Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[OH:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51][N:52]([CH3:69])[C:53](=[O:68])[C@H:54]([NH:66][CH3:67])[CH2:55][C:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:66]([C@@H:54]([C:53](=[O:68])[N:52]([CH2:51][CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[O:43][CH2:42][CH2:41][OH:40])[CH3:69])[CH2:55][C:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=1)[CH3:67])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
At 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (125 mg, 0.65 mmol) was added to a solution of (2E)-5-(tertbutoxycarbonylamino)-5-methylhex-2-enoic acid (158 mg, 0.65 mmol) and 1-hydroxy-7-azabenzotriazole (88 mg, 0.65 mmol) in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml). The solution was stirred for 20 min at 0° C. A solution of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (265 mg, 0.65 mmol) in dichlromethane (3 ml) and ethyldiisopropylamine (0.11 ml, 0.65 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (first: 2:1 (500 ml), then: 3:1) as elutent, to give 378 mg of (3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)=[O:11])=[C:7]([NH:20][C:21]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])[C:6]=2[CH:32]=1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:33]([O:36][CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)=[O:11])=[C:7]([NH:20][C:21]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:30])[CH3:31])[CH2:25][CH2:24]3)=[O:22])[C:6]=2[CH:32]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(N)cc23)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 180 is dissolved in dichloromethane (8 ml), and thereto are added acetoxy acetylchloride (36 mg) and pyridine (36 μl) under ice-cooling, and the mixture is stirred at room temperature for 17 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform, then chloroform/methanol=50/1) to give trans-5-acetoxyacetylamino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (110 mg). A portion of this product is dissolved in ethanol, and treated with 4N hydrogen chloride in ethyl acetate to give the title compound (16 mg).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH:21]=[CH2:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:27].C(O)C>C(OCC)C>[IH:27].[CH2:20]([N:19]1[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)[CH:21]=[CH2:22]
Reactant: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: C=CCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.89 g, 2.5 mmol), aqueous hydriodic acid (10 mL, 57%), and ethanol (10 mL). Heat to reflux. After 1 hour, cool to ambient temperature, pour the reaction mixture into diethyl ether (250 mL), and stir to give a solid. After 1 hour, collect the solid by filtration, rinse with diethyl ether, and dry in vacuo to give the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[C:8]1[C:9]([Cl:22])=[C:10]([Cl:21])[C:11](C)=[C:12]([C:17](O)=[O:18])[C:13]=1[C:14](O)=[O:15].[OH-].[Na+]>C1COCC1.C(OCC)C>[Cl:21][C:10]1[CH:11]=[C:12]([CH2:17][OH:18])[C:13]([CH2:14][OH:15])=[CH:8][C:9]=1[Cl:22]
Reactant: Cc1c(Cl)c(Cl)c(C)c(C(=O)O)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc(Cl)c(Cl)cc1CO
Temperature: 25 °C
Yield: 88 %

Procedure:
To a slurry of LiAlH4 (1.61 g, 42.54 mmol) in dry THF (75 mL) cooled to −78° C., a solution of dimethyl 4,5-dichlorobenzene-1,2-dicarboxylic acid (5.0 g, 21.27 mmol) in dry THF (25 mL) was added dropwise over a period of 1 h. After slow warming of the system to RT over a period of 2 h the mixture was heated at reflux overnight. The heterogeneous mixture was then cooled to 0° C. and sodium hydroxide solution (15%, 100 mL) cooled to 0° C. was very slowly added. This was followed by addition of ice-cold water (100 mL), and the reaction mixture was diluted with diethyl ether (200 mL) and the organic layer was separated, dried over MgSO4. Removal of solvents gave a white solid which was passed through a pad of silica gel to afford pure product in 88% yield (3.85 g). 1H NMR (500 MHz, CDCl3): δ 7.60 (s, 2H), 4.65 (s, 4H), 4.50 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Br)cc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Br)cc3)cc21

Procedure:
Prepared analogously to Example 2, from 6-[4-(4-bromo-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH2:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][CH2:18][NH:19]CC(C2C=CC=CC=2)CO)=[CH:15][CH:14]=1)[CH3:8]>CS(C)=O>[CH2:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][C:18]([NH2:19])=[O:3])=[CH:15][CH:14]=1)[CH3:8]
Reactant: O=C(O)C(=O)O
Reactant: CCOCCOc1ccc(CCNCC(CO)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CCOCCOc1ccc(CC(N)=O)cc1

Procedure:
from N-[(R or S)-3-hydroxy-2-phenylpropyl]-p-(2-ethoxyethoxy)phenylacetamide there was prepared (R or S)-β-[[[p-(2-ethoxyethoxy)phenethyl]amino]methyl]-phenethyl alcohol oxalate m.p. 152°-154° C., [α]D -9° (DMSO, c=1%)
Reaction SMILES: SC1SC(S)=NN=1.CC1C2C(C)(C)C(C2)CC=1.[CH:18]12[CH2:26][CH:22]([C:23]1([CH3:25])[CH3:24])[CH2:21][CH2:20][C:19]2([S:28][C:29]1[S:30][C:31]([SH:34])=[N:32][N:33]=1)[CH3:27].[O:35]1[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:36]1>C(O)(C)C>[CH:18]12[CH2:26][CH:22]([C:23]1([CH3:24])[CH3:25])[CH2:21][CH2:20][C:19]2([S:28][C:29]1[S:30][C:31]([S:34][CH2:36][CH:37]([OH:35])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[N:32][N:33]=1)[CH3:27]
Reactant: CCCCCCCCCCCCCCC1CO1
Reactant: CC1(Sc2nnc(S)s2)CCC2CC1C2(C)C
Agent: CC1=CCC2CC1C2(C)C
Agent: Sc1nnc(S)s1
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCC(O)CSc1nnc(SC2(C)CCC3CC2C3(C)C)s1
Temperature: 120 °C

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (161.3 g, 1.08 mol) and alphapinene (161.3 g, 1.18 mol) were charged to a reaction vessel and cautiously heated to 120° C. (exothermic reaction). The reaction was maintained at 135° C. for one hour. The intermediate product was stripped under vacuum at 135° C. to remove any unreacted pinene and filtered hot. Methanol (200 ml), hexane (150 ml) and water (15 ml) were charged. The hexane layer was removed and discharded. The methanol layer was stripped of methanol by rotary evaporation and the intermediate product residue was mixed with toluene (200 ml) and then extracted with 1M sodium bicarbonate solution (50 ml). The toluene layer was dried over magnesium sulfate and the solvent removed by rotary evaporation. The yield was 134.1 g (0.468 mol) of the purified intermediate, 2-(2-pinanylthio)-5-mercapto-1,3,4-thiadiazole. This product was reacted with 1,2-epoxyhexadecane (112.3 g, 0.468 mol) by charging both reagents and isopropanol (100 ml) and bringing the reaction to reflux. The solvent was then stripped by rotary evaporation to afford the product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[O:18])[CH2:16][CH3:17])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=2)O1>C(O)C.C1(C)C=CC=CC=1.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>[CH3:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)=[C:8]([C:15](=[O:18])[CH2:16][CH3:17])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCC(=O)c1cc(C)c(C)cc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1cc(C)c(C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C

Procedure:
A vigorously stirred solution of triflate 83 (10.5 g, 33.8 mmol), aqueous sodium carbonate (50.8 mL of a 2.0 M solution, 102 mmol), tert-butyl 4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (10.45 g, 33.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (3.91 g, 3.38 mmol) in ethanol/toluene (1:1, 100 mL) was degassed via three vacuum/nitrogen ingress cycles and heated to 75° C. for 30 min. The reaction mixture was poured into ice water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-25% EtOAc/hexanes as eluent) afforded 84 as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16](Cl)[N:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc(Cl)nc(NCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(NCc3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 57.7 %

Procedure:
To a solution of 2-(benzylamino)-6-chloroisonicotinic acid (0.9 g, 3.43 mmol) in THF (8.57 mL) and water (8.57 mL) were added (4-methylphenyl)boronic acid (0.70 g, 5.14 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.14 g, 0.17 mmol) and cesium carbonate (3.35 g, 10.3 mmol). The mixture was purged with nitrogen and was heated to 120° C. in the microwave reactor for 7 min. The mixture was filtered with Celite and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→80% dichloromethane/methanol) gave the title compound (0.63 g): LC-MS [M+1]=318.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22](Cl)(=[O:24])=[O:23])[CH2:17]2.[N:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22]([NH:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][N:28]=1)(=[O:24])=[O:23])[CH2:17]2
Reactant: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reactant: Nc1ccncn1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1ccncn1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: [OH-].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.[CH3:29][S:30][CH2:31][C:32](=[N:37][OH:38])[C:33]([CH3:36])([CH3:35])[CH3:34].[CH3:39][N:40]([S:44][N:45]([CH3:47])[CH3:46])[C:41](F)=[O:42]>C1C=CC=CC=1>[CH3:39][N:40]([S:44][N:45]([CH3:47])[CH3:46])[C:41]([O:38][N:37]=[C:32]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:31][S:30][CH3:29])=[O:42]
Reactant: CSCC(=NO)C(C)(C)C
Reactant: CN(C)SN(C)C(=O)F
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CSCC(=NOC(=O)N(C)SN(C)C)C(C)(C)C
Reaction time: 20 h
Yield: 73.7 %

Procedure:
A mixture of 2.5 g powdered potassium hydroxide, 0.1 g. of dicyclohexyl-18-crown-6, and 6.0 g (0.037 mole) of 1-methylthio-3,3-dimethyl-2-butanone oxime in 200 ml of benzene was stirred 2 hrs. at 28° C. Then 5.9 g (0.037 mole) of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride was added rapidly. The mixture was stirred 20 hrs. at room temperature, water washed three times, dried (MgSO4), and the benzene solvent was removed in vacuo. The product, 1-methylthio-3,3-dimethyl-2-butanone O-[N-methyl-N-(dimethylaminosulfenyl)carbamoyl]oxime, was obtained as a heavy syrup which would not crystallize, 8 g. (73.7 percent yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:28][CH:22]([CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCCCCC(C)N
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCC(C)NC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-methyl-hexylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H29NO5 [M−H]−: 350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)C(c1cccc(Cl)c1)C1(O)CCCCC1

Procedure:
In an analogous manner to Example 1, step 1 2-(3-chlorophenyl-2-(1-hydroxycyclohexyl)-N-[4-(trifluoromethyl)benzyl]acetamide was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and 4-trifluoromethylbenzylamine. MS (ESI) m/z 426/428 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.C[C:26]([N:28](C)C)=O>O.ClCCl.[Zn].[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([C:9]2[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][N:6]3[C:2]([C:26]#[N:28])=[CH:3][N:4]=[C:5]3[N:10]=2)=[CH:12][CH:13]=1)=[O:16]
Reactant: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1
Reactant: CC(=O)N(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Temperature: 160 °C

Procedure:
350 mg 4-(3-bromo-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described in example 11), 5.6 mg Zn, 63.7 mg Zn(CN)2 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct are suspended in dimethylacetamide and the mixture is heated for 45 min under microwave irradiation to 160° C. The workup is performed by diluting the mixture with water and dichlormethane, extracting the aqueous layer twice and drying the combined organic layers over Na2SO4. The compound is isolated by evaporation of the solvent and chromatography on silica gel (dichloromethane/methanol).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1Cl>CN(C=O)C.O>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1
Reactant: COC(=O)c1cccnc1Cl
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C

Procedure:
A mixture of 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared according to Preparation 5 above) (3.2 g, 15.4 mmol) and 2-chloro-nicotinic acid methyl ester (1.78 g, 10.4 mmol) was dissolved in DMF (10 mL) and heated to 100° C. for 2 h. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to afford the product as yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[O:8][N:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[F:20][C:17]([F:18])([F:19])[C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:10]=1
Reactant: CCOC(=O)c1noc(-c2cnccc2C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
15.8 g of 3-ethoxycarbonyl-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole are initially charged in 13 ml of methanol, and, with ice-cooling at 0° C., a solution of 2.8 g of lithium hydroxide in 50 ml of water is added dropwise. The mixture is stirred at room temperature for 2 h, 20 ml of ice-water are added and the mixture is extracted with 200 ml of diethyl ether. The aqueous phase is adjused to pH=2 using dil. HCl, and the precipitated product is filtered off with suction. After drying, 13.8 g of 5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole-3-carboxylic acid are obtained as a white solid of mp. 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[ClH:28]>O>[ClH:1].[ClH:28].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:24][CH2:23]1
Reactant: Fc1ccc(-c2cc(Cl)nc3ccccc23)cc1
Reactant: OCCN1CCNCC1
Agent: Cl
Solvent: O
Product: OCCN1CCN(c2cc(-c3ccc(F)cc3)c3ccccc3n2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 16 g of 2-chloro-4-(4-fluorophenyl)quinoline and 25.4 g of 1-(2-hydroxyethyl)piperazine is stirred at 130° C. for 3 hours. After cooling, water is added and the resulting mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (150 g) with chloroform - methanol (100 : 1). The eluates pooled are concentrated to give an oily residue, which is treated with ethanolic hydrogen chloride to afford the hydrochloride. Recrystallization from ethanol - ethyl acetate gives 16.7 g of the title compound, m.p. 210°-218° C.