Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O.C(=O)=O>O>[OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])=[O:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C=O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Temperature: 50 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
A 100 ml flask containing 10.0 g lactose and 50 ml water was warmed to 50° C. and treated with 80 mg lactase 30,000 enzyme as in Example 3. After 6 hours the solution was analyzed by HPLC and found to contain 10% lactose, 45% D-glucose, and 45% D-galactose, based on the lactose added. The mixture was heated to 75° C. briefly to denature the protein, and was then filtered. A 2.5 cm interior diameter by 60 cm length glass column was packed with about 300 ml of BIO-RAD AG 50W-X8 resin in the calcium form, minus 400 mesh. BIO-RAD AG 50W-X8 is the trademark for a cationic ion exchange resin sold by Bio-Rad, Richmond, Calif. The column was heated to 70° C. The mobile phase was deionized water which had been filtered and degassed and which was pumped at a flow rate of 4.0 ml per minute. Typical pressure was 30 psig. The sample injection loop was 10 ml. The run time was approx. 55 minutes. The filtered reaction mixture described above was concentrated to 30% by weight solids, then injected in portions into the column. By using a refractive index detector to monitor the eluant, the mixture was separated into two groups of fractions. The combined first group of fractions contained 0.8 g of lactose and 4. 2 g D-glucose. The combined second group of fractions contained 0.3 g of D-glucose and 4.4 g of D-galactose. The second group of fractions was concentrated to 10% by weight solids for the isomerization step. The D-galactose solution, stirred at room temperature in a small flask, was treated with 2.0 g calcium hydroxide and 0.15 g calcium chloride, and the precipitate formed within 1.5 hours. The precipitate of calcium hydroxide-tagatose complex was neutralized with CO2 to give 2.2 g D-tagatose.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH:29]=2)[C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:8][C:7]=2[CH:27]=1.[H][H]>C(O)C.[Pd]>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:28]2[CH2:29][CH2:30][CH:31]([C:34]([F:35])([F:36])[F:37])[CH2:32][CH2:33]2)[C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:8][C:7]=2[CH:27]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cc(C2=CCC(C(F)(F)F)CC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1cc(C2CCC(C(F)(F)F)CC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
6-Trifluoromethyl-4-(4-trifluoromethyl-cyclohex-1-enyl)-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (10 mg, Example 139b) was subjected to catalytic hydrogenation in ethanol (1 mL) using 10% Pd/C (10 mg, Aldrich) as catalyst. The reaction was conducted at room temperature under 1 atmosphere hydrogen for 2 days. The catalyst was filtered through a Celite® pad, the filter cake was washed with methanol and the filtrate was evaporated in vacuo to give the title compound as a film. MS (ESI, pos. ion) m/z: 565(M+1).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][CH:3]3[O:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[O:5][CH2:4]3)[CH2:21]2)=[CH:18][CH:19]=1
Reactant: BrCC1COc2ccccc2O1
Reactant: Clc1ccc(C2CCCNC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1
Temperature: 130 °C
Yield: 69.8 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15 mmol), 3-(4-chloro-phenyl)piperidine (38 mg, 0.165 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 ml) was heated in a microwave reactor at 110-150° C. for 290 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 36 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>CCOCC.CCCCCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: C[Si](C)(C)Cl
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)C#CCOC1CCCCO1
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
To 24.4 parts of 3-tetrahydropyranyloxy-1-propyne dissolved in 300 parts by volume of anhydrous ether and cooled to -50° C is added 74 parts by volume of 2.4 molar n-butyl lithium in hexane. The mixture is stirred for 45 minutes and allowed to warm to 30° C and then 19.3 parts of trimethylsilyl chloride in 50 parts by volume of dry ether is added and the mixture allowed to stand for about 12 hours. The mixture is cooled to 5° C and water is added. The ethereal layer is washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent is removed and the residual liquid is distilled at 0.20 mm at 67°-69° to provide 1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne (Tetrahedron 29, 883 (1973).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:1][CH:2]2[NH:6][C:5](=[O:7])[CH:4]=[CH:3]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCCCC1
Reactant: O=C1C=CC(O)N1
Product: O=C1C=CC(OC2CCCCC2)N1
Temperature: 90 °C

Procedure:
A mixture of 5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 150 cm3 of cyclohexane with 2.5 g of Amberlite IR 120 H is heated to 90° C. for 3 hours. After filtering, evaporating the solvent under reduced pressure and chromatographing the residue on silica (eluent: ethyl acetate-n-hexane, 1--1), 4.98 g of the expected product is obtained. m.p. 65°-66° C.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].N1C=CC=CC=1.[NH:14]1[CH:18]=[C:17]([CH:19]2[CH2:28][CH2:27][CH2:26][C:25]3[C:24]([NH2:29])=[CH:23][CH:22]=[CH:21][C:20]2=3)[N:16]=[CH:15]1.C(O)C(N)(CO)CO>ClCCl>[NH:16]1[C:17]([CH:19]2[CH2:28][CH2:27][CH2:26][C:25]3[C:24]([NH:29][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:23][CH:22]=[CH:21][C:20]2=3)=[CH:18][N:14]=[CH:15]1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1cccc2c1CCCC2c1c[nH]cn1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cccc2c1CCCC2c1cnc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of 1-propanesulfonyl chloride (20.5 mg, 0.14 mmol) in dichloromethane (250 mL) was added pyridine (78 mL, 0.96 mmol) followed 5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenamine (30 mg, 0.096 mmol) dissolved in CH2Cl2 (1 mL). The CH2Cl2 was removed under vacuum and the reaction gently shaken at ambient temperature overnight. To the reaction was added 1.0 mL of CH2Cl2 followed by 200 mg of polymer supported trisamine (Argonaut laboratories). The reaction was shaken at room temperature for 30 minutes, the filtrate collected and the volume brought to 5 mL with dichloromethane. The organic layer was extracted with 10% aqueous citric acid (3×4 mL), brine (2×4 mL), filtered (Varian CE1000M)® and the solvent removed under vacuum. The resulting oil was dissolved in 2 mL of acetonitrile and 0.5 g of Amberlyst resin was added. The reaction was shaken at room temperature for 72 hours and filtered. The resin was washed with acetonitrile (2×2 mL), methanol (2×2 mL), and suspended in 2 M methanolic ammonia (2 mL) for 2 hours. The resin was filtered, washed with 0.5 mL of methanol and then retreated with ammonia as described. The ammonia and methanol filtrates were combined and the solvent removed under vacuum. The crude material was purified using reverse phase preparative HPLC. (6.7 mg, 21.9% yield).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4])=[N+:21]=[N-:22]
Reactant: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CBr)[C@H]2SC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@H]2SC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution, prepared at 30° C., of 7β-bromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid (about 0.15 mmol), prepared according to the process described in Example 43, in 10 ml of ethanol and 0.3 ml of water is mixed with a solution of 0.03 g of sodium azide in 0.5 ml of water. The reaction mixture is stirred for 15 hours at room temperature with exclusion of light and is then worked up according to the process described in Example 41. 7β-Azidoacetylamino-3-methoxy-3-cephem-4-carboxylic acid is thus obtained, which in a thin layer chromatogram (silica gel; system: n-butanol/pyridine/acetic acid/water, 42:24:4:30) shows an Rf value of 0.40; ultraviolet absorption spectrum (in ethanol): λmax at 264 mμ; infrared absorption spectrum (in mineral oil): characteristic bands at 4.65μ and 5.64μ.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[CH3:2].CCCCCC.C([Li])CCC.[CH3:27][S:28]SC.[OH-].[Na+]>C(OCC)C>[CH2:1]([O:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[C:8]=1[S:28][CH3:27])[CH3:2]
Reactant: CSSC
Reactant: CCOCOCc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOCOCc1ccc2c(c1SC)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
1.05 g of 1-[(ethoxymethoxy)methyl]-3,4-methylenedioxybenzene was dissolved in 10 ml of diethyl ether, 2 ml of a 2.52 M n-butyllithium hexane solution was added thereto at 0° C., and the mixture was stirred for 2 hours, and then 471 mg of methyldisulfide was added dropwise at −70° C. After completing the dropwise addition, the mixture was further stirred at room temperature for 12 hours. A 1N aqueous sodium hydroxide was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 561 mg of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18]C)[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl.O.CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1C(CC(=O)c1cc[nH]c(=O)c1)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
To a solution of 3-(4-bromo-phenyl)-1-(2-methoxy-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 109, step 1; 190 mg) in dioxane (9 mL) was added concentrated hydrochloric acid (1 mL) and the mixture was heated to 100° C. for 2 h. The solution was cooled to rt and added to a mixture of water and EtOAc. The inorganic phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude title compound as a white foam, MS (ESI+): m/z=396.1 ([M+H]+, 1Br).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl>[O:31]1[CH2:32][CH2:33][N:28]([CH2:2][C:3]2[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nc(CN2CCOCC2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
tert-Butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate (57; 2.0 g, 8.7 mmol) was taken up in 25 mL of CH2Cl2 along with Et3N (1.82 mL, 13.05 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.85 mL, 10.88 mmol) was added and the resulting reaction mixture was stirred at 0° C. for 60 min. Morpholine (48; 3.0 mL, 35 mmol) was then added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc and washed with dilute aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. This material was purified by filtering through a short column of silica gel. The filtrate was concentrated to afford 1.88 g of tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate 58. The Boc group was removed by treating tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate 58 with 20 mL of 25% TFA in CH2Cl2 for 18 h at room temperature. After all the solvent had been removed by concentrating and drying under high vacuum, the resulting residue was treated with a mixture of pentane/EtOAc to afford 2.17 g 4-(morpholinomethyl)thiazol-2-amine 59 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 62 %

Procedure:
Using 5-chlorosalicylic acid and 3-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:15][CH2:16][CH2:17][C@H:18]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]([O:21]C(C)(C)C)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)C>C(OCC)(=O)C>[CH2:47]([O:46][C:44]([NH:43][CH2:42][CH2:41][N:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:15][CH2:16][CH2:17][C@H:18]([N:26]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:19]([OH:21])=[O:20])=[O:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-{bis[(tert-butoxy)carbonyl]amino}pentanoate XXXI (3.00 g, 4.04 mmol) in ethyl acetate (20 mL) was added HCl (3.5 M solution in EtOAc, 20 mL). The reaction mixture was stirred for 30 min at r.t. before adding ethyl ether (about 50 mL). The precipitate was filtered and washed with ether to give (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-{bis[(tert-butoxy)carbonyl]amino}pentanoic acid as a white crystalline solid (1.82 g, 3.14 mmol, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](=[O:11])(=[O:10])[NH:17][CH2:16][CH2:15][O:14][CH3:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COCCN
Solvent: CCCCO
Product: COCCNS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorobenzenesulphonyl chloride (500 mg 2.1 mmol) and 2-methoxyethylamine (230 mg, 3.1 mmol) in n-butanol (10 ml) was heated at reflux for one hour. The volatiles were removed by evaporation and residue purified by chromatography eluting with hexane/ethyl acetate (50:50) to give the title compound. NMR: 3.04 (q, 21), 3.08 (s, 3H), 3.22 (t, 2H), 7.60 (dd, 31), 7.82 (d, 1H), 7.92 (d, 1H), 8.0 (s, 2H); m/z: 282 [M−H]−.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.C([Li])(CC)C.[CH2:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:15][CH3:16].C(I)C>C1COCC1.C1CCCCC1>[CH3:16][CH2:15][CH:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:3][CH3:4]
Reactant: CCCc1ccccc1C(=O)N(CC)CC
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC)c1ccccc1C(=O)N(CC)CC
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a solution of 9.3 ml (0.058 mol) of tetramethylethylenediamine in 340 ml of THF at -78° C. was added 52 ml of a 1.1M solution (0.057 mol) of s-butyl lithium in cyclohexane. The solution was then treated with a solution of 11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75 ml of THF at -78° C. and the solution stirred for fifteen minutes and then treated with a solution of 8.3 ml (0.104 mol) of ethyl iodide in THF. The solution was stirred for an hour and a half at -78° C. and then quenched by the addition of saturated ammonium chloride added dropwise at -78° C. The mixture was then allowed to warm to ambient temperature, diluted with diethyl ether, washed first with dilute hydrochloric acid, then with water, then with saturated sodium bicarbonate, then with brine, dried and taken to dryness to give 12.91 g of crude product which was chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 3.23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].C(C1C=CC(C=O)=CC=1)(C)(C)C.O=P(Cl)(Cl)Cl.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was treated with 4-chloromethyl-2-(4-tert-butyl-phenyl)-5-methyl-oxazole (prepared from 4-tert-butyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) and sodium hydride in N,N-dimethylformamide to yield [rac]-3-{7-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-{7-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-2-ethoxy-propionic acid as colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[C:3]([NH:14][CH:15]([CH3:17])[CH3:16])=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:5]=[N:6][CH:7]=1>C(N(CC)CC)C>[CH3:17][CH:15]([NH:14][C:3]1[CH:2]=[CH:7][N:6]=[N:5][C:4]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[CH3:16]
Reactant: CC(C)Nc1c(Cl)cnnc1N1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccnnc1N1CCNCC1

Procedure:
Following the general procedure of PREPARATION 28 and making non-critical variations but starting with 1-[5-chloro-4-(1-methylethyl)amino-3-pyridazinyl]piperazine (PREPARATION 32, 1.7 g) and triethylamine (0.81 g), the title compound is obtained, NMR (CDCl3) 1.28, 2.06, 3.05, 3.11, 3.59, 4.75, 6.39, and 8.49 δ; CMR (CDCl3) 22.2, 43.2, 46.2, 50.6, 103.7, 138.7, 148.4 and 154.5 δ.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.CC[O-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:6]1[CH:7]=[C:3]([C:2]([F:9])([F:8])[F:1])[N:4]=[CH:5]1)[CH3:20]
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.0 g (14.7 mmol) 4-(trifluoromethyl)-1H-imidazole are initially introduced into 5.5 ml (4.7 g, 14.7 mmol) 21% strength sodium ethylate solution in ethanol and 1.8 ml (2.7 g, 16.2 mmol) ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and the filtrate is concentrated in vacuo. Diisopropyl ether is added to the residue, the mixture is filtered again, the filtrate is concentrated again on a rotary evaporator and the residue is dried in vacuo. The product is obtained as a 9:1 mixture of the two regioisomers and is further reacted as such.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:26][CH3:27])[C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH2:26]([N:11]([C:12]1[CH:13]=[C:14]([CH:23]([CH3:24])[CH3:25])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=1)[CH3:27]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ccc(C(=O)O)cc1)c1cc(C(C)C)c2c(c1)C(C)(C)CO2
Yield: 91.9 %

Procedure:
Following general procedure I and using 4-[ethyl-(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 24, 0.045 g, 0.117 mmol) and 2 mL of 5M potassium hydroxide solution in 20 mL of ethanol, the title compound (0.038 g, 86%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.80 (d, 2H, J=9.0 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.67 (d, 1H, J=2.1 Hz), 6.50 (d, 2H, J=9.0 Hz), 4.21 (s, 2H), 3.66 (q, 2H, J=7.2 Hz), 3.01 (heptet, 1H J=7.0 Hz), 1.26 (s, 6H), 1.18 (t, 3H J=7.2 Hz), 1.16 (d, 6H, J=7.0 Hz).