]1[CH2:37][CH3:38])[CH3:30]
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCN1CC(N)CN1CC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(NC(=O)c2cc(S(C)(=O)=O)ccc2OC)CN1CC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 109.7 %

Procedure:
Triethylamine (1.01 g, 0.010 mole) was added to a stirred mixture of 5-methylsulfonyl-2-methoxybenzoic acid (2.30 g, 0.010 mole) in 50 ml of methylene chloride. The mixture was cooled to 0° C. for 20 minutes and maintained at this temperature while ethyl chloroformate (1.09 g, 0.010 mole) was added dropwise. After another 20 minutes of stirring at 0° C., a solution of 1,2-diethyl-4-aminopyrazolidine (2.43 g, 0.010 mole) in 10 l of methylene chloride was added dropwise. The reaction mixture was allowed to come to ambient temperature and was stirred for 18 hrs. The reaction mixture was then extracted with 10% sodium bicarbonate solution, the methylene chloride layer separated and dried over magnesium sulfate. The methylene chloride solution was concentrated to give 3.90 g of a tanbrown solid which was recrystallized from water. A sulfate salt was prepared which was converted back to the free base. The solid free base that formed was recrystallized from ethanol-isopropyl ether to give 1.03 g (29%) of title compound; m.p. 123°-124° C. The compound was vacuum dried at 110° C.; the melting point was unchanged.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CCCCCC.[C:33](=[O:35])=[O:34].Cl>C1COCC1>[CH2:1]([O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[C:15]([C:33]([OH:35])=[O:34])=[C:16]([F:19])[C:17]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
36.8 g of the compound (10) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 100 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 26.5 g (76 mmol) of 4-decyloxy-2,3,5,6-tetrafluorobenzoic acid (11).