Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[S:25][CH:24]3[CH:26]=[C:27](Br)[S:28][CH:23]3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:53])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]#[CH:52])=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[S:25][CH:24]3[CH:26]=[C:27]([C:52]#[C:51][C:48]4[NH:47][C:46]([CH:42]5[CH2:43][CH2:44][CH2:45][N:41]5[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:53])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=4)[S:28][CH:23]3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C2=CC3SC(Br)=CC3S2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#CC2=CC3SC(c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)=CC3S2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 17.8 %

Procedure:
(1-{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (140 mg, 0.440 mmol), {1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (130 mg, 0.254 mmol), Pd(PPh3)4 (29 mg, 0.0254 mmol), CuI (10 mg, 0.0508 mmol) and triethylamine (0.354 mmol, 2.54 mmol) were combined in DMF (2.5 mL) and degassed with N2 for 17 min. The reaction was heated to 85° C. for 4 h then cooled to RT, diluted with EtOAc and washed with saturated aqueous NaHCO3 (2×) and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by HPLC chromatography to afford the title compound (34 mg, 18%). MS (ESI) m/z 749 [M+H]+.
Reaction SMILES: [CH3:1]N(CCN(C)C)C.C([Li])(CC)C.[CH2:14]([N:16]([CH2:26][CH3:27])[C:17](=[O:25])[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:15].IC>C1COCC1.[Cl-].[Na+].O>[CH2:26]([N:16]([CH2:14][CH3:15])[C:17](=[O:25])[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:1])[CH3:27]
Reactant: CCN(CC)C(=O)Oc1cccnc1
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)Oc1cnccc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To the cooled (-78° C.) solution of TMEDA (516.5 mg, 4.40 mmol) in anhydrous THF (10 mL) was slowly added sec-butyl lithium (1.3 M, 3.38 mL, 4.40 mmol), and the resultant solution was stirred at -78° C. for 10 minutes. 3-Pyridyl diethylcarbamate (776 mg, 4.0 mmol) in THF (3 mL) was slowly added, and the mixture was stirred at -78° C. for 30 minutes. Iodomethane (275.4 μL, 4.40 mmol) was then added, and the mixture was stirred for two hours. Brine (1 mL) was added, and the mixture was slowly warmed up to room temperature. The organic layer was decanted, and the residue washed with ethyl acetate (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel eluting with hexane/EtOAc (1:2 and 0:1) to provide 765 mg (92% yield) of the title compound. TLC Rf 0.28 (1:2 hexane/EtOAc). MS (DCI/NH3) m/e 209 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.34 (s, 1H, ArH), 8.32 (d, J=6.9 Hz, 1H, ArH), 7.16 (d, J=69 Hz, 1H, ArH), 3.48 (q, J=7.5 Hz, 2H, NCH2), 3.41 (q, J=7.5 Hz, 2H, NCH2), 1.28 (t, J=7.5 Hz, 3H, CH3), 1.22 (t, J=7.5 Hz, 3H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:22][C:23]1[CH:32]=C2C(C=CC=C2)=C[CH:24]=1.CC(C)=O>CCCCCC>[CH:22]([O:13][C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1])=[C:23]([CH3:32])[CH3:24]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)=COc1c(Br)cc(Br)cc1C(C)(C)C
Temperature: 23 °C
Reaction time: 56 h

Procedure:
In a 3000 mL 3-neck flask, equipped with Ar inlet and magnetic stirrer, is placed 2,4-dibromo-6-tert-butylphenol (70.0 g, 226 mmol), K2CO3 (37.6 g, 276 mmol, 1.2 eq), Nal (3.38 g, 22.6 mmol, 0.1 eq), p-methallyl chloride (33.9 mL, 339 mmol, 1.5 eq), and acetone (1500 mL). The reaction mixture is vigorously stirred at 23° C. for 56 hrs, and monitored by TLC analysis (pet. ether). The solids are removed by filtration, washed with acetone, and the filtrates rotoevaporated (bath temperature kept below 35° C.) to give an oil. The oil is dissolved in hexane (100 mL), and stirred with silica gel (80 g). The slurry is filtered through a pad of Celite, and eluted with additional hexane (6×100 mL). The filtrate is evaporated to give 2,4-dibromo-6-tert-butylphenyl isobutenyl ether as a yellow oil. The material is stored in the freezer and is used as soon as possible.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C([O:6][CH2:7][C:8]1[C:17]2[C:12](=[C:13]([NH:18][C:19](=[O:28])[C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)=O.[OH-].[Na+]>C(O)C.O1CCOCC1.ClCCl>[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=1[C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH2:7][OH:6])=[O:28]
Reactant: O=C(Nc1cccc2c(COC(=O)c3c(Cl)cccc3Cl)ccnc12)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1cccc2c(CO)ccnc12)c1c(Cl)cccc1Cl
Yield: 30 %

Procedure:
A mixture of 4-(2,6-dichlorobenzoyloxymethyl)-8-(2,6-dichlorobenzoylamino)quinoline (100 mg), 1N sodium hydroxide solution (0.4 ml) in ethanol (2 ml) and dioxane (1 ml) was refluxed for 5 hours. After cooling, the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-hydroxymethylquinoline (20 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[CH2:16](I)[CH3:17].O.[CH2:20]1COCC1>CCOC(C)=O>[CH2:3]([O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=[O:6])[CH3:20]
Reactant: C1CCOC1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(CC)c2ccccc12
Temperature: 70 °C
Yield: 74 %

Procedure:
To a suspension of NaH (50-60% dispersion in mineral oil, 548.0 mg, 11.4 mmol, 2.0 eq) in THF (20 mL), 1H-indole-3-carboxylic acid methyl ester (1.0 g, 5.7 mmol, 1.0 eq) was added and after 20 min also ethyl iodide (507.0 μL, 6.3 mmol, 1.1. eq) was added. The reaction was heated at 70° C. for 1 h. The mixture was cooled down to 0° C. and water (10 mL) was added carefully. AcOEt was added and the organic phase was collected and concentrated, to give the crude compound that was purified through SiO2 column (10 g) with gradient elution from 100% cyclohexane to cyclohexane-EtOAc 80:20. The title product (860 mg, 74% yield) was obtained.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[OH:25])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([O:17][C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2OCc2ccccc2)C1
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a DMF (10 mL) solution of the title compound of Step C (0.52 g, 1.5 mmol), Cs2CO3 (0.54 g, 1.7 mmol) and KI (0.20 g, 1.20 mmol) was added benzyl bromide (0.20 mL, 0.29 g, 1.7 mmol). After 48 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine (2×) and dried. Silica gel chromatography (5-20% EtOAc in hexanes) gave 0.65 g (99%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.42-7.36 (m, 3H), 7.34-7.31 (m, 2H), 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 5.09 (s, 2H), 4.88-4.83 (m, 1H), 4.26 (ddd, J=9.7, 6.5, 0.9 Hz, 2H), 4.05 (dd, J=9.8, 4.0 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[F:23][C:20]([F:21])([F:22])[C:19]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=[N:17][N:18]=1
Reactant: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 1-(4-benzyloxy-phenyl)-5-trifluoromethyl-1H-tetrazole (45.3 mmol) in ethanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-carbon catalyst (6 g). After 2 h, the mixture was filtered and the filtrate was evaporated to give the title compound (10.4 g) as a cream solid. T.l.c. (Dichlormethane/ethanol/ammonia(200:8:1)) Rf 0.3.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C.[I-].ClC1C=[CH:27][CH:26]=[CH:25][N+]=1C.C1CCCCC1.CCOC(C)=O>C(Cl)Cl>[N:16]1([C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:17][CH2:18][CH2:27][CH2:26][CH2:25][CH2:20][CH2:19]1
Reactant: C[n+]1ccccc1Cl
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.4 %

Procedure:
To a mixture of heptamethyleneimine (254 μl; 2 mmol; 1 eq) and boc-beta-alanine (416.3 mg; 2.20 mmol; 1.10 eq) in DCM (30 ml), are added triethylamine (832 μl; 6 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1533 mg; 6 mmol; 3 eq). The mixture is stirred overnight at RT. The reaction is followed by TLC (cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated to give 1.066 g of an orange oil, which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title product is isolated as a slightly yellow solid (477 mg; 84%).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8].O>C(Cl)Cl>[CH3:6][S:7]([O:5][CH:2]([C:3]#[CH:4])[CH3:1])(=[O:9])=[O:8]
Reactant: C#CC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C#CC(C)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
But-3-yn-2-ol (25 ml, 317 mmol) was dissolved in DCM (6 vol) under nitrogen atmosphere. TEA (66 ml, 475.5 mmol) was added and the mixture was cooled to 5° C. Methanesulfonyl chloride (29 ml, 380.4 mmol) was added drop-wise. The reaction was then allowed to warm up to RT and the stirring was continued overnight. The reaction mixture was then poured into water, and extracted with DCM (twice). The collected organic phases were washed with a saturated solution of NaHCO3, dried over Na2SO4 filtered and concentrated under vacuum to give the title compound as a thick oil (34 g).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])C)=O)C1C=CC=CC=1.C(N1CCOCC1)C.ClC(O[CH2:32][CH:33]([CH3:35])[CH3:34])=O>O1CCCC1>[C:33]([O:19][C:17](=[O:18])[C@@H:12]1[CH2:13][CH2:14][CH2:16][NH:11]1)([CH3:35])([CH3:34])[CH3:32]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1
Temperature: -15 °C
Reaction time: 10 h

Procedure:
0.566 g (2.134 mmol) of N-(benzyloxycarbonyl)-L-leucine was taken up in 15 ml of tetrahydrofuran and cooled to -15° C. 0.245 g (2.134 mmol) of N-ethylmorpholine and 0.291 g (2.134 mmol) of isobutyl chloroformate were added. After 5 minutes the tetrahydrofuran solution prepared as described in the previous paragraph was added, followed by 0.451 g (4.27 mmol) of N-ethylmorpholine. The mixture was stirred at room temperature for 10 hours, the solvent was then removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution and then dried over anhydrous sodium sulphate. The solvent was removed under a vacuum to give 1.5 g of crude N-[3(S)-[[N-(benzyloxycarbonyl)-L-leucyl]amino]-2-(R and S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as an oil. The two isomers were separated by chromatography on silica gel using 50% n-hexane in ethyl acetate for the elution. There were obtained 180 mg of isomer 1 of N-[3(S)-[[N-(benzyloxycarbonyl)-L-leucyl]-amino]-2(R or S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a crystalline material; Rf (System A): 0.34; MS: m/e 582 [M+H]+, and 70 mg of isomer 2 as a crystalline material; Rf (System A): 0.28; MS: m/e 582 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[S:12]([OH:14])=[O:13].O.[OH-].[Na+].[CH3:18]I>CO>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:12]([CH3:18])(=[O:14])=[O:13])=[CH:4][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: CI
Reactant: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Yield: 56 %

Procedure:
The product of Step A is placed in a three-liter flask to which is added water (300 ml.), methanol (500 ml.) sufficient 10N sodium hydroxide to attain a pH of 9 and methyl iodide (520 g.; 3.66 moles). The reaction mixture is refluxed for 36 hours with the occasional addition of 10N sodium hydroxide to maintain pH 9. The alcohol is distilled at reduced pressure and the reaction solution is acidified with hydrochloric acid. The product is filtered, washed with water, dried and recrystallized from ethanol (800 ml.) to give 150 g. (yield 56%) 2,4-dichloro-5-methylsulfonylbenzoic acid, m.p. 210°-211° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:35]([O:37][C:38](=[O:41])[CH2:39][NH2:40])[CH3:36].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:41])=[O:30])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a mixture of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (150 mg, 0.345 mmol), glycine ethyl ester hydrochloride (63 mg, 0.449 mmol) and diisopropylethylamine (0.078 ml, 0.449 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (70 mg, 0.518 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.690 mmol). After stirring the resulting mixture at room temperature for 3 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 2:1 elution) to give ethyl (±)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}acetate (168.9 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:19]=1.OO.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:23])=[N:7][C:6]=2[CH:19]=1
Reactant: Clc1ccc2sc(SCCN3CCOCC3)nc2c1
Reactant: O=C([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(CCN1CCOCC1)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolved in 4 ml of acetic acid were 0.80 g (2.5 mmol) of the compound obtained in Example 31, and 0.37 ml (3.3 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic quantity of sodium tungstate were successively added to the solution, which was stirred at room temperature for 1 hour. The solution was poured in 80 ml of water, neutralized with sodium hydrogencarbonate and extracted with 80 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.52 g of the title compound in the form of white crystalline powders (62% yield).
Reaction SMILES: C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)CCCC1.[CH:30]1([CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][C:38]=2[F:44])[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:47][C:48](=[O:57])[CH2:49][S:50]C1SC(N)=NC=1)C>>[Br:43][C:40]1[CH:41]=[CH:42][C:37]([N:36]([CH2:35][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([S:50][CH2:49][C:48]([OH:57])=[O:47])=[CH:13][N:14]=2)=[C:38]([F:44])[CH:39]=1
Reactant: Fc1cc(Br)ccc1NCC1CCCC1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(Br)cc2F)s1

Procedure:
The title compound was prepared via {2-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-bromo-2-fluoro-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH:3]=[CH:4][CH:5]([OH:7])[CH3:6].[CH:9](=O)[CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:10]([CH:9]1[O:8][CH:2]([CH3:1])[CH:3]=[CH:4][CH:5]([CH3:6])[O:7]1)[CH2:11][CH3:12]
Reactant: CCCC=O
Reactant: CC(O)C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1OC(C)C=CC(C)O1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 580 g (5 moles) of hex-3-ene-2,5-diol, 3 g of p-toluenesulfonic acid, 360 g (5 moles) of n-butanal and 1 l of toluene was refluxed, and the resulting water of reaction (108 ml) was removed in the course of 3 h. Thereafter, the mixture was left to cool to room temperature, 10 ml of a 25% strength aqueous sodium hydroxide solution were added, the mixture was washed neutral with a little water and the toluene was removed under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 681 g (4 moles) of 2-propyl-4,7-dimethyl-4,7-dihydro-1,3-dioxepin of boiling point 70° C./0.1 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.CN(C)P(=O)(N(C)C)N(C)C.[CH:26]([N-]C(C)C)(C)C.[Li+].BrC[CH2:36][CH:37]([CH3:39])[CH3:38]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:26])([CH2:14][CH2:36][CH:37]([CH3:39])[CH3:38])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)CCBr
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(CCC(C)C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of Example 155A (15 g. 77.2 mmol) and hexamethylphosphoric triamide (14.8 mL, 77.2 mmol) in 200 mL anhydrous tetrahydrofuran was added 2 M lithium diisopropyl amide (45 mL, 90 mmol) while maintaining the temperature below −70° C. After 30 minutes at −78° C., 1-bromo-3-methylbutane (10.6 mL, 85 mmol) was added and the reaction stirred for 16 hours at room temperature. Most of the solvent was removed under vacuum and the residue partitioned between ethyl acetate and 1 N HCl. The crude product was purified on silica using 5% ethyl acetate in hexanes to give the product as a colorless oil (18.6 g, 92%). 1H NMR (300 MHz, CDCl3) δ ppm 0.86 (d, J=5.15 Hz, 3 H) 0.88 (d, J=5.15 Hz, 3 H) 1.04 (m, 2 H) 1.51 (m, 1 H) 1.51 (s, 3 H) 1.88 (ddd, J=13.33, 10.57, 6.25 Hz, 1 H) 2.02 (m, 1 H) 3.64 (s, 3 H) 3.79 (s, 3 H) 6.85 (m, 2 H) 7.23 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](C(C)(C)C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22].[CH3:30][C:31]([CH3:34])([O-])[CH3:32].[K+].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:13]=[C:24](\[O:23][CH2:21][CH3:22])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:15][C:16]=1[C:31]([CH3:34])([CH3:32])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)OCC
Reactant: CC(C)(C)c1cc(OCc2ccccc2)ccc1C=O
Reactant: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c(C(C)(C)C)c1)OCC
Temperature: -20 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
4-(Benzyloxy)-2-tert-butylbenzaldehyde (0.66 g; 2.44 mmole) and ethyl ethoxyacetate (0.39 g; 2.93 mmole) were dissolved in dry tetrahydrofuran (10 ml) and cooled to −20° C. Potassium tert-butoxide (0.33 g; 2.93 mmole) dissolved in dry tetrahydrofuran (1 ml) was slowly added and the reaction was stirred overnight at −20° C. The reaction was quenched with acetic acid (0.19 g; 3.18 mmole). The crude product was isolated, redissolved in toluene and refluxed over night with p-toluenesulfonic acid (0.05 g; 0.25 mmole) in a Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium hydrogen carbonate, dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (50-100%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.26 g (25% yield) of ethyl (2Z)-3-[4-(benzyloxy)-3-tert-butylphenyl]-2-ethoxyacrylate.