Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.CS(C)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[CH2:30]([NH:37][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])cc3O2)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CNCc1ccccc1)CO2
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A 3 L three necked flask equipped with a heating mantle, thermocouple and mechanical stirrer is charged with [7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (356.8 g, 0.977 mol), DMSO (1 L) and benzylamine (261.7 g, 2.44 mol). The slurry is heated to maintain an internal temperature of 90° C. Heating is continued for 18 h, and then the solution is allowed to cool to 30° C. over 2 h. Water (400 mL) is added over 15 min. then seed crystals (˜100 mg) are added resulting in rapid formation of a precipitate. The slurry is stirred for 30 min prior to additional water (2 L) being added over 1.5 h. The slurry is stirred for 4 h, the solids are collected by vacuum filtration, washed with water (2 L) and suction dried under nitrogen giving the title compound (302.87 g, 103%) as a yellow powder (94% ee). Yield is high due to trapped water, m.p. 98° C. (dried sample). LCMS (Basic Method): 2.05 min, 301 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 7.77-7.70 (m, 1H), 7.47-7.18 (m, 6H), 7.10-7.06 (m, 1H), 4.47 (dd, J=2.5, 11.5 Hz, 1H), 4.37-4.29 (m, 1H), 4.15 (dd, J=7.1, 11.5 Hz, 1H), 3.73 (s, 2H), 2.82-2.70 (m, 2H), 2.43 (br s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@:30]([OH:34])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@](C)(O)c1ccccn1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@](C)(O)c3ccccn3)cc1-2
Yield: 9 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted (2S)-2-(2-pyridyl)but-3-yn-2-ol via General Procedure E to afford 7.7 mg (9%) of 9-fluoro-10-[(3S)-3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=450.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.Cl>CO.C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)OC(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyl (2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoate of step 3 (0.38 mmol, 157 mg) in MeOH/THF/H2O (1:2:2 mL) was added LiOH monohydrate (0.96 mmol, 40 mg). The mixture was stirred at r.t. for 2 h. HCl (1N) was added until pH 1. The mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous, MgSO4 and concentrated. The crude acid was used without further purification.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.P(=O)(O)(O)O>O.C(O)C>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Ethylacetamide 3 (260 g, 1 mol) and 3-amino-4-cyanopyrazole 4 (108 g, 1 mol) were dissolved in a mixture of water (7 L) and ethanol (4 L). Eighty five percent aqueous phosphoric acid (67 ml, 1 mol) was added and the mixture was stirred at room temperature for 8 h. The reaction mixture was then cooled to 5° C. and the crystalline product that formed was collected, washed with water and dried at 60° C. to afford zaleplon (275 g, 90.2%) which was 99.36 pure by HPLC and contained 0.21% regioisomer 5.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=3)[NH2:15])=[CH:8][C:6]=2[N:7]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].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.O>[NH2:15][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[N:11][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:36]4[CH:37]=[N:38][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Reactant: Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a 50 mL sealed tube, 3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)aniline (1.1 g, 0.0032 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (1.15 g, 0.0048), potassium phosphate (2.04 g, 0.0096 mol), DMF (20 mL) and water (7 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.23 g, 0.0002 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 105° C. for 1 hour. The reaction mass was cooled to room temperature and added ice cold water. The precipitate was obtained and the solid was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 2% methanol in chloroform) to provide the title compound (1.4 g, 87%). 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.47 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.07-7.03 (m, 2H), 6.71 (d, J=8.1 Hz, 1H), 5.33 (s, 2H), 4.55 (br s, 4H), 3.83 (t, J=4.8 Hz, 4H), 1.49 (s, 9H). LC-MS (ESI): Calculated mass: 500.2; Observed mass [M+H]+: 501.1 (RT=1.09 min).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:10]=2)[N:5]=1.[ClH:22]>CO.C(OCC)(=O)C.O1CCOCC1>[ClH:3].[ClH:22].[CH3:21][O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH:12]=[CH:13][C:4]([NH:2][CH3:1])=[N:5]3)=[CH:10][CH:9]=2)[CH:19]=1
Reactant: COc1ccnc(-c2ccc3ccc(Cl)nc3c2)c1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1ccc2ccc(-c3cc(OC)ccn3)cc2n1

Procedure:
To a solution of methylamine in methanol (40% w/w, 5 ml) was added 2-chloro-7-(4-methoxypyridin-2-yl)quinoline (140 mg). The mixture was heated in a steel autoclave at 120° C. for 16 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, 5% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 7-(4-methoxypyridin-2-yl)-2-methylaminoquinoline dihydrochloride (106 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](F)=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[NH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:40])[NH:42][CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)F)cc2)N1
Reactant: NCCN1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)NCCN3CCCC3)cc2)N1
Yield: 81.1 %

Procedure:
In a manner similar to the method described in example 55b, racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.28 mmol) was reacted with N-(2-aminoethyl)pyrrolidine (0.4 g, 3.5 mmol), N-methylmorpholine and 4-dimethylaminopyridine in tetrahydrofuran to give racemic(2′R, 3R, 4′S)-2′-{5-bromo-2-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]-phenyl}-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.17 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)=[O:42])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (84.3 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.02 ml) and diisopropylethylamine (0.218 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (34.0 mg, 28%) as white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:27][N:13]3[C:14](=[O:26])[NH:15][C:16]4[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:21]=4[C:12]3=[N:11][CH2:10]2)=[CH:5][CH:4]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[N:39]=[C:40]=[O:41]>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[NH:39][C:40]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:27][N:13]3[C:14](=[O:26])[NH:15][C:16]4[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:21]=4[C:12]3=[N:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:41]
Reactant: CNc1ccc(C2CN=C3c4ccc(C(=O)OC)cc4NC(=O)N3C2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)NC(=O)N1CC(c3ccc(N(C)C(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)CN=C21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
To a solution of methyl 3-[4-(methylamino)phenyl]-6-oxo-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline-9-carboxylate (5.1 mg, 0.014 mmol) in 0.7 mL THF was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0024 mL, 0.017 mmol) and the reaction stirred at rt. After 15 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. At 1 hour the reaction was quenched with 1 mL MeOH and evaporated. The resulting solid was crystallized from EtOAc/hexane to give the title compound as an off-white solid (6.4 mg, 80%). 1H NMR (Acetone-d6) δ: 9.70 (br. s, 1H), 8.57 (dd, J=7.3, 2.3 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.69 (dd, J=8.4, 1.6 Hz, 1H), 7.50-7.59 (m, 4H), 7.25-7.39 (m, 2H), 7.06 (d, J=2.9 Hz, 1H), 4.39-4.47 (m, 1H), 3.88-3.97 (m, 4H), 3.62-3.79 (m, 2H), 3.34 (s, 3H), 3.15-3.27 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:19])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:19])[C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 420 mg (1.3 mmol) of trans-3-{4-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol in 10 ml CH2Cl2 was treated at 0° C. with 0.11 ml (1.43 mmol) methanesulfonylchloride, 0.16 ml (1.95 mmol) pyridine and 159 mg (1.3 mmol) DMAP. The reaction was stirred for 3.5 h at room temperature, water (2 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 540 mg (quantitative) of trans-Methanesulfonic acid 3-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester, MS: 402 (MH+, 1Br).
Reaction SMILES: Br[CH:2]([CH2:16][CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:16]([C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)[CH3:17]
Reactant: CCC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Reactant: Nc1ccccn1
Product: CCc1c(-c2ccc3sc(=O)n(C)c3c2)nc2ccccn12

Procedure:
5-(3-Ethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (1.47) was prepared in substantially the same manner as that of Example 14 from 5-(2-bromobutyryl)-3-methyl-2-benzothiazolinone (4.71 g) and 2-aminopyridine (3.53 g). mp. 273°-274° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[N:10]=3)[CH:23]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-difluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.78) (0.15 g, 0.33 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.103 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.16 g) which was subsequently deprotected.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:43][CH:44]1[C:49]2[CH:50]=[C:51]([C:53](=[N:55]O)[NH2:54])[O:52][C:48]=2[CH2:47][CH2:46][CH2:45]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:55]=[C:53]([C:51]3[O:52][C:48]4[CH2:47][CH2:46][CH2:45][CH:44]([OH:43])[C:49]=4[CH:50]=3)[N:54]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C(N)=NO)cc21
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc(-c3cc4c(o3)CCCC4O)no2)cc1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 5 (5a) using 4-isobutylbenzoic acid (0.12 g, 0.66 mmol), 1-hydroxybenzotriazole (0.11 g, 0.78 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.72 mmol), 4-{[t-butyl(dimethyl)silyl]oxy}-N′-hydroxy-4,5,6,7-tetrahydro-1-benzofuran-2-carboximidamide (0.19 g, 0.6 mmol) that was obtained in Example 7 (7d), and tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 1.2 ml, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2-1:1) as the eluent to afford the title compound (0.15 g) in a yield of 75% as a pale yellowish oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@@H:9]1[C@@H:10](I)[CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[SnH](CCCC)CCCC>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@@H]1[C@@H](I)C[C@@H]2NC(=O)OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Yield: 91 %

Procedure:
A sample of (1R,2S,4S,5R)-2-benzyloxycarbonylamino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (43.3 g) was dissolved in benzene (580 mL) prior to the addition of Bu3SnH (27.8 g) and AIBN (0.7 g). The resulting mixture was warmed to a gentle reflux for 3 h. After cooling, the solvent was removed and hexane was added. The resulting white solid was collected by vacuum filtration to give (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (29.5 g). MS found: (M+Na)+=397.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:38][CH:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41].N1C=CC=CC=1>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:38][CH:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(NC(=O)Cc1ccc(F)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 4-fluorophenylacetic acid (4.5 g, 29.3 mmol) and 1-hydroxybenzotriazole (4.35 g, 32.2 mmol) in dichloromethane (140 ml) was added dicyclohexylcarbodiimide (6.65 g, 32.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was cooled to 0° C., and then a solution of diethyl aminomalonate hydrochloride (6.2 g, 29.3 mmol) in pyridine (4.5 ml, 29.3 mmol) and DMF (10 ml) was added. The temperature was allowed to rise to ambient temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% NaHCO3 solution. The organic layer was washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (8.5 g, 93%).
Reaction SMILES: [C:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Li+]>>[C:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([OH:16])=[O:15])=[CH:27][CH:28]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(Oc1ccc(C(=O)CCCCC)cc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCC(Oc1ccc(C(=O)CCCCC)cc1)C(=O)O
Yield: 80.7 %

Procedure:
1-[4-Hydroxyphenyl]-1-hexanone (384 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Hexanoylphenoxy]decanoate (628 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J=9.0 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.60-4.65 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.86-1.97 (m, 2H), 1.61-1.70 (m, 2H), 1.38-1.52 (m, 2H), 1.20-1.34 (m, 14H), 1.18 (t, J=7.2 Hz, 3H), 0.78-0.87 (m, 6H); 13C NMR (101 MHz, CDCl3): δ 199.17, 171.36, 161.78, 130.95, 130.46 (2C), 114.72 (2C), 76.66, 61.51, 38.41, 32.84, 32.00, 31.76, 29.52, 29.35 (2C), 25.31, 24.41, 22.83, 22.74, 14.33, 14.26, 14.14. The resulting ester (628 mg, 1.6 mmol) was saponified with lithium hydroxide (193 mg, 8.0 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Hexanoylphenoxy]decanoic Acid (468 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 5.77 (br s, 1H), 4.70 (dd, J=5.8, 6.6 Hz, 1H), 2.89 (t, J=7.4 Hz, 2H), 1.97-2.03 (m, 2H), 1.67-1.74 (m, 2H), 1.44-1.60 (m, 2H), 1.23-1.37 (m, 14H), 0.90 (t, J=6.8 Hz, 3H), 0.87 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.76, 176.29, 161.56, 131.20, 130.70 (2C), 114.81 (2C), 76.12, 38.56, 32.78, 32.03, 31.80, 29.53, 29.40, 29.36, 25.36, 24.51, 22.87, 22.76, 14.33, 14.20. The acid (468 mg, 1.3 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Hexanoylphenoxy]decanoate (459 mg, 93%) as a white solid. mp 275-280° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.44-4.48 (m, 1H), 2.89-2.96 (m, 2H), 1.88-1.96 (m, 2H), 1.63-1.71 (m, 2H), 1.44-1.61 (m, 2H), 1.24-1.38 (m, 14H), 0.84-0.93 (m, 6H); 13C NMR (101 MHz, CD3OD): δ 200.89, 177.86, 163.36, 130.27 (2C), 129.60, 114.75 (2C), 79.54, 37.94, 33.18, 31.86, 31.49, 29.44, 29.38, 29.21, 25.73, 24.55, 22.58, 22.45, 13.36, 13.23; LRMS (ESI): m/z 769.8 (M2H+), 747.8 (2M-Na++2H+), 363.2 (M-Na++2H+); HPLC: 3.min.