Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[C:22]([OH:23])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]C(C)([O-])C.[K+].IC>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[C:22]([O:23][CH3:25])[C:17]=3[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3c(O)c(F)ccc23)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: COc1c(F)ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred solution of 4-(6-fluoro-7-hydroxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 3.80 mmol) in N-methyl-2-pyrrolidone (33 mL) was added potassium tert-butoxide (2.09 g, 17.12 mmoles). To the resulting deep red solution was added iodomethane (1.20 mL, 19.02 mmoles). The resulting yellow solution was stirred at room temperature for 6 hours when the reaction was quenched with water (55 mL) and acidified with HClaq. The resulting mixture was extracted with. Et2O (4×110 mL). The combined extracts were washed with brine (110 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 1.2 g of the methyl ether. The white, solid product was further purified via recrystallization from 1:1; Et2O/Pet. ether yielding 963 mg (72%) as a white, crystalline solid, mp 94-96° C. Analysis calculated for C18H23N2FO4: 61.70% C, 6.62% H, 7.99% N. Found: 61.75% C, 6.73% H, 7.94% N.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:21][CH:20]3[CH3:22])=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH:19]4[CH2:21][CH:20]4[CH3:22])[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1CC1C)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CC2C)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.66 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-2-methylcyclopropanecarboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The isomers are purified by chromatography (preparative HPLC).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[CH2:6][C:5]1=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C>[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[C:6](=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:5]1=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1(C)CC(Cl)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(Cl)C(=Cc2ccc(F)cc2)C1=O
Reaction time: 0.5 h
Yield: 69 %

Procedure:
10% strength aqueous sodium hydroxide solution (50 cc) is added to a mixture of 2,2-dimethyl-4-chloro-1-cyclopentanone (10 g) and 4-fluorobenzaldehyde (8.4 g) in ethanol (100 c) at 0° C. After 30 minutes, a thick slurry is filtered and the solid washed and then dried. 2,2-Dimethyl-4-chloro-5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g), m.p. 69° C., is obtained. Sodium hydride (3.1 g; 80% strength dispersion in mineral oil) in anhydrous DMSO (50 cc) is heated to 80° C. until the solid is dissolved completely. The solution is then diluted with THF (100 cc) and thereafter cooled to -10° C. A solution of trimethylsulphonium iodide (11.5 g) in dimethyl sulphoxide (80 cc) is added to the mixture in the course of 10 minutes and the mixture is stirred for o15 minutes at -10° C. A solution of 2,2-dimethyl-4-chloro- 5-(4-fluorobenzylidene) -1-cyclopentanone (11.8 g) is then added in THF (100 cc). The mixture thereby produced is left at room temperature, then poured into water and extracted with ether, washed with water, dried and distilled. 7-(4-Fluorobenzylidene)-4,4-dimethyl-1-oxaspiro [2.4]hept-5-ene, used directly for the next step, is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=O)[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH3:27]>>[CH3:12][O:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:2]3=[N:3][CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]3[N:8]=[C:22]2[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH3:27]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Product: CCOc1cc(-n2c(C)nc3cc(C)cnc32)ccc1C(=O)OC
Yield: 83.6 %

Procedure:
Method B applied to 2-chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and 4-acetylamino-2-ethoxybenzoic acid methyl ester (142 mg, 0.6 mmol) afforded the title compound as viscous oil (136 mg, 84%). 1H NMR (DMSO) δ 1.34 (t, J=6.9Hz, 3H), 2.46 (s, 3H), 2.61 (s, 3H), 3.82 (s, 3H), 4.12 (q, J=6.9Hz, 2H), 7.22 (d, J=8.0Hz, 1H), 7.50 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.98 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([CH:7]([C:15](=[O:17])[CH3:16])C(OC(C)(C)C)=O)=[O:6]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:7][C:15](=[O:17])[CH3:16])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)c1cccc(Cl)c1
Yield: 9120 %

Procedure:
A solution of tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate (8.82 g) in trifluoroacetic acid (40 mL) was stirred for 1 hour under an ice-bath. The volatile was removed in vacuo, and the residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give 1-(3-chlorophenyl)-1,3-butanedione as a pale orange crystal (533 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[N:20]=[C:19](Cl)[N:18]=[C:17]([NH:22][C@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([CH3:33])([CH3:32])[CH2:24]3)[N:16]=2)[CH2:11][C@@H:10]1[CH2:34][OH:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCO.[Pd].[OH-].[OH-].[Pd+2]>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([NH:14][C:15]2[N:16]=[C:17]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([CH3:33])([CH3:32])[CH2:24]3)[N:18]=[CH:19][N:20]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)C[C@@H](Nc2nc(Cl)nc(N[C@H]3C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C3)n2)c2ccccc21
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C[C@H](Nc2ncnc(N[C@@H]3C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C3)n2)c2ccccc21
Reaction time: 96 h
Yield: 34.9 %

Procedure:
To a solution of {(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-chloro-6-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}-methanol (0.083 g, 0.16 mmol) in EtOH (1.11 mL) was added Pd (10% on carbon) (0.0170 g, 0.0160 mmol) and the mixture was stirred under an atmosphere of hydrogen for 4 d. The reaction was purged with nitrogen for 30 minutes then Pd(OH)2 (20% on carbon dry weight) (0.022 g, 0.016 mmol) was added and the mixture was stirred for 4 h under an atmosphere of hydrogen. Filtration of the mixture through a pad of celite, followed by flash chromatography (50-100% EtOAc/hexanes) afforded the title compound (0.027 g, 35%). LC/MS: Rt=1.81 min, ES+ 484 (FA standard).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][CH2:16][C:17](OCC)=[O:18]>C(O)C(F)(F)F>[F:15][CH2:16][C:17]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:18]
Reactant: CCOC(=O)CF
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CF)CC1
Yield: 53.1 %

Procedure:
A solution of 500 mg of tert-butyl piperidin-4-ylcarbamate and 345 mg of ethyl fluoroacetate in 1 ml of trifluoroethanol was heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added to the resulting residue. Then, this was extracted with EtOAc, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate and brine. This was then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform to chloroform/methanol=30/1) to obtain 345 mg of tert-butyl [1-(fluoroacetyl)piperidin-4-yl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)[S:9]1(=[O:35])=[O:34].[ClH:36]>CCOCC.CO.CCOCC>[ClH:36].[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[S:9]1(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Reaction time: 16 h
Yield: 87 %

Procedure:
tert-butyl (1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-yl)carbamate (0.40 g, 0.80 mmol) was dissolved in ether:methanol (9:1) and 2 mL of 2N HCl in ether added. The solution was allowed to stand for 16 hr whereupon a colorless solid had formed. The solid was removed by filtration and washed with ether to afford 0.33 g (87%) 1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine dihydrochloride. HPLC purity 98.7% at 210-370 nm, 5.5 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C20H25FN4O2S+H+, 405.17550; found (ESI, [M+H]+Obs'd), 405.1768.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=O)[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=O)[CH3:18])[O:8][CH:7]=[CH:6]1)(=O)[CH3:2].C[O-].[Na+].[H-].[Na+].[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=CC=1>CO>[CH2:1]([O:4][C@H:5]1[C@H:10]([O:11][CH2:12][C:13]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[C@@H:9]([CH2:15][O:16][CH2:17][C:18]2[CH:31]=[CH:28][CH:29]=[CH:30][CH:25]=2)[O:8][CH:7]=[CH:6]1)[C:2]1[CH:31]=[CH:28][CH:29]=[CH:30][CH:25]=1
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: C1=C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
3,4,6-Tri-O-acetyl-D-glucal (5.0 g, 18.4 mmol) was dissolved in methanol (100 mL) and a solution of sodium methoxide in methanol (0.25 mL, 25% solution by weight, 1.1 mmol). The solution was stirred at room temperature for 3 hours. The solvent was removed and the resulting residue was co-evaporated with toluene (3×10 mL) before being taken up in a 4:1 solution of NMP:THF and cooled to 0° C. Solid NaH (3.3 g of 60% suspension, 82.5 mmol) was added and the mixture was stirred for 30 minutes before the addition of BnBr. The reaction mixture was stirred at room temperature overnight, quenched with methanol and the solvent removed. The residue was suspended in ethyl acetate, washed with 1 N HCl, brine, and saturated NaHCO3 (100 mL each). The ethyl acetate solution was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified on a silica gel column (80 g) using an ISCO automated chromatography system, eluting with a 0→50% gradient of ethyl acetate in heptane, to give 3,4,6-tri-O-benzyl-D-glucal (7.2 g, 94%).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])C)([CH3:3])C.C([Li])CCC.CCCCCC.[C:19](#[N:21])[CH3:20].[Cl-].[NH4+].[O:24]1CC[CH2:26][CH2:25]1>>[OH:24][CH:25]([C:26]1[CH:3]=[CH:1][N:4]=[CH:5][CH:7]=1)[CH2:20][C:19]#[N:21]
Reactant: C1CCOC1
Reactant: CC#N
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: N#CCC(O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Diisopropylamine (1.98 g, 19.6 mmol) was added dropwise to a solution of a butyllithium/hexane solution (10.5 ml, 16.8 mmol) in anhydrous tetrahydrofuran (20 ml) at −80° C. over five minutes, the temperature was raised to 0° C., and the mixture was stirred for 30 minutes. The mixture was cooled to −80° C. again, then acetonitrile (573 mg, 14.0 mmol) was added dropwise to the mixture over seven minutes, and after 20 minutes, 4-pyridinecarboxyaldehyde (758 mg, 7.08 mmol) was added dropwise thereto over 10 minutes. After 50 minutes, a saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, and the temperature was raised to room temperature. The whole was continuously extracted (ethyl acetate and water) for four days. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-hydroxy-3-(4-pyridyl)propionitrile (666 mg, colorless crystals, 63.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:32]([O:34]CC)=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:32]([OH:34])=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(C(=O)OCC)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(CC(=O)NC(C(=O)O)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Ethyl 2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate (0.45 g, 0.9 mmol) in ethanol (5 ml) is stirred together with 1N sodium hydroxide solution (2.7 ml) for 2 hours at 50° C. Then 1N hydrochloric acid (2.7 ml) is added and the mixture is concentrated by evaporation in vacuo. The evaporation residue is partitioned between water and chloroform. The combined chloroform extracts are shaken once with water, then the organic phase is dried, filtered and evaporated down in vacuo. The evaporation residue is crystallized with ether.
Reaction SMILES: [Cu][C:2]#[N:3].[CH2:4]([NH:11][C:12]([C:14]1[S:18][C:17](I)=[N:16][C:15]=1[CH3:20])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O.O>[CH2:4]([NH:11][C:12]([C:14]1[S:18][C:17]([C:2]#[N:3])=[N:16][C:15]=1[CH3:20])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(I)sc1C(=O)NCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a stirred mixture of copper(I) cyanide (0.19 g, 2.10 mmol) in anhydrous N,N-dimethylformamide (6 mL) at 150° C. was added N-benzyl-2-iodo-4-methylthiazole-5-carboxamide (0.30 g, 0.84 mmol). The resulting reaction mixture was stirred at same temperature for 10 minutes, and then allowed to cool to ambient temperature and diluted with water (50 mL). The resulting precipitate was filtered, washed with water (50 mL) and ethyl acetate (100 mL). The organic filtrate was washed with water (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-20% ethyl acetate in hexanes) to afford the title compound as a clear oil (0.09 g, 39%): 1H NMR (300 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 6.17 (br s, 1H), 4.63 (d, J=5.6 Hz, 2H), 2.73 (s, 3H); MS (ES−) m/z 256.2 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17]CC3C=CC(OC)=CC=3)[CH:12]=2)[N:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:7]1=[O:34])#[N:2].Br.C(O)(=O)C>>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:7](=[O:34])[N:6]([CH2:5][C:4]3[CH:35]=[CH:36][CH:37]=[CH:38][C:3]=3[C:1]#[N:2])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccc(CNc2cc(-c3cn(Cc4ccccc4C#N)c(=O)n3-c3ccc(F)cc3)ccn2)cc1
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1ccccc1Cn1cc(-c2ccnc(N)c2)n(-c2ccc(F)cc2)c1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To 1.5 g of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-[2-(4-methoxybenzylamino)pyridin-4-yl]-4-imidazolin-2-one (Compound of Example 5) was added 3 ml of 25% hydrogen bromide-acetic acid solution, and the mixture was stirred at 70° C. for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was made alkali with an aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 572 mg of the title compound as colorless crystal. Melting point:182-183° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[CH3:18][S:19](OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=[O:21])=[O:20]>>[CH3:18][S:19]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[CH2:8][CH2:9]1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1

Procedure:
Commercially available tert-butyl [trans-4-(2-hydroxyethyl)cyclohexyl]carbamate (500 mg, 2.05 mmol) was reacted according to the procedure described for Intermediate 6 to give the product as a white solid (yield 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][N:16](Cl)[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N:16]([CH3:17])[CH3:15])[CH:5]=[N:4][CH:3]=1
Reactant: CN(C)Cl
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1cncc(Br)c1
Temperature: 200 °C
Yield: 88.5 %

Procedure:
To a solution of 3,5-dibromopyridine (XLII) (2.37 g, 10.0 mmol) in dry DMF (20.0 mL) was added K2CO3 (4.5 g, 33 mmol) and dimethylamino hydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at 200° C. in a sealed tube. The solution was cooled to room temperature and excess DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic phase was separated. The aqueous phase was washed with EtOAc and the combined organic phases were dried over MgSO4, and concentrated to afford 5-bromo-N,N-dimethylpyridin-3-amine (XLIII) as an off-white solid (1.78 g, 8.85 mmol, 88% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.94 (s, 6H), 7.25 (t, J=2 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H); ESIMS found C7H9BrN2 m/z 201.1 (M+H).
Reaction SMILES: C(N(CC)CC)C.ClC([O:11][CH2:12][CH3:13])=O.[Cl:14][C@H:15]1[C@H:19]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@@H:18]([CH2:29][O:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)[C@H:17]([OH:39])[CH2:16]1.C(O)CO>C(Cl)Cl>[OH:11][CH2:12][CH2:13][O:27][C:26](=[O:28])[CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][C@H:19]1[C@H:15]([Cl:14])[CH2:16][C@@H:17]([OH:39])[C@@H:18]1[CH2:29][O:30][C:31]1[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](COc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: ClCCl
Product: O=C(CCC/C=C\C[C@@H]1[C@@H](COc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl)OCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22 %

Procedure:
Triethylamine (15 μL, 0.11 mmol) and ethyl chloroformate (15 μL, 0.16 mmol) were added sequentially to a solution of (Z)-7-[(1R,2S,3R,5R)-5-chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic acid (U.S. Provisional Patent Application No. 60/644,069, filed on Jan. 14, 2005, incorporated by reference herein, 10.5 mg, 0.025 mmol) in CH2Cl2 (0.2 mL) at room temperature. After 2.5 h, triethylamine (15 μL, 0.11 mmol) and ethylene glycol (200 μL, 3.59 mmol) were added. After stirring overnight at room temperature, the reaction mixture was partitioned between H2O (5 mL) and CH2Cl2 (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×5 mL). The combined organic phase was washed with 1 N HCl (5 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% MeOH/CH2Cl2) afforded 2.5 mg (22%) of the title compound (1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[C:7]([C:9]([OH:11])=O)=[CH:8][C:5]=2[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[C:7]([C:9]([N:39]3[CH2:38][CH2:37][CH:36]([C:33]4[C:32]5[CH:42]=[CH:43][C:29]([F:28])=[CH:30][C:31]=5[O:35][N:34]=4)[CH2:41][CH2:40]3)=[O:11])=[CH:8][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc2c(cc1OC)C(C(=O)O)=C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(C(=O)N1CCC(c3noc4cc(F)ccc34)CC1)=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.0 g of 4,5-dimethoxybenzocyclobutene-1-carboxylic acid (prepared according to the process described in Tetrahedron (1973) 29 p. 73) are dissolved in 130 ml of tetrahydrofuran, and 6.9 g of carbonyldiimidazole are added. The mixture is stirred at room temperature for 2 hours until the gaseous evolution has ceased. A solution of 8.5 g of 6-fluoro-3-piperid-4-yl-1,2-benzisoxazole in 100 ml of tetrahydrofuran is then added dropwise. The mixture is stirred at room temperature overnight. The expected product precipitates. It is filtered off and dried in a desiccator over phosphorus pentoxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[N:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[C:15]([C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1)#[CH:16]
Reactant: COc1ccc(-c2cnc(C#C[Si](C)(C)C)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1cnc(-c2ccc(OC)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.00 g (7.08 mmol) 2-(4-methoxyphenyl)-5-((trimethylsilyl)ethynyl)pyrazine in 50 mL DCM are added 2.08 g (7.44 mmol) TBAF*H2O and the reaction mixture is stirred at r.t. for 30 min. The mixture is washed with 50 mL water (3×) and the organic layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 100/0→80/20).