Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1C=C(C=CC=1C)C(NOC)=[O:7])N.[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:24](NOC)=[O:25])[N:19]=[CH:18][C:17]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36](I)[CH:35]=1.C(N(CC)CC)C>C(O)C>[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:24]([OH:25])=[O:7])[N:19]=[CH:18][C:17]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Reactant: CONC(=O)c1ccc(C)c(NN)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 (242 mg, 1.19 mmol, 1.0 eq) in 25 mL of ethanol was added 2-benzoyl-3-phenylamino-acrylonitrile 4 (296 mg, 1.19 mmol, 1.0 eq, preparation: Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine (161 μL, 1.19 mmol, 1.0 eq) and the mixture was heated to 65° C. All solids dissolved when temperature reached 65° C. After three hours, LC-MS indicates consumption of the hydrazine. The solids were filtered to provide 3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 5 (95 mg, 25%) as a beige solid: HPLC (4 minute gradient) tR 2.10 min; MS m/z 322 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 7.99 (d, J=7.6, 1 H), 7.81 (s, 2 H), 7.78 (s, 1 H), 7.57 (m, 4 H), 7.02 (s, 2 H, NH2, 2.18 (s, 3 H) ppm; 13C NMR (DMSO-d6, 75 MHz) 187.6, 166.3, 152.0, 141.3, 141.2, 139.6, 135.9, 131.6, 131.2, 130.1, 129.8, 128.6, 127.8, 102.6, 17.4 ppm.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@@H:3]([O:5][C:6](=O)[O:7]C1C=CC([N+]([O-])=O)=CC=1)[CH3:4].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]3[CH2:38][C@H:37]([CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[O:36][C:33]3=[CH:34][N:35]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]([F:19])([F:18])[C@@H:3]([O:5][C:6]([N:42]1[CH2:43][CH2:44][CH:39]([C@@H:37]2[O:36][C:33]3=[CH:34][N:35]=[C:30]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:25][CH:26]=4)[CH:31]=[C:32]3[CH2:38]2)[CH2:40][CH2:41]1)=[O:7])[CH3:4]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester (85 mg) is added to a solution of (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (100 mg) and N,N-diisopropyl-ethylamine (60 μL) in tetrahydrofuran (2 mL) at room temperature. The solution is stirred at room temperature overnight and then washed with 1 N aqueous NaOH solution (3×), water, and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:3) to give the title compound. LC (method 1): tR=1.00 min; Mass spectrum (ESI+): m/z=499 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=1[NH2:23].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](=[O:18])[NH:23][C:22]1[C:21]([F:20])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid (500 mg, 1.9 mmol, Eq: 1.00) and 2,6-difluoroaniline (294 mg, 2.28 mmol, Eq: 1.2) in pyridine (10 mL) at 0° C. was added POCl3 (437 mg, 266 μL, 2.85 mmol, Eq: 1.5). The reaction was warmed to RT and stirred for 2 h. The mixture was evaporated and water was added and the resulting mixture was extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give 1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (462 mg) as a light yellow foam.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[I:17]I.O>O1CCCC1>[CH2:6]([C:12]1[O:13][C:14]([I:17])=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCc1ccco1
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1ccc(I)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of n-BuLi (24.7 mL, 1.6 M in hexanes, 39.5 mmol, 1.4 equivalents) was added dropwise to a solution of 2-hexylfuran (4.3 g, 28.3 mmol) in dry tetrahydrofuran (THF, 50 mL) at −78° C. under N2. The reaction mixture was warmed to 0° C., stirred for 10 min and cooled again to −78° C. To this solution was added slowly iodine (9.3 g, 36.7 mmol) in 25 mL of THF, and the solution was warmed slowly to 0° C. and stirred for 2 h at 0° C. After addition of 100 mL of water, the solution was extracted with hexane. The organic layer was washed with aqueous Na2S2O3 solution (30 mL) and water, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane) to afford 6 g of 2-hexyl-5-iodofuran (76%) as a pale brownish oil. 1H NMR (300 MHz, CDCl3): δ6.37 (d, J=3.14 Hz, 1H), 5.88 (d, J=3.16 Hz, 1H), 2.60 (t, J=7.56, 7.56 Hz, 2H), 1.58 (td, J=15.11, 7.66, 7.66 Hz, 2H), 1.24-1.39 (m, 6H), 0.86 (t, J=6.77, 6.77 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.3, 120.6, 108.0, 84.3, 31.6, 28.8, 28.3, 27.8, 22.6, 14.1 ppm. HRMS (FD): m/z calcd for C10H15IO: 278.0168. Found 278.0172.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:15]([NH:22][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Yield: 85 %

Procedure:
2,6-dichloro-9-isopropylpurine (1 mmol) and benzylamine (3.5 mmol) were heated with stirring in 3 ml of n-butanol (3 hour, 110° C.). The reaction mixture (after evaporation of n-butanol) was worked up as above for the compound 2, yield 85-90%.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH3:14]>CO>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH2:14])=[O:8]
Reactant: N
Reactant: COC(=O)c1cc(Br)c(Cl)cc1O
Solvent: CO
Product: NC(=O)c1cc(Br)c(Cl)cc1O
Temperature: 65 °C

Procedure:
A mixture of methyl 5-bromo-4-chloro-2-hydroxybenzoate (2.655 g, 10.00 mmol) in a solution of ammonia (50.0 ml, 100 mmol) in MeOH was heated at 65° C. for 72 hr. After concentration, the title product was obtained as solid (2.53 g). ESI-MS m/z: 252.1 [M+1]+, Retention time 1.19 min; 1HNMR (CDCl3, 400.342 MHz) δ 7.15 (s, 1H), 7.61 (s, 1H), 12.2 (brs, 1H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1.CO.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1cncc2[nH]c3ccc(Cl)cc3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(Cl)cc2c1[nH]c1cncc(F)c12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
Sodium nitrate (1.5 eq, 53 mmol, 4.5 g) was added portionwise to a solution of Intermediate 65 (1.0 eq, 35 mmol, 7.8 g) in trifluoroacetic acid (200 mL) and the resulting mixture heated at 70° C. for 3 h. After cooling to RT the trifluoroacetic acid was removed on a rotary evaporator to afford a crude solid which was suspended in a small volume of methanol and added dropwise to a vigorously stirred mixture of saturated sodium bicarbonate solution (500 mL). The resulting slurry was stirred for 15 min then the precipitated solids were collected by suction filtration, washed with water (300 mL) and then dried in vacuo to afford 6-chloro-4-fluoro-8-nitro-9H-β-carboline (about 9.5 g) which was used in the subsequent step without further purification. Retention Time (LC, method: ammonium acetate standard): 1.79 min. MS (M+H+): 266
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:30][CH:27]4[CH2:29][CH2:28]4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=CC1CC1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(CC3CC3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with cyclopropanecarboxaldehyde to provide 30 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[OH-].[NH4+:12]>O1CCOCC1>[NH2:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:12])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyano-benzyl bromide (4.00 g) was combined with 1,4-dioxane (2 mL) and conc. aq. ammonium hydroxide (30 mL). The reaction mixture was sealed with a teflon plug and stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness in vacuo. The crude material consisted of a mixture of the desired mono- and undesired bis-benzyl adducts. The undesired product was removed by repeated precipitation from hot methanol, enriching the desired product in the filtrate. After three cycles, pure title compound was isolated as the hydrobromide salt (2.38 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH3:30][C:31]([CH3:35])([CH3:34])[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2
Reactant: CC(C)(C)C=O
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NCC(C)(C)C)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 97.1 %

Procedure:
To a solution of (3R)-3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropionamide (0.5 g, 1.3 mmol) and trimethylacetaldehyde (0.26 mL, 2.3 mmol) in 1,2-dichloroethane (10 mL), was added sodium triacetoxyborohydride (0.53 g, 2.5 mmol) at room temperature. After 1 day, the mixture was extracted with methylene chloride (50 mL) and water (20 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 25 mL) and brine (25 mL), and dried over MgSO4. Removal of solvent gave a yellow oil, which was purified by prep HPLC to give (3R)-3-[7-(2,2-dimethyl-propylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethyl-propionamide as a white solid (0.59 g, 99% yield): mp 111-113° C.; 1H NMR (CDCl3) δ 1.01 (s, 9H, 3 CH3), 1.43 (t, J=7 Hz, 3H, CH3), 2.89 (s, 3H, CH3), 2.98 (d, J=6 Hz, 2H, CH2), 3.07 (dd, J=6, 15 Hz, 1H, CHH), 3.11 (s, 3H, CH3), 3.45 (dd, J=9, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.12 (d, J=16 Hz, 1H, CHH), 4.33 (d, J=16 Hz, 1H, CHH), 5.59 (dd, J=7, 9 Hz, 1H, NCH), 6.47-6.51 (m, 2H, Ar), 6.79-7.01 (m, 4H, NH, Ar), 7.22 (t, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.75, 27.63, 32, 27, 35.52, 36.67, 37.54, 48.56, 53.10, 54.49, 55.95, 64.42, 107.82, 108.77, 111.25, 112.66, 114.58, 119.22, 132.35, 132.96, 143.09, 148.16, 148.41, 148.81, 169.97, 170.79. Analy. calculated for C27H37N3O4: C, 69.35; H, 7.98; N, 8.99. Found: C, 69.70; H, 7.95; N, 8.74.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:26]1[CH3:25])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc2ccccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 mL of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide. The mixture was stirred while 13.11 g (100 mmoles) of 2-methylindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 20 g (116.9 mmoles) of benzyl chloride in 120 mL of ether was added during 45 minutes. The stirring was continued for 21.5 hours. Water (200 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 25.85 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 22-25 were combined giving 2.28 g (10%) of slightly impure 1-benzyl-2-methylindole as a pale yellow oil which solidified upon standing. Fractions 26-35 were combined giving 8.42 g of 1-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as a pale yellow oil. The 8.42 g was combined with the 7.50 g of a similar mixture from fractions 23-28, and chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed as before. Fractions 21-24 were combined giving 3.59 g of 1-benzyl-2-methylindole as a pale yellow oil which solidified. Fractions 25-30 were combined giving 7.66 g of a mixture of 1-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.C(O[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C)CCC.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:24]([N:18]1[CH2:19][CH:7]2[CH:8]([C:3]([O:2][CH3:1])([O:10][CH3:11])[CH:4]=[CH:5][C:6]2=[O:9])[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC1(OC)C=CC(=O)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(OC)C=CC(=O)C2CN(Cc3ccccc3)CC21
Reaction time: 1 h

Procedure:
To a solution of 22.9 g of 4,4-dimethoxy-2,5-cyclohexadien-1-one [J. Org. Chem., 52, 2763 (1987)] and 46 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 150 cm3 of dry dichloromethane are added dropwise 3 cm3 of trifluoroacetic acid. Once the reaction mixture has reached reflux it is allowed to return to room temperature and is then stirred for for one hour. After addition of 5 g of potassium carbonate, the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a column of silica gel (particle size 0.06-0.20 mm), eluting with a mixture of cyclohexane and ethyl acetate (90/10 then 80/20 by volume). 19 g of (3aRS,7aSR)-2-benzyl-7,7-dimethoxy-2,3,3a, 4,7,7a -hexahydro-1H-4-isoindolone are obtained in oil form.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.C([Li])CCC.CON(C)[C:28](=[O:30])[CH3:29].[Cl-].[NH4+]>C1COCC1.O>[Si:13]([O:12][CH:7]([C:4]1[S:3][C:2]([C:28](=[O:30])[CH3:29])=[N:6][CH:5]=1)[C:8]([F:11])([F:10])[F:9])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC(c1cnc(Br)s1)C(F)(F)F
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ncc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In THF (5 mL) was dissolved 2-bromo-5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazole (515 mg, 1.37 mmol) obtained in Step 2. n-Butyllithium (1.65 mol/L solution in n-hexane, 1.24 mL, 2.05 mmol) was added dropwise at −78° C. and the mixture was stirred at −78° C. for 30 minutes. A solution of N-methoxy-N-methylacetamide (1.38 mL, 13.7 mmol) in THF (1 mL) was added to the reaction mixture and the mixture was stirred at −78° C. for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-(5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl) thiazol-2-yl)ethanone (437 mg, 94%).
Reaction SMILES: [C:1]1([S:7][C:8]2[S:12][C:11]([CH2:13][NH:14][OH:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:20]=[C:21]=[O:22])(C)C>O1CCOCC1>[OH:15][N:14]([CH2:13][C:11]1[S:12][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[C:21]([NH2:20])=[O:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCc1ccc(Sc2ccccc2)s1
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(Sc2ccccc2)s1
Reaction time: 1 h

Procedure:
To a solution of N-(5-phenylthiothien-2-ylmethyl)-hydroxylamine (2.5 g) in dioxan (50 ml) at room temperature under nitrogen, was added trimethylsilylisocyanate (2.42 g) and the resulting solution stirred for 1 hour, quenched with saturated aqueous ammonium chloride, extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a white solid, recrystallised from ether/petroleum ether to give a white crystalline solid m.p. 127°-129° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[C:60]([C:61](Cl)=[O:62])=[CH:59][N:58]=[CH:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[N:56]([CH3:55])[CH:57]=[N:58][CH:59]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1cncc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-methyl-1H-imidazole-5-carbonyl chloride as starting materials in 31% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.41 (s, 1H), 9.38 (s, 1H), 8.97 (s, 1H), 8.91 (s, 1H), 8.22 (m, 3H), 7.85 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.00 (m, 2H), 3.83 (s, 3H), 2.98 (m, 6H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.
Reaction SMILES: C(O[C:5]1[C:6](OC(=O)C)=[C:7]([I:11])[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-].[K+].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1>CO>[C:19]1([CH3:18])[CH:20]=[CH:21][C:22]([S:25]([N:28]=[C:7]2[CH2:6][CH2:5][CH2:10][CH2:9][I:11]2[C:7]2[CH:6]=[CH:5][CH:10]=[CH:9][CH:8]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N=C2CCCCI2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 113.3 %

Procedure:
Diacetoxyiodobenzene (12.88 g, 40 mmol) was added to a solution of KOH (5.61 g, 100 mmol) and p-toluenesulfonamide (6.85 g, 40 mmol) in methanol (160 mL) at 8° C. A yellow color developed within 1 minute. The cooling bath was removed, and the solution was allowed to warm to RT with stirring for 3 hours. Water (180 mL) was added and the reaction was refrigerated overnight. The precipitate was collected by filtration and dried overnight in a vacuum dessicator to yield 10 g (66%) of a light yellow solid which was used with out further purification or characterization.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=[O:26])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][Mg]Cl>O1CCCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]([OH:26])[CH3:28])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: Cc1noc(C)c1-c1ccc2nc(C=O)n3c2c1OC[C@@H]3c1ccccn1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2nc(C(C)O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carbaldehyde (8 mg, 0.02 mmol) in tetrahydrofuran (1 mL) at 0° C., 3.0 M methylmagnesium chloride in THF (0.01 mL, 0.04 mmol) [Aldrich, cat. #189901] was added dropwise. After continued stirring for 30 min at 0° C., the reaction was quenched by adding saturated aqueous ammonium chloride (0.5 mL) dropwise. The resulting mixture was diluted with ethyl acetate/brine (3:1), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the desired product as a mixture of diastereomers (4 mg, 50%). LCMS for C21H21O3N4 (M+H)+: calculated m/z=377.2. found 377.1.