Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH:3]([OH:30])[C:4]([CH3:29])([CH3:28])[CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:32][C:2]([F:1])([F:31])[C:3](=[O:30])[C:4]([CH3:29])([CH3:28])[CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C(=O)C(F)(F)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 0.75 h
Yield: 70 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanal (from Ex 109(b), (140 mg, 0.376 mmol) in THF (3 ml) at 0° C. was added trimethyl(trifluoromethyl)silane (267 mg, 1.88 mmol) and tetrabutyl-ammonium fluoride in THF (0.376 ml, 0.376 mmol, 1M THF solution). The reaction mixture was stirred at 0° C. for 30 minutes, and then at room temperature overnight. After quenching with 4N HCl, the reaction was stirred for 30 minutes and was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give the crude 1,1,1-trifluoro-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-ol. The crude alcohol in DCM (1 ml) was treated with commercially available Dess-Martin periodinane (187 mg, 0.440 mmol). The reaction was complete in 45 minutes and was filtered through a plug of SiO2 using DCM and concentrated to give the crude product. The crude material was purified via chromatography on silica gel eluting with 10% ethyl acetate in hexane to afford the compound of Example 6 as a colorless viscous oil (90 mg, 70% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.21 (1 H, s) 7.85 (1 H, s) 7.70 (2 H, dd, J=9.16, 4.58 Hz) 7.63 (1 H, d, J=8.65 Hz) 7.43 (1 H, dd, J=8.90, 1.78 Hz) 7.37 (2 H, d, J=7.12 Hz) 7.27-7.33 (4 H, m) 7.22 (1 H, t, J=7.12 Hz) 4.80 (1 H, s) 1.43 (6 H, d, J=5.09 Hz). LC/MS (m/z) 441.24 [(M+H)+]; HPLC Rt: 4.066 min.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].CN([CH:15]=[N:16][C:17](=[O:19])[CH3:18])C.CCOCC>N1C=CC=CC=1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10]/[N:11]=[CH:15]/[NH:16][C:17](=[O:19])[CH3:18]
Reactant: NNc1cc(F)ccc1Br
Reactant: CC(=O)N=CN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)N/C=N/Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (1.21 g, 5 mmol) in pyridine (3 mL) was added a solution of N-((dimethylamino)methylene)acetamide (600 mg, 5.26 mmol) in pyridine (2 mL) and the mixture stirred at room temperature under nitrogen for 1 h. The precipitate formed was collected, washed with CH2Cl2 and then with ether to obtain 1.15 g (3.16 mmol, 63% yield) of the title compound which was contaminated with 1 mole of dimethylamine hydrochloride as a white crystalline powder: HPLC: 2.22 min (AP 84% at 220 nm); LC/MS m/z 274/276 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.00 (3H, s, 9-Me), 2.51 (6H, s, 2 N—CH3), 6.45 (1H, dt, J=8.5, 3 Hz, 5-CH), 6.89 (1H, dd, J=12, 3 Hz, 3-CH), 7.43 (1H, dd, J=8.5, 6 Hz, 6-CH), 8.68 (1H, d, J=9.5 Hz, 7-CH), 8.88 (2H, br.s, NH2+), 9.24 (1H, s, 7-NH), 10.54 (1H, d, J=9.5 Hz, 2-NH); No signals from the rotational isomer were observed; 13C NMR (CDCl3, 125.8 Hz) δppm 22.6 (9-CH3), 33.9 (2 NCH3), 99.6 (d, J=28 Hz, 3-CH), 99.7 (1-C), 105.0 (d, J=24 Hz, 5-CH), 133.5 (d, J=10.6 Hz, 6-CH), 137.1 (7-CH), 144.9 (d, J=11.6 Hz, 2-C), 162.4 (d, J=244 Hz, 4-CF), 168.5 (8-C═O). No signals from the rotational isomer were observed; Anal. calcd for C9H9BrFN3O.Me2NH.HCl.1/2H2O: C36.24, H4.99, N15.37, found C35.88, H4.87, N15.23. An analytical sample of the title compound without contamination of dimethylamine hydrochloride was obtained by column purification (SiO2, 10-15% EtOAc—CH2Cl2): TLC Rf 0.55 (20% EtOAc—CH2Cl2); HPLC: 2.17 min (AP 88% at 220 nm); LC/MS m/z 274/276 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.99 (3H, s, 9-Me), 6.45 (1H, dt, J=8.5, 3 Hz, 5-CH), 6.88 (1H, dd, J=12, 3 Hz, 3-CH), 7.43 (1H, dd, J=9, 6 Hz, 6-CH), 8.69 (1H, d, J=9.5 Hz, 7-CH), 9.23 (1H, s, 7-NH), 10.52 (1H, d, J=9.5 Hz, 2-NH); About 16% of rotational isomer was also observed as a set of minor peaks: 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.11 (3H, s, 9′-Me), 6.58 (1H, dt, J=8.5, 3 Hz, 5′-CH), 7.10 (1H, dd, J=11.6, 3 Hz, 3′-CH), 7.29 (1H, d, J=2.4 Hz, 7′-CH), 7.50 (1H, dd, J=8.7, 6 Hz, 6′-CH), 8.35 (1H, s, 2′-NH), 10.70 (1H, s, 7′-NH); 13C NMR (DMSO-d6, 125.8 Hz) δppm 22.6 (9-CH3), 99.7 (d, J=29 Hz, 3-CH), 99.8 (d, J=3 Hz, 1-C), 105.0 (d, J=24 Hz, 5-CH), 133.6 (d, J=10.6 Hz, 6-CH), 137.1 (7-CH), 144.9 (d, J=11.6 Hz, 2-C), 162.5 (d, J=241 Hz, 4-CF), 168.5 (8-C═O); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 22.9 (9′-CH3), 100.7 (d, J=3 Hz, 1′-C), 101.6 (d, J=29 Hz, 3′-CH), 106.8 (d, J=24 Hz, 5′-CH), 133.6 (d, J=9.6 Hz, 6′-CH), 162.4 (d, J=242 Hz, 4′-CF), 168.6 (8′-C═O); HRMS (ESI) calcd for C9H10BrFN3O (M+H) 273.9991, found 274.0004 (δ+4.6 ppm); Anal. calcd for C9H9BrFN3O: C39.43, H3.31, N29.15, found C39.67, H2.99, N29.09.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20](C)[CH3:21])#[N:2].[Cl:23][C:24]([Cl:31])([Cl:30])[CH2:25][O:26][C:27](Cl)=[O:28]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20]([CH3:21])[C:27]([O:26][CH2:25][C:24]([Cl:31])([Cl:30])[Cl:23])=[O:28])#[N:2]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(C)CCC=C1c2ccccc2CCn2cc(C#N)cc21
Solvent: c1ccccc1
Product: CN(CCC=C1c2ccccc2CCn2cc(C#N)cc21)C(=O)OCC(Cl)(Cl)Cl

Procedure:
2-Cyano-6,11-dihydro-11-(3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazepine (5 g., 17.2 mmoles) and 2,2,2-trichloroethylchloroformate (4 g., 18.8 mmoles) in 100 ml. benzene were refluxed for 18 hours. The mixture was poured onto water, washed with dilute hydrochloric acid and then with water, dried over sodium sulfate and concentrated under vacuum to yield 7.1 g. of dark red oil. It was adsorbed on 250 g. silica gel and eluted with 2 liters benzene. The eluate was discarded.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:27]3[CH2:26][CH:25]2[CH:24]=[CH:23]3)[CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)OC(=O)N1C(=O)C=CC1C(C)(C)O[SiH2]C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1C(C)(C)O[SiH2]C(C)(C)C
Yield: 67 %

Procedure:
2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (27) (4 g; 12.2 mmol) and freshly distilled cyclopentadiene (8 mL; 12 eq.) were heated in a sealed tube in toluene for 6 h at 110° C. Concentration and purification by flash chromatography (10% EtOAc/90% hexanes) afforded 3.23 g (67%) of the desired product 28. 1H NMR (CDCl3) □.6.1 (bs, 1H), 6.0 (bs, 1H), 3.8 (dd, 1H), 3.6 (d, 1H), 3.5 (s, 1H), 3.3 (s, 1H), 3.1 (dd, 1H), 2.9 (s, 1H), 2.6 (bs, 1H), 1.6 (d, 2H), 1.5 (s, 9H), 1.3 (d, 1H), 0.9 (s, 9H), 0.15 (s, 3H), 0.1 (s, 3H)ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH3:19])=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Yield: 75 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-hydroxy-2-methylindole (1 mmol) in 5 ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting oil residue was purified by column chromatography to give 5-(2-chloropyrimidin-4-yloxy)-2-methyl-1H-indole in a yield of 75%.
Reaction SMILES: [N:1]([CH:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1
Reactant: [N-]=[N+]=NC1CCCc2cccnc21
Agent: [Pd]
Solvent: CO
Product: NC1CCCc2cccnc21
Yield: 70.6 %

Procedure:
To a solution of the azide (41.0 g, 0.256 mol) in methanol (250 mL) was added Pd/C (10%, 4.1 g) and the mixture was hydrogenated at 30 psi on a Parr shaker. The mixture was filtered through celite and the cake was washed with methanol. The combined filtrates were evaporated and the residual oil was distilled (Kugelrohr, bp 115-140° C. @ 0.2 Torr) to provide 26.8 g (71%) of 8-amino-5,6,7,8-tetrahydroquinoline (AMD7488) as a pale yellow oil. 1H NMR (MeOH-d4) δ 1.81-1.98 (m, 2H), 2.03-2.15 (m, 1H), 2.38-2.46 (m, 1H), 2.88-2.92 (m, 2H), 4.41 (dd, 1H, J=9.3, 6.3 Hz), 7.30 (dd, 1H, J=7.5, 4.5 Hz), 7.62 (d, 1H, J=7.5 Hz), 8.47 (d, 1H, J=4.5 Hz); 13C NMR (MeOH-d4) δ 21.12, 28.72, 28.89, 52.28, 124.86, 134.35, 138.96, 148.49, 152.57. ES-MS m/z 149 (M+H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[CH:29]1([CH2:32][O:33][C:34]2[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:29]1([CH2:32][O:33][C:34]2[N:39]=[CH:38][C:37]([C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][C:11]=4[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=3[CH3:28])=[CH:36][CH:35]=2)[CH2:30][CH2:31]1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccc(OCC2CC2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)c(-c2ccc(OCC3CC3)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.5 g), [6-(cyclopropylmethoxy)pyridin-3-yl]boronic acid (0.47 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution (5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.53 g, 91%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1[C:39]2[C:34](=[CH:35][C:36]([C:40]3C=CC=CC=3)=[CH:37][CH:38]=2)N=C(N2C=C(C(O)=O)C=N2)N1.CC1C=C(B(O)O)C=CC=1>>[O:27]=[C:19]1[C:18]2[C:13](=[CH:14][C:15]([C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[CH:16][CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reactant: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Agent: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc3c(=O)[nH]c(-n4cc(C(=O)O)cn4)nc3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 3-methylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found, 347.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.04 (s, 1H), 12.87 (s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=7.0 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]1=[O:12].C1COCC1>[Pd].CO>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3](=[O:12])[N:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cn(C)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N)cn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixture of 1,3-dimethyl-5-nitropyridin-2(1H)-one (Step 20.1) (16.4 g, 98 mmol), Pd/C 10% (2.0 g), THF (200 mL) and MeOH (200 mL) was stirred for 3 hr at rt under a hydrogen atmosphere (0.1 bar). The reaction mixture was filtered over celite and concentrated. The crude material was purified by chromatography (CH2Cl2/MeOH/NH3 98/1/1) to afford the title product (10.3 g, 70.8 mmol, 73% yield) as a green oil. The green oil was triturated in diethyl ether to afford a powder. tR: 0.21 min (LC-MS 2); ESI-MS: 139 [M+H]+ (LC-MS 2); Rf=0.35 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[S:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[C:11]=1[NH:17][C:18](=[S:19])[N:3]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:1][CH3:2]
Reactant: CCNCCC(=O)O
Reactant: Cc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Yield: 39.3 %

Procedure:
A mixture of 3-ethylaminopropionic acid (19.8 g), 2,6-dimethylphenyl-isothiocyanate (16.3 g), triethylamine (20 g) and methylene chloride (200 mL) was heated at reflux for 3 hours. The cooled reaction mixture was extracted with 1N NaOH (150 mL). The aqueous layer was separated and acidified with 2N HCl. The solid formed was collected by filtration. Recrystallization from ethanol afforded the title compound (11 g) as a white solid, m.p. 115°-118° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl[C:35]1[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[N:36]=1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:35]3[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[N:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Product: COc1cc(OC)nc(N2CN(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)n1

Procedure:
The title compound, MS: m/e=610.0 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxypyrimidine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][CH:16]([F:33])[C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH:16]([F:33])[F:15])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)F)nn1-c1cccc2ncccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 4-t-butylbenzene-1-sulfonyl chloride (0.070 g, 0.30 mmol), 3-(difluoromethyl)-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.045 g, 0.17 mmol), and DMAP (0.020 g, 0.17 mmol) in pyridine (2 mL) was heated at 80° C. for 5 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 5% methanol in ethyl acetate), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.040 g, 0.085 mmol, 53%). 1H NMR (400 MHz, CD3OD) δ 8.88 (dd, J=2.0, 4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.77 (dd, J=7.2, 8.4 Hz, 1H), 7.63 (dddd, J=0.8, 1.6, 1.2, 7.2 Hz, 1H), 7.53-7.43 (m, 5H), 7.31 (dd, J=0.8, 7.2 Hz, 1H), 6.71 (t, J=54.8 Hz, 1H), 6.42 (s, 1H), 1.35 (s, 9H); MS: (ES) m/z calculated for C23H23F2N4O2S [M+H]+ 457.2. found 457.2.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)C.NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1NC(=O)C1C=CC(OC)=CC=1.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1B(O)O>>[N+:12]([C:6]1[C:7]([C:43]2[S:42][CH:46]=[CH:45][CH:44]=2)=[CH:8][CH:9]=[CH:10][C:5]=1[OH:4])([O-:14])=[O:13]
Reactant: OB(O)c1cccs1
Reactant: CC(=O)Oc1ccc(Br)cc1[N+](=O)[O-]
Agent: COc1ccc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2N)cc1
Product: O=[N+]([O-])c1c(O)cccc1-c1cccs1
Temperature: 120 °C
Yield: 32 %

Procedure:
Following the same procedure as in Example 44, step 2 (scheme 32) but substituting bromide 155 for bromide 328 (1.00 g, 3.85 mmol) and boronate 116 for 2-thiophene boronic acid (517 mg, 4.04 mmol) and heating at 120° C., the title compound 298 was obtained (270 mg, 32% yield). 1H NMR: (DMSO-d6) δ (ppm): 11.21 (bs, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.80 (dd, J=8.6, 2.3 Hz, 1H), 7.49 (dd, J=3.5, 1.2 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.11 (dd, J=5.1, 3.5 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)=[O:7])C.O[Li].O>CO.O>[C:14]1([C:11]2[N:10]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:20])=[O:3])[S:13][N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)Nc1nc(-c2ccccc2)ns1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)Nc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a stirred solution of 3-phenyl-[1,2,4]thiadiazol-5-ylamine (0.25 g, 0.00141 mol) in chloroform (2.5 mL) was added mono ethylmalonylchloride (0.233 g, 0.00155 mol) dropwise, the resulting mixture was stirred for 3 hours. The mixture was then concentrated and the residue was stirred in ethyl acetate. The filtrate was removed and concentrated to afford 0.26 g (63%) of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid ethyl ester. LC-MS purity: 292.07 (M+1)+, 67%. To a solution of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid ethyl ester (0.26 g, 0.00089 mol) in a mixture of methanol (3 mL) and H2O (1 mL) was added LiOH.H2O (0.112 g, 0.00267 mol). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The resulting residue was diluted with cold water, acidified with 2NHCl and the product was extracted with ethyl acetate. The ethyl acetate layer washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.105 g (45%) of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid. LCMS: 264.27 (M+1)+: 97.64%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>N1C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[O:13][C:17](=[O:18])[N:16]([CH3:20])[CH3:15]
Reactant: CC1(C)CN(c2ccccc2)NC1=O
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN(C)C(=O)OC1=NN(c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of 4,4-dimethyl-1-phenyl-3-pyrazolidinone (1.90 g) in a mixture of 25 mL pyridine and 4 mL triethylamine at 0° C. is added N,N-dimethylcarbamoyl chloride (1.37 mL). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with methylene chloride (100 mL) and washed with 10% aqueous hydrochloric acid (200 mL). The organic layer is dried (MgSO4), filtered and evaporated. Chromatography on silica gel gave a light yellow solid. Recrystallization from ethanol gave 1.80 g (73%) of pale yellow crystals. (MP-99°-100° C.;
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[C:14]([CH3:21])[C:13]=1[CH3:22]>CO.[Pd]>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:21])[C:13]=2[CH3:22])[C:4]([NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])c(-c2c([N+](=O)[O-])ccc(C)c2C)c1C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(-c2c(N)ccc(C)c2C)c1C
Reaction time: 12 h
Yield: 100 %

Procedure:
3.0 g (10 mmol) of the compound (34) and 500 mg (5 mol %) of 10% Pd/C were added to 50 ml of a methanol solvent and were stirred for 12 hours under hydrogen atmosphere. After the completion of the reaction, solid matter was removed by filtration and thereafter, the resultant was purified by column chromatography (ethyl acetate:hexane=1:5) to obtain 2.4 g (10 mmol) of 5,6,5′,6′-tetramethylbiphenyl-2,2′-diamine (35) (yield was 100%).
Reaction SMILES: N1(C2C3C(=CC=CC=3)NC=2)CCOCC1.[N:16]1([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[N:16]1([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCCCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc2c(N3CCOCC3)c[nH]c2c1
Product: c1ccc2c(N3CCCCC3)c[nH]c2c1
Yield: 71.3 %

Procedure:
Following a method similar to 3-morpholin-4-yl-1H-indole using 3-Piperidin-1-yl-1-triisopropylsilanyl-1H-indole (0.30 g, 0.84 mmol) and 1N solution of tetrabutylammonium fluoride (1.30 mL). Purify by flash chromatography using 20 to 50% of EtOAc in hexanes to give the title compound (0.12 g 71%). MS (ES) 201.1 (M+1)+.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8](=[O:20])[C@H:9]([CH3:19])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:20])[C@H:9]([CH3:19])[N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCCCCCN(CCCCCC)C(=O)[C@H](C)Nc1ccccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)C(=O)[C@H](C)N(c1ccccc1C#N)c1ccccc1[N+](=O)[O-]
Yield: 41.3 %

Procedure:
The crude (2-cyanophenyl)alanine dihexylamide (0.76 g), 2-fluoronitrobenzene (0.30 g) and anhydrous potassium carbonate (0.36 g) in 8 ml of N,N-dimethylformamide were refluxed under heating for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane-ethyl acetate=5:1) to give 0.42 g of N-(2-nitrophenyl)-(2-cyanophenyl)alanine dihexylamide.