Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:25]4[S:24][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH:26]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1cc2ccccc2s1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol) and benzothiophene-2-boronic acid (283 mg, 1.59 mmol) the subtitle compound was obtained (386 mg, 57%). The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl.N([O-])=O.[Na+].[F:18][B-](F)(F)F.[H+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:18])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: Fc1ccc(Cl)c(C(F)(F)F)c1
Yield: 37.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)benzenamine (19.5 g, 100 mmoles), water (40 ml) and c.hydrochloric acid (40 ml) were heated with stirring on a steam bath until a white solid formed. The mixture was cooled (ice-salt bath) and a solution of sodium nitrite (7 g, 101 mmoles) in water (15 ml) was added over 15 mins. After stirring for a further hour at 0°, tetrafluoroboric acid (30 g of 40% aqueous solution) was added dropwise over 15 minutes. After one hour the solid was filtered off, washed with water (10 ml), methanol (30 ml) and ether (30 ml) and then dried in vacuo. The dry compound was heated at 140°-180° until no more fumes were observed. The cooled residue was dissolved in ethyl acetate, washed with 5% aqueous sodium hydroxide, dried Na2SO4) and the solvent was removed in vacuo. The residue was distilled in vacuo (12 mmHg, oven temperature 50°-55°) to give the sub-title compound as a colourless oil (7.5 g). M+ 200/198; nmr (CDCl3)δ7.8-7.2 (m).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[OH:16][C:15]([CH3:17])([CH3:14])[CH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-methylpyridin-3-ol (2.54 g, 23.3 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium solution (1.6 M in n-hexane, 32 mL, 51.2 mmol) dropwise at −20° C. After addition, the mixture was allowed to warm to room temperature and stirred at the same temperature for 1 h. Then the mixture was cooled to −78° C., and acetone (2.03 g, 35.0 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with acetic acid (5.8 mL) and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with acetone/n-hexane (1:1) to give 3.90 g (quant.) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:25])[O:5][N:4]=1)[CH3:2].[OH-].[Na+].CCOCC.O>CO>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:25])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the above 2-(3-ethyl-5-methyl-4-isoxazolyl)-γ-oxo-indole-3-butanoic acid, methyl ester in 250 ml methanol is treated with 250 ml of 2N sodium hydroxide solution; and the mixture is heated 15 minutes to 40°-45° and then stirred at room temperature for 1 hour. Ether and water are added to the mixture and the layers then separated. The ether layer is washed with water; after which the combined aqueous layers are washed with ether, treated with charcoal and filtered through celite. The aqueous basic solution is made acidic by careful addition of concentrated HCl and extracted with ether. The ether solution is then washed with water, brine, dried over MgSO4, filtered and evaporated. The resulting foam is crystallized to give the title compound, m.p. 98°-110° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20]CC2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of ethyl (E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.30 g), 5% palladium-carbon (28.00 g), ethanol (150 ml) and tetrahydrofuran (150 ml) was stirred under a hydrogen atmosphere at room temperature for 3 hrs. Palladium-carbon was filtered off and the filtrate was concentrated. The obtained crystals were collected by filtration to give ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (9.01 g, yield 83%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 75–76° C.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=O)OCC(F)(F)F.C1OCCOCCOCCOCCOCCOC1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[Br:48][C:49]1[C:50]([OH:58])=[C:51]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH:52]=O>C1COCC1>[Br:48][C:49]1[C:50]([OH:58])=[C:51](/[CH:52]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:54]=[C:55]([Cl:57])[CH:56]=1
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(Cl)cc(Br)c1O
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (3.18 g, 10.0 mmol) in THF (100 mL) at −78° C. was added 18-crown-6 (13.2 g, 50.0 mmol). The solution was stirred for 10 min then a solution of potassium hexamethyldisilazide in THF (0.91 M, 11.0 mL, 10.0 mmol) was added slowly. The reaction was stirred for 20 min then 3-bromo-5-chloro-2-hydroxy benzaldehyde (2.35 g, 10 mmol) was added. The reaction was allowed to stir at −78° C. for 2 hr, then was quenched with saturated NH4Cl (20 mL) The mixture was extracted with Et2O (3×100 mL) and the organic layer was dried (Na2SO4) and concentrated. Flash chromatography on silica gel (15% EtOAc/hexanes) gave, the title compound (2.48 g, 85%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=16.0 Hz, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 6.57 (d, J=16.0 Hz, 1H), 3.84 (s, 3H); MS (ES) m/e 291, 293 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@@H:16]1[CH2:28][OH:29])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C(OCC)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:17][C@@H:16]1[CH:28]=[O:29])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Add triethylamine (1.1 mL, 7.79 mmol) and sulfurtrioxide-pyridine complex (0.63 g, 3.89 mmol) to an ice cold solution of (2R,4R)-4-benzyloxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.95 mmol) in dimethyl sulfoxide (2 mL). Stir 30 minutes, warm to room temperature and stir 30 minutes. Dilute with ethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil (0.59 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][CH:10]([C:14]([F:17])([F:16])[F:15])[CH:11](O)[OH:12])[CH:7]=1.C(Cl)(=O)C(Cl)=[O:24].CS(C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:24])([C:14]([F:17])([F:16])[F:15])[CH:11]=[O:12])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)(C)CC(C(O)O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: COc1ccc(Cl)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Yield: 98.1 %

Procedure:
2 g (6.12 mmol) of 4-(5-chloro-2-methoxyphenyl)-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol is oxidized with 854.6 mg (6.733 mmol) of oxalyl chloride and 1.05 ml (14.812 mmol) of DMSO as described in Example 2 according to Swern. After the working-up, 1.95 g (98.4%) of the desired aldehyde is obtained, which is incorporated in crude form into the next stage.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.[Li+].CC([N-]C(C)C)C.[I:19]I>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([I:19])[O:8][C:7]=12
Reactant: II
Reactant: Clc1nccc2ccoc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nccc2cc(I)oc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
7-Chlorofuro[2,3-c]pyridine (7.60 g, 49.7 mmol) was placed in a three-necked flask fitted with a thermometer and nitrogen inlet and then anhydrous tetrahydrofuran (150 mL) was added. The solution was cooled to −78° C. To this cold solution was added gradually 2 M LDA solution (32.3 mL, 64.6 mmol) by syringe and the resulting mixture was stirred for 2 h at −78° C. Then a solution of iodine (15.1 g, 59.5 mmol) in dry THF (100 mL) was added at −78° C. and the resulting mixture was allowed to warm to RT overnight. The reaction was quenched with aqueous sodium thiosulfate (75 mL) and diluted with ethyl acetate (150 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×75 mL). All organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give 13.7 g (99%) of the title compound as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 7.40 (d, J=6.0 Hz, 1 H), 8.17 (d, J=6.0 Hz, 1H).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.CCOCC.Cl>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([B:1]([OH:6])[OH:2])=[CH:17][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of triisopropyl borate (4.6 mL, 20 mmol) in THF (1 mL) at -78° C. under nitrogen was added 4-fluorophenylmagnesium bromide (2M solution in diethylether, 10 mL) dropwise. The mixture was allowed to warm to room temperature. Ether (50 mL) was added, followed by 10% HCl (50 mL). The ether layer was then washed with H2O (25 mL) and brine (25 mL). The dried (MgSO4) ether layer was concentrated to dryness. The residue was triturated with hexanes to provide an off-white solid which was filtered and dried under vacuum to afford 1.38 g of 4-fluorophenyl boronic acid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH3:32])[N:23]=3)[N:20]=2)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=1)=[O:12])[CH2:4][CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].[OH-].[K+].[CH2:43]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:43][O:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH3:32])[N:23]=3)[N:20]=2)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:14]=1)=[O:12])[CH2:4][CH2:5][S:6]([CH3:9])(=[O:7])=[O:8]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](CO)CCS(C)(=O)=O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](CCS(C)(=O)=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methanesulfonyl-propyl)-amide (102 mg, 0.173 mmol) was dissolved in THF (1.9 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (97 mg, 1.73 mmol), 18-crown-6 (46 mg, 0.173 mmol), and iodomethane (11 μl, 0.173 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-60% EtOAc) to afford 30 mg (29%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methanesulfonyl-propyl)-amide as an off-white solid. MS: [M+Na]+=627).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+:12]>C1COCC1>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][C:4]=2[O:5]1.[Na+:12]
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [O-]c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sesamol (415 mg, 3.0 mmol) was added, as a solution in THF (2 ml), to a suspension of mineral oil-free NaH under a water cooling bath. The mixture was stirred at 25° C. for 20 min. yielding a clear solution. The solvent was evaporated at 40° C. under reduced pressure and the resulting solid sodium 3,4-(methylenedioxy)phenoxide was dried in vacuo at 25° C. for 30 min before use.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(Cl)Cl>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1ccc(-n2cc(N)cn2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2cc(NC(=O)OCC(Cl)(Cl)Cl)cn2)cc1
Yield: 94.3 %

Procedure:
Intermediate 6b (150 mg, 0.87 mmol) dissolved in DCM (10 mL) was cooled using an ice bath, and then treated sequentially with triethylamine (0.18 mL, 1.30 mmol) and trichloroethyl chloroformate (0.15 mL, 1.08 mmol). The mixture was stirred with cooling for 45 min, then evaporated to dryness. Residue was purified by FCC, eluting with 0-30% ethyl acetate in cyclohexane, to give the title compound as a beige solid (286 mg, 95%). LCMS (Method 3): Rt 4.25 min, m/z 348/350/352 [MH+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CCCCC1>C(OCC)(=O)C>[C:42]([O:41][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:25]([NH:1][C@H:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCOC(=O)C(Br)CCCCCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)CC[C@H](N)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)C(CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
1.2 g of t-butyl rel-α-[3(S)-amino-2-oxo-6(R)-phenylperhydroazepin-1-yl]acetate was treated with 2.15 g of ethyl 2-bromo-9-t-butoxycarbonylaminononanoate prepared as described in Preparation 4) in a similar manner to that described in Example 4, to afford a reaction product, which was subjected to column chromatography through silica gel using a mixture of cyclohexane and ethyl acetate in the ratio of 1:1 by volume as the eluent.
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O[CH2:26][CH:27]=[CH:28][CH2:29]OC(=O)C)(=O)C>O1CCCC1.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>[CH2:12]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:26][CH:27]=[CH:28][CH2:29][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:29][CH2:28][CH2:27][CH3:26])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: CCCCCCCCCCNCCCCCCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCN(CC=CCN(CCCCCCCCCC)CCCCCCCCCC)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of di-n-decylamine (10.9 g, 36.6 mmol) and 2-butene-1,4-diol diacetate (3.15 g, 18.3 mmol) in tetrahydrofuran (THF) (150 ml) is treated with tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to a oil that is redissolved in THF (500 ml) and treated with 20% aqueous sodium hydroxide (250 ml). The mixture is stirred for one hour, concentrated, and extracted with ether. The ether extracts are dried and concentrated giving an orange oil which is purified by medium pressure chromatography (silica gel; 25% ethyl acetate in hexanes). The title compound is isolated as 5.8g (49% yield) of a clear oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].C(OCC)(=O)C>O>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])([O-:14])=[O:13]
Reactant: NCC(F)(F)F
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCC(F)(F)F)cc2c1=O
Temperature: 140 °C
Yield: 25.3 %

Procedure:
A mixture of 200 mg (0.628 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 1.08 ml (13.68 mmol) of 2,2,2-trifluoro-ethylamine in a closed vial is heated in a microwave reactor at 140° C. for 20 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase dried and concentrated to yield a precipitate which is filtered off and submitted to purification by medium pressure chromatography on a RP-C18 column (20 μM material) with tetrahydrofuran/water 4:3 as eluent, containing 0.1% TFA. During concentration of the fractions the product precipitates and is collected by filtration, giving 63 mg of a red powder, m.p. 250° C. (decomp.).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]#[N:21])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1CC=CCC=1>[Pd].CN(C)C=O>[C:20]([CH2:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[N:17][C:16]=1[CH3:18])#[N:21]
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CN(C)C=O
Product: Cc1nc2c(O)cccn2c1CC#N
Yield: 100 %

Procedure:
8-Benzyloxy-3-cyanomethyl-2-methylimidazo[1,2-a]pyridine (40 g, 0.14 mol), 1,4-cyclohexadiene (50 g, 0.62 mol), dimethylformamide (600 ml) and palladium black (2 g) are stirred together and heated. At 45° C., asudden exotherm occurs and the temperature rises rapidly to 75°-80°. Heating is discontinued and the mixture stirred for1 hr. The catalyst is removed by filtration and the cyclohexadiene removed in vacuo. The dimethylformamide is removed in vacuo (0.1 mm) at 55°to afford 3-cyanomethyl-2-methyl-8-hydroxy imidazo[1,2-a]pyridine (27 g, 0.14 mol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Clc1cnccn1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnccn1
Temperature: 25 °C
Yield: 80 %

Procedure:
To an ice cooled solution of the compound of step 7b (941 mg, 5.0 mmol) in tetrahydrofuran (30 mL) under nitrogen, was added sodium hydride (80% dispersion in mineral oil, 180 mg, 7.5 mmol), portionwise. The reaction mixture stirred fifteen minutes followed by the dropwise addition of 2-chloropyrazine (590 mg, 5.1 mmol). The reaction was stirred 24 hours gradually warming to room temperature. Additional sodium hydride (40 mg) was added and stirring at room temperature continued until complete disappearance of starting material by TLC. The reaction mixture was then treated with a 10% aqueous solution of potassium hydrogen sulfate (20 ml) and the volatiles evaporated in vacuo. The mixture was then diluted with ethyl acetate (50 ml) and the organic phase was washed with saturated sodium hydrogen carbonate (2×20 ml). The organic phase was then dried (MgSO4), filtered and concentrated in vacuo. The resultant orange oil (1.37 g) was purified by flash silica gel chromatography (ethyl acetate:hexane=1:1), resulting in product isolated as an oil, in 80% yield (1.07 g). [α]23D =-62.8° (c 1.35, CHCl3). MS (CI/NH3) m/e 266 (M+H)+, 283 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28-8.27 (d, J=1.1 Hz, 1H), 8.13-8.12 (d, J=2.58 Hz, 1H), 8.08-8.06 (dd, J=2.58, J=1.5 Hz, 1H), 4.66-4.61 (dd, J=10.83, J=4.6, 1H), 4.58-4.51 (m, 1H), 4.50-4.45 (dd, J=10.83, J=3.13, 1H, 3.92-3.87 (dd, J=8.3, J=6.25, 2H), 2.41-2.29 (m, 1H), 2.26-2.16 (m, 1H), 1.41 (s, 9H).