Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].O=[C:11]1[CH:16]([C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12]1>C(O)C>[CH3:7][C:6]1[N:8]=[C:17]([C:18]([F:21])([F:20])[F:19])[C:16]2[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:12][C:11]=2[N:9]=1
Reactant: CC(=N)N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(c(C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 15.4 %

Procedure:
1.3 mL of sodiumethoxide (21% wt. ethanol solution) was added at room temperature to a solution in which 283 mg (3.0 mmol) of acetamidine hydrochloric acid salt was dissolved in 5 mL of absolute ethanol. After stirring of 15 minutes, to the resulting solution, was added a solution in which 590 mg (2.0 mmol) of t-butyl 3-oxo-4-(trifluoroacetyl)-piperidin-1-carboxylate obtained in PREPARATION 47 was diluted with 5 mL of absolute ethanol. The resulting mixture was heated to 80° C. and stirred for 18 hours. After cooling to room temperature, ethanol was distilled off under reduced pressure, followed by washing with saline which was diluted with ethylacetate. An organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and then the residue was purified by column chromatography (10:1 hexane:ethyl acetate) to give 98 mg of the title compound in a yield of 16%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-:27])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cncc2cn(-c3c(Cl)cccc3Cl)nc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (5.4 g, 19.1 mmol) in DCM (100 mL) was added mCPBA (5.2 g, 30.0 mmol). The reaction mixture was stirred for 1.5 hours, warmed to room temperature, and stirred for a further 16 hours. Sodium thiosulfate (sat. aq.) was added and the layers were partitioned. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to afford the title compound as a beige solid (5.04 g, 89% yield). LCMS (Method C): RT=2.45 min, m/z: 298 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]=[C:7]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(-c3cccnc3)c2c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(-c2cccnc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
5-Nitro-3-(3-pyridyl)-1H-indole (0.60 g) was added portionwise to a stirredsuspension of sodium hydride (0.11 g of 60% dispersion in mineral oil) in dry N,N-dimethylformamide (10 ml) at room temperature, and the mixture wasstirred for 30 minutes. Ethyl 4-bromobutanoate (0.40 g) was added and the mixture was stirred for 18 hours. Further sodium hydride (0.11 g of 60% dispersion) was added, the mixture was stirred for 30 minutes and then further ethyl 4-bromobutanoate (0.40 g) was added. Stirring was continued for an additional 4 hours and then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed twice with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed using dichloromethane/methanol (100:1) as eluent. The product fractions were combined and evaporated, and the residue was triturated with ether to give the title compound (0.51 g), m.p. 76°-78° C. Found: C,64.92; H,5.48; N,11.95. C19 H19N3O4 requires: C,64.58; H,5.42; N,11.89%.
Reaction SMILES: C(O)C.[C:4]1([CH:10]([CH3:13])[C:11]#[N:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:14].[H][H]>C(OC)(C)(C)C>[ClH:14].[C:4]1([CH:10]([CH3:13])[CH2:11][NH2:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C#N)c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Product: CC(CN)c1ccccc1
Yield: 76.2 %

Procedure:
Charge to an autoclave hydrogenation apparatus under nitrogen water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). Stir the mixture rapidly and pressurize to 75 to 78 psi with hydrogen. Heat the mixture 50° C. to 64° C. for 3 hours. Depressurize and filter the reaction mixture to afford two lots of filtrate. Concentrate filtrates under reduced pressure to approximately 400 mL each. Add methyl tert-butyl ether (MTBE) (2.2 L each) to each lot. Stir the precipitate overnight. Filter and wash solids with fresh MTBE (100 mL) and dry overnight. Combine the lots to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[C:8](=[CH:29][C:25]3[CH:24]=[C:23]4[C:28]([C:20](/[CH:19]=[CH:18]/[C:15]5[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=5)=[N:21][NH:22]4)=[CH:27][CH:26]=3)[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: O=C1Cc2nc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)nc2C1=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 78.8 %

Procedure:
The title compound (E/Z=3:1, 63 mg, 84%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 70° C., reflux 60 min) using 5-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (33.7 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.83 (s, 1H), 10.92 (s, 1H), 8.91 (s, 1H), 8.57 (d, J=6.0 Hz, 3H), 8.37 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.90 (d, J=16.4 Hz, 1H), 7.75-7.70 (m, 2H), 7.57 (d, J=16.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H); Z isomer: δ 13.80 (s, 1H), 11.03 (s, 1H), 9.15 (s, 1H), 8.57 (d, J=6.0 Hz, 2H, buried under the doublet at 8.57), 8.34 (d, J=8.4 Hz, 1H, partially overlapping with the doublet at 8.37), 8.25 (d, J=9.2 Hz, 1H), 8.20 (s, 1H), 7.86 (d, J=14.4 Hz, 1H, partially overlapping with the doublet at 7.90), 7.75-7.70 (m, buried under the multiplet 7.75-7.70), 7.56 (d, J=16.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H); MS ESI 400.0 [M+H]+, calcd for [C22H14ClN5O+H]+ 400.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12](O)=[O:13])[C:10]=2[CH:11]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O.COCCOC>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cnc2cccc(C(=O)O)c2c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cnc2cccc(CO)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
35.0 g (187 mmol) of the compound from example 21A are introduced into 440 ml of 1,2-dimethoxyethane, 32.3 ml (233 mmol) of triethylamine are added, and the mixture is stirred at room temperature for 30 min Then 22.3 ml (233 mmol) of ethyl chloroformate are added dropwise at 15° C., and the mixture is stirred at room temperature for 15 min. The precipitated solid is filtered off and washed with 1,2-dimethoxyethane. The filtrate is then concentrated, and the residue is taken up in 440 ml of ethanol. 13.1 g (345 mmol) of sodium borohydride are added dropwise as a solution in 210 ml of water to the solution obtained in this way. After a reaction time of 16 h at room temperature, the precipitated solid is filtered off with suction and washed with ethanol, and the filtrate is concentrated in a rotary evaporator. The resulting residue is taken up in 800 ml of water and 600 ml of dichloromethane/methanol (8:2). The aqueous phase is again extracted with 600 ml of dichloromethane/methanol (8:2), and the combined organic phases are washed with saturated sodium chloride solution. Concentration and drying result in 23.0 g (71% of theory) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28]C[CH2:26][CH2:25]1.C([N:33](C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:33]([CH2:14][CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: Clc1ccccc1N1CCCCC1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccccc1N1CCN(CCCc2cc(-c3ccccc3)no2)CC1
Yield: 86.9 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (26.4 mg, 0.13 mmol), (2-chlorophenyl)piperidine HCl (25.5 mg, 0.11 mmol), and diisopropylethyl amine (19.0, 0.11 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (69.3 mg, 0.33 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22 hr and followed the same processes as in Example 1 to obtain 36.5 mg (87.7%) of the target compound.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>O1CCCC1>[OH2:12].[NH2:2][C:3]1[C:4]([C:11]([N:13]=[CH:14][NH:17][NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:2][C:3]1[C:4]([C:11]([N:13]=[CH:14][NH:17][NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: Nc1cccnc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: C1CCOC1
Product: Nc1nc(N)c(C(=O)N=CNNc2cccnc2)nc1Cl
Product: O
Temperature: 0 °C

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide (970 mg., 0.0025 mole) is added to a solution of 3-aminopyridine (940 mg., 0.01 mole) in dry tetrahydrofuran (20 ml.) and the mixture is heated at reflux for 2 hours, then added to crushed ice-water (200 ml.) to precipitate 423 mg. of 3,5-diamino-6-chloro-N-[(3-pyridylamino)aminomethylene]2-pyrazinecarboxamide hemihydrate, m.p. 220°-2° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]([C:35]1[CH:40]=[CH:39][C:38]([O:41][S:42]([C:45]([F:48])([F:47])[F:46])(=[O:44])=[O:43])=[C:37]([CH3:49])[CH:36]=1)([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:30]COC)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[C:15]([CH3:34])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>ClCCl>[CH2:8]([C:10]([C:35]1[CH:40]=[CH:39][C:38]([O:41][S:42]([C:45]([F:46])([F:47])[F:48])(=[O:44])=[O:43])=[C:37]([CH3:49])[CH:36]=1)([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:30])([C:26]([F:27])([F:28])[F:29])[C:22]([F:23])([F:24])[F:25])=[C:15]([CH3:34])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)(c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of trifluoromethanesulfonic acid 4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl ester (Example 26-(3); 2.41 g, 3.79 mmol) in dichloromethane (20 mL) at room temperature, and the mixture was stirred for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target product as a colorless oil (2.24 g, 99%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([OH:19])=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH:21]1([CH2:20][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)[C:17](=[O:19])[NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1ccccc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 2-(4-benzoylamino-phenyl)-3-cyclopentyl-propionic acid (20.2 mg, 0.06 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (39.8 mg, 0.09 mmol), and 2-aminothiazole (9.0 mg, 0.09 mmol) in methylene chloride (2 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.25 mL, 0.18 mmol). The reaction mixture was stirred at 25° C. for 16 h. At this time, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with a 1N aqueous hydrochloric acid solution (1×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded {N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-benzamide (95%) as a white solid: mp 285-290° C.; EI-HRMS m/e calcd for C24H25N3O2S (M+) 419.1667, found 419.1667.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)=[CH2:15]>C(O)C>[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=Cc1ccc(CCl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=Cc1ccc(CC(C(C)=O)C(=O)OCC)cc1
Yield: 95 %

Procedure:
Ethyl acetoacetate (27.61 g, 0.21 mol) was dissolved in ethanol (100 ml) which was cooled in an ice-water bath, and sodium ethoxide (15.59 g, 0.22 mol) was added. 4-Vinylbenzyl chloride (33.92 g, 0.2 mole) was added. The mixture was refluxed for 16 hours, then the resulting slurry was filtered to remove any salt, and the solution collected. The solvent was removed under reduced pressure to give ethyl 2-(4-vinylbenzyl)-3-oxobutanoate in the form of a light red liquid (49 g) in 95% yield.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:18]3[C:19]4[C:11]([CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([N:7]([C:8]2[C:18]3[C:19]4[C:11]([CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(Nc2ccc3c4c(cccc24)CC3)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Yield: 83.8 %

Procedure:
4.66 g (0.018 mol) of the above prepared 5-[N-(4-tolyl)amino]acenaphthene was mixed with 4.99 g (0.022 mol) of iodo benzene, 0.13 g (0.002 mol) of copper powder, 2.76 g (0.02 mol) of anhydrous potassium carbonate and 5 ml of nitrobenzene, and the resultant mixture was stirred at 200° C. for 25 hours. The reaction was determined to be finished when disappearance of 5-[N-(4-tolyl)amino]acenaphthene was identified. 100 ml of toluene was added thereto to dissolve the reaction product, and the mixture was filtrated and concentrated. The concentrated material thus obtained was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4) to obtain 5.06 g (yield: 83.8%, melting point: 147.0°-148.0° C.) of 5-[N-(4-tolyl)-N-phenylamino]acenaphthene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][CH:13]=2)[CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][CH:13]=2)[CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc(NC2CCCNC2)c2cc[nH]c2n1
Product: c1ccc(CN2CCCC(Nc3ccnc4[nH]ccc34)C2)cc1

Procedure:
Reaction of N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine with benzaldehyde using the method of Example 8 affords the title compound.
Reaction SMILES: Cl.Cl[Sn]Cl.[N+:5]([C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[OH:15])([O-])=O>>[NH2:5][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[OH:15].[I:14][C:12]1[CH:13]=[CH:8][C:9]([OH:15])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1O
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1cc(I)ccc1O
Product: Oc1ccc(I)cc1

Procedure:
2-amino-4-iodophenol was prepared by the HCl and SnCl2 reduction of 2-nitro-4-iodophenol which was obtained from the nitration of p-iodophenol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=S)=[CH:4][CH:3]=1.CI.[CH3:17][NH2:18]>CC#N.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:18]\[CH3:17])=[CH:4][CH:3]=1
Reactant: S=c1ccccn1-c1ccc(I)cc1
Reactant: CN
Solvent: CC#N
Solvent: CI
Solvent: CO
Product: C/N=c1\ccccn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (98 mg, 0.31 mmol) in CH3CN (5 mL), CH3I (0.25 mL, 4.0 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give a solid. The solid was dissolved in MeOH (7 mL). To the solution, CH3NH2 (2M in THF, 0.80 mL, 1.6 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine (59 mg).
Reaction SMILES: [NH:1]1CCN[CH2:3][CH2:2]1.[CH:7]1([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.BrCC#N>>[CH:7]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([CH2:3][C:2]#[N:1])[CH2:18][CH2:19]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C1CNCCN1
Reactant: C1CCC(CN2CCNCC2)CC1
Agent: N#CCBr
Product: N#CCN1CCN(CC2CCCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Cyclohexylmethyl-piperazine piperazine (commercially available from Fluorochem Ltd) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=222.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.45-2.20 (m, 8H), 2.00 (d, 2H), 1.70-1.55 (m, 5H), 1.50-1.40 (m, 1H), 1.20-1.05 (m, 3H), 0.85-0.70 (m, 2H).
Reaction SMILES: [Al:1].CC(O[Al]OC=O)=O.O.[N+:11]([O-:14])([OH:13])=[O:12]>O>[N+:11]([O-:14])([O-:13])=[O:12].[Al+3:1].[N+:11]([O-:14])([O-:13])=[O:12].[N+:11]([O-:14])([O-:13])=[O:12]
Reactant: [Al]
Reactant: O=[N+]([O-])O
Agent: CC(=O)O[Al]OC=O
Solvent: O
Product: O=[N+]([O-])[O-]
Product: [Al+3]
Reaction time: 1 h

Procedure:
Next an alumina precursor, basic aluminum nitroformoacetate (ANFA), was prepared. A solution was prepared by dissolving aluminum formoacetate (for preparation see Kirk-Othmer, Encyclopedia of Chemical Technology, 3d edition, Vol. 2, 202-204 (1978); Al:carboxylate=1:2; formate:acetate=1:1) in water with heating to yield a 6.4 wt.% fired solids content solution. A basic aluminum nitrate solution was prepared by charging a thick walled flask with 300 g of deionized water and 62.9 ml of concentrated HNO3, stirring and heating to a boil and adding 26.98 g of aluminum powder to the boiling mixture over a period of 2 hours in 5 lots of roughly 5 g each. Deionized water was added occasionally to keep the solution volume above 300 ml. After 4 hours when the dissolution of the aluminum was essentially complete, the solution was filtered through a Whatman #5 filter and found to be 18.5 wt. % alumina. A mixture of 200 g of the basic aluminum nitrate solution and 576.1 g of the aluminum formoacetate solution was boiled for 1 hour and filtered through a Whatman #5 filter. This resulting basic aluminum nitroformoacetate solution was found to contain 13.6 wt. % alumina.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Sn]([N:33]=[N+:34]=[N-:35])(CCCC)CCCC)CCC>ClC1C=CC=CC=1Cl.CCOCC>[Br:1][C:2]1[C:3]([C:18]2[NH:35][N:34]=[N:33][N:19]=2)=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1c(Br)cccc1NS(=O)(=O)c1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: O=S(=O)(Nc1cccc(Br)c1-c1nnn[nH]1)c1ccccc1
Yield: 76.6 %

Procedure:
A solution of N-(3-Bromo-2-cyanophenyl)-benzenesulfonamide (Intermediate 21, 0.22 g) and tributyltin azide (0.43 g) in 1,2-dichlorobenzene (1.5 mL) was heated by microwave irradiation at 130° C. for 2 hours. The mixture was diluted with ether and extracted with aqueous 1M sodium hydroxide. The aqueous solution was acidified with 1N hydrochloric acid to pH 1 and then extracted with ethyl acetate. The organic solution was washed with brine and then dried with sodium sulfate, filtered and the filtrate was evaporated. The residue was triturated with ether and the solid was collected by filtration to give the title compound as a colorless solid (0.19 g).
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]([C@@H:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][C@H:29]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[Si](C)(C)[O:46][CH2:47][CH2:48]O[Si](C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]2([O:46][CH2:47][CH2:48][O:34]2)[CH2:30][C@H:29]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: O=C1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](COCc2ccccc2)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (2.5 mL) was added dropwise to a 0° C. solution of (4R)-4-benzyl-3-({(1R,2R)-2-[(benzyloxy)methyl]-4-oxocyclohexyl}carbonyl)-1,3-oxazolidin-2-one (57.89 g, 138 mmol) and 1,2-bis-(trimethylsilyloxy)ethane (35.4 g, 172 mmol) in CH2Cl2 (400 mL) followed by stirring at rt for 4 h. Triethylamine (3 mL) was then added at 0° C. and the mixture was washed with saturated aqueous NaHCO3 solution and dried over Na2SO4. Concentration in vacuo gave (4R)-4-benzyl-3-({(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}carbonyl)-1,3-oxazolidin-2-one as a thick, tan colored syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36-7.22 (10H, m), 4.48 (1H, m), 4.42 (2H, s), 4.11 (1H, dd, J= 3.1, 8.9 Hz), 3.97 (4H, m), 3.94-3.90 (1H, t, J= 9.0 Hz), 3.67 (1H, m), 3.44-3.38 (2H, m), 3.09 (1H, dd, J= 3.3, 13.5 Hz), 2.92 (1H, dd, J= 8.3, 13.5 Hz), 2.52 (1H, m), 1.97 (1H, m), 1.86-1.76 (3H, m), 1.57-1.50 (1H, m), 1.44 (1H, t, J= 12.8 Hz).