Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[K].CC(C)([O-])C.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)=[O:6]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxybenzoic acid (6.9 g, 50 mmole) in DMF (100 ml) was added potassium-tert.-butoxide (6.17 g, 55 mmole) and the mixture was stirred at room temperature for one hour. 4-Methoxybenzyl chloride (9.4 g, 60 mmole) was added and the mixture was stirred for 16 hours at 60° C. The mixture was evaporated under reduced pressure and ethyl acetate (250 ml) were added. The organic phase was washed five times with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 10.5 g=81%
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([F:31])[C:19]=1[F:32].ClC1SC(COC2C=CC(CCC(OCC)=O)=C(F)C=2F)=C(C2C=CC(Cl)=CC=2)C=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([F:31])[C:19]=2[F:32])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCc1ccc(-c2cc(Cl)sc2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1F
Product: CCc1ccc(-c2cc(Cl)sc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 196 by coupling of [5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.26-7.33 (m, 4H), 6.95 (s, 2H), 6.85 (t, J=8.8 Hz, 2H), 6.59-6.64 (t, J=8.4 Hz, 1H), 6.62 (t, J=8.4 Hz, 1H), 5.13 (s, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.67-2.74 (m, 4H), 1.29 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H19ClF2O3S, 435.1 (M−H). found 435.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=O)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[S:37])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1cccc(C(CNCC(=S)N(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide (0.38 g, 1.0 mmol) in dry toluene (20 ml), Lawesson's reagent (0.58 g, 1.2 mmol) was added one-pot and the mixture was heated to reflux and stirred for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (petroleum ether:AcOEt from 9:1 to 8:2) to give pure title compound as a colourless oil (0.11 g, 28% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:46])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH2:44][CH3:45])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:46])=[CH:17][C:18]=4[O:43][CH2:44][CH3:45])=[N:42][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCOc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 155 %

Procedure:
A solution of 0.0749 g (0.0712 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-221) in 3 mL of dichloromethane was stirred with 3 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.060 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-piperidin-4-yl-benzamide (I-222) as a white solid.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]3[CH:16]([CH3:20])[CH2:17][CH2:18][N:19]=[C:11]3[C:10]3(OCCC[O:21]3)[C:9]=2[CH:8]=1.[NH4+].[OH-]>>[Br:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]3[CH:16]([CH3:20])[CH2:17][CH2:18][N:19]=[C:11]3[C:10](=[O:21])[C:9]=2[CH:8]=1
Reactant: CC1CCN=C2N1c1ccc(Br)cc1C21OCCCO1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC1CCN=C2C(=O)c3cc(Br)ccc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To cold concentrated H2SO4 (3 mL) was added 8′-bromo-4′-methyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole] (0.252 g, 0.747 mmol) in four portions with cooling in an ice bath. The reaction was then allowed to stir at room temperature for 1 hr. The mixture was poured onto ice and basified with NH4OH to pH 11 with cooling in an external ice bath. The reaction mixture was extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (96/2/1) to give the title compound as a red solid (0.138 g, 66% ). Anal. Calc'd for C12H11BrN2O: C, 51.64; H, 3.97; N, 10.04; Found: C, 51.23; H, 3.89; N, 9.88. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 278/280 [M+H]; 1 Br pattern observed. m.p.: 127-129° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[OH:24][CH2:25][CH2:26][N:27]([CH2:46][CH2:47][OH:48])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36]3[CH:42]=[C:41]([C:43]([O-])=[O:44])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1>>[OH:24][CH2:25][CH2:26][N:27]([CH2:46][CH2:47][OH:48])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36]3[CH:42]=[C:41]([C:43]([NH:20][C:18]4[CH:17]=[CH:16][C:14]5[NH:15][C:11]([C:8]6[CH:9]=[CH:10][C:5]([N:4]([CH2:21][CH2:22][OH:23])[CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=6)=[N:12][C:13]=5[CH:19]=4)=[O:44])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Reactant: Nc1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2c1)c1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1

Procedure:
Compound 289 was prepared according to the procedure similar to that described in Scheme V from 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5-aminobenzimidazole and 2-(4-(bis(2-hydroxyethyl)amino)phenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C35H37N7O5: 636.29; found: 636.06.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][NH2:42])[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:41][CH2:40][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(CCN)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCCN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 16.7 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.039 g (0.33 mmole) of 2-(4-methyl-piperazin-1-yl)-ethylamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 20:80-100:0) to give 0.021 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[2-(4-methyl-piperazin-1-yl)-ethyl]-benzamide (I-47) as a white solid.
Reaction SMILES: C([C@@H](N[C@H](C(O)=O)C)CCC1C=CC=CC=1)(OCC)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C@@H:34]([C:42]([OH:44])=[O:43])[NH:33]1>>[CH2:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH:34]([C:42]([OH:44])=[O:43])[NH:33]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O=C(O)C1Cc2ccccc2CN1

Procedure:
The first step of Method-I consists of condensation of N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanine (III) with the para-toluene sulfonate salt of the benzyl ester of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (IV) to give the benzyl ester of (S, S, S)-2-{2-{(1-ethoxycarbonyl)-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid or quinapril benzyl ester which is isolated as the maleic acid salt (V).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:17][C:18]([C@@H:20]1[CH2:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH2:22][NH:21]1)=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:17][C:18]([CH:20]1[CH2:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH2:22][N:21]1[S:40]([C:37]1[CH:36]=[CH:35][C:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][CH:38]=1)(=[O:42])=[O:41])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCCCN)NC(=O)C1Cc2c([nH]c3ccccc23)CN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
6-Amino-2-{[2-(biphenyl-4-sulfonyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carbonyl]-amino}-hexanoic acid methyl ester was prepared according to the above procedure from 6-tert-Butoxycarbonylamino2-(S)-[(2,3,4,9-tetrahydro-1H-β-carboline-3-(S)-carbonyl)-amino]-hexanoic acid methyl ester (37 mg, 0.08 mmol) and biphenyl-4-sulphonyl chloride (24 mg, 0.1 mmol) to deliver 6 mg of the TFA salt. MS (APCI) M+575.5
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[Br:1][C:2]1[C:7]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
5-Bromo-6-chloro-3-pyridinecarboxylic acid (68.0 g, 0.288 mol, CAN 29241-62-1) was dissolved in DMSO (1000 mL). To this solution was added with stirring potassium hydroxide (48.25 g, 0.86 mol) and after 10 minutes of stirring at room temperature 2,2,2-trifluoroethanol (26.9 mL, 0.374 mol) was added. The mixture was stirred at room temperature for 24 h. Water (1000 mL) and concentrated hydrochloric acid (107 mL, 1280 mmol, 37%) was added and the suspension was stirred vigorously for 4 hours. The precipitate was filtered, washed with water (4×100 mL) and vacuum dried over night to give the title compound (80.4 g) as an off white solid; MS (EI) 299, 301 (M)+.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:30])[N:11]3[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:32]1[N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:34]([Br:37])=[CH:35][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.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].ClCCl>[Br:37][C:34]1[N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:32]([C:15]2[C:6]([O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[C@@H:10]([CH3:30])[CH2:9][CH2:8]3)=[N:36][CH:35]=1
Reactant: C[Si](C)(C)CCOCn1c(Br)cnc1Br
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1CCc2c(ccc(-c3ncc(Br)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
A mixture of (S)-(5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.200 g, 0.49 mmol), 2,5-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole (0.178 g, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.046 g, 0.06 mmol), and cesium carbonate (0.549 g, 1.68 mmol) in water (3 mL) and 1,4-dioxane (10 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature and filtered through a short pad of celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate/petroleum ether) to afford ((S)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.091 g, 32%) as a white solid. MS (ESI, pos. ion) m/z 560, 562 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[N:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cn3)CC2)c(C)c1
Yield: 59.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 21 and oxazolidin-2-one (174 mg), the title compound (449 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][CH2:29][OH:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:36]([Si:40](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:28][CH2:29][O:30][Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In N,N-dimethylformamide (15 ml) was dissolved 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxyethyl)piperazine (739 mg) and imidazole (226 mg). Under ice cooling, tert-butylchlorodiphenylsilane (0.70 ml) was added to the resulting solution, followed by stirring at room temperature for 23 hours. The reaction mixture was distilled off under reduced pressure. The residue was extracted with methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic layer thus obtained was washed with dilute hydrochloric acid and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography (hexane:ethyl acetate=2:1˜:2) using as a carrier silica gel, whereby the title compound (804 mg) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].C(#N)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:14]1[N:15]=[C:11]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])([CH3:10])[CH3:9])[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole, acetonitrile and pyridine was added acetic anhydride. The solution was heated to reflux for 1 h. After a routine aqueous work up, the crude product was purified by prep HPLC to give 4-(1-acetylpyrrolidin-2-yl)-2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazole: 1H NMR (CDCl3): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9 (br, 2H), 2.1 (m, 4H), 2.3 (m, 2H), 3.1 (s, 3H), 3.5 (m, 1H) 3.7 (m, 1H), 4.5 (m, 1H), 5.0 (m, 1H), 6.8 (m, 2H), 7.1 (m, 5H), 7.6 (m, 2H), 7.7 (m, 1H), 7.8 (m, 1H), 7.9 (m, 1H), 8.2 (m, 1H); LC/MS M+H 562 (observed).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([CH3:56])[NH2:55]>CN(C=O)C>[CH3:53][N:54]([CH3:56])[NH:55][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CN(C)N
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NN(C)C)s1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (90 mg, 0.29 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (104 mg, 0.32 mmol), N,N-diisopropyl ethyl amine (250 μL, 1.47 mmol) and 1,1-dimethylhydrazine (0.03 mL, 0.39 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 0 to 2% methanol in dichloromethane) afforded the title compound (45 mg, 44%) as a white solid. MS: m/e=349.3 [M+H]+.
Reaction SMILES: C(=O)=O.[CH2:4]([OH:26])[C@H:5]1[O:10][C@H:9]([O:11][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:8]([OH:23])[C@@H:7]([OH:24])[C@@H:6]1[OH:25]>C([O-])(=O)/C=C\C([O-])=O.[Na+].[Na+]>[O:11]=[CH:9][C@@H:8]([C@H:7]([C@@H:6]([C@@H:5]([CH2:4][OH:26])[OH:10])[OH:25])[OH:24])[OH:23]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])/C=C\C(=O)[O-]
Agent: O=C=O
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
In vitro studies. Intestinal glucohydrolases were isolated from rat intestine. Male 150- to 250-g rats were fasted overnight and sacrificed by CO2 anesthesia. The entire small intestine was removed, flushed with 50 to 100 ml of cold saline and placed on an ice-cold glass plate. The mucosal layer was removed and homogenized in 5 times its volume of 0.5 M NaCl, 0.5 M KCl and 5 mM EDTA, pH 7.0. This homogenate was centrifuged at 20,000× g for 30 min and the pellet washed by suspension and recentrifugation three times in fresh salt solution. The resulting pellet was finally homogenized in 5 times its volume of 0.9% NaCl and centrifuged at 200× g for 10 min. The incubation mixtures contained 10 μl of this enzyme preparation plus 3.3 μmole of sucrose and test compound in a final volume of 100 μl of 0.1 M sodium maleate buffer, pH 5.9. All determinations were performed in duplicate or triplicate. One set of determinations was heat inactivated at 90° C. for 2 min immediately after adding the enzyme. The others were incubated for 30 min at 37° C. in a water bath and then heat inactivated. Glucose concentrations were determined by glucose dehydrogenase (Seragen Diagnostics, Indianapolis, Ind.). Glucose produced at each concentration of test compound was compared with that produced with no drug present.