Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([OH:25])=O)=[CH:14]3)=[O:10])[CH2:4]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:25])=[CH:14]3)=[O:10])[CH2:4]1
Reactant: C1COCCN1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a colorless foam (42%).
Reaction SMILES: [Si]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[NH:23][CH2:22][C@@H:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:72]1[CH:80]=[CH:79][CH:78]=[C:77]2[C:73]=1[CH:74]=[CH:75][N:76]2[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[N:23]([C:72]5[CH:80]=[CH:79][CH:78]=[C:77]6[C:73]=5[CH:74]=[CH:75][N:76]6[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:22][C@@H:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cccc21
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(-c3ncc4c(n3)N3CCOC[C@H]3CN4)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1ccc2c(N3C[C@@H]4COCCN4c4nc(-c5cccc6[nH]ccc56)ncc43)cccc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 181 using (R)-2-(1-(tert-butyldimethylsilyl)-1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x12, 60 mg, 0.142 mmol), cesium carbonate (93 mg, 0.285 mmol), palladium(II) acetate (1.59 mg, 0.007 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (10.2 mg, 0.021 mmol), and tert-butyl 4-bromo-1H-indole-1-carboxylate (126 mg, 0.427 mmol) in dioxane 2 mL (8 mg, 12%). ESI-MS m/z [M+H]+ calc'd for C30H30N6O3, 523.24; found 523.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][C:10]2([CH3:25])[CH3:24])[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O>[O:29]1[CH2:30][CH2:31][N:26]([C:2]2[N:7]=[C:6]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:5]=[C:4]([N:9]3[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][C:10]3([CH3:25])[CH3:24])[N:3]=2)[CH2:27][CH2:28]1
Reactant: CCCCCCOC1CC(C)(C)N(c2nc(Cl)nc(Cl)n2)C(C)(C)C1
Reactant: C1COCCN1
Solvent: O
Product: CCCCCCOC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
9.7 g of the product from Example 10 are heated under reflux for 3 hours with 50 ml of morpholine. The orange reaction mixture is poured into water. The crude product precipitating during this is dissolved in ethyl acetate and purified chromatographically on an SiO2 column. The purified product is a viscous material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:4]([C:30](=O)[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:3]=1.O.NN>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:28])[CH3:29])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:31]3[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=3[F:37])[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2c(F)cccc2F)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1c(F)cccc1F)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in methanol is refluxed with hydrazine hydrate to give 8-chloro-6-(2,6-difluorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:10]1[CH:53]=[CH:52][C:13]2[N:14](COCC[Si](C)(C)C)[C:15]([CH:17]([C:23]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[C:28]4[C:24]=3[CH:25]=[CH:26][N:27]4[S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][C:12]=2[CH:11]=1)#[N:9].C(C1C=CC2N=C(C(C3C(C)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)C(OCC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N>CCO>[C:8]([C:10]1[CH:53]=[CH:52][C:13]2[NH:14][C:15]([CH:17]([C:23]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[C:28]4[C:24]=3[CH:25]=[CH:26][N:27]4[S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][C:12]=2[CH:11]=1)#[N:9]
Reactant: CCOC(=O)C(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCOC(=O)C(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
HCl in dioxane (4 M, 2.28 mL, 9.13 mmol) was added to a solution of a mixture of (±)-ethyl 2-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)acetate and (±)-ethyl 2-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)acetate (600 mg, 0.913 mmol) in EtOH (12 mL) at room temperature. The resulting mixture was stirred at 60° C. overnight then partitioned between EtOAc and sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried, and concentrated to give the title compound. The residue was taken onto the next step without further purification. MS (ESI+) m/z 527.3 (M+H).
Reaction SMILES: [CH:1]1([C@@H:7]2[NH:32][C:31](=[O:33])[O:30][CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][CH2:25][C:24]3[CH:36]=[C:37]4[C:21](=[CH:22][C:23]=3[O:38][CH3:39])[N:20]3[C:16](=[N:17][CH:18]=[CH:19]3)[CH:15]=[C:14]4[O:13][C@H:12]3[CH2:40][N:9]([C@H:10]([C:41]([O:43]C)=[O:42])[CH2:11]3)[C:8]2=[O:45])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:1]1([C@@H:7]2[NH:32][C:31](=[O:33])[O:30][CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][CH2:25][C:24]3[CH:36]=[C:37]4[C:21](=[CH:22][C:23]=3[O:38][CH3:39])[N:20]3[C:16](=[N:17][CH:18]=[CH:19]3)[CH:15]=[C:14]4[O:13][C@H:12]3[CH2:40][N:9]([C@H:10]([C:41]([OH:43])=[O:42])[CH2:11]3)[C:8]2=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)OCC(C)(C)CCCc1cc3c(cc4nccn4c3cc1OC)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c3cc1CCCC(C)(C)COC(=O)N[C@@H](C1CCCCC1)C(=O)N1C[C@@H](C[C@H]1C(=O)O)Oc3cc1nccn12
Temperature: 50 °C

Procedure:
To a solution of the product from Step 9, methyl (3R,5S,8S)-8-cyclohexyl-18-methoxy-13,13-dimethyl-7,10-dioxo-2,11-dioxa-6,9,21,24-tetraazapentacyclo[15.9.2.13,6.020,27.021,25]nonacosa-1(26),17,19,22,24,27-hexaene-5-carboxylate (100 mg, 0.161 mmol) in THF (4 mL), MeOH (1 mL) and water (1 mL) was added LiOH (39 mg, 1.61 mmol). The mixture was then heated to 50° C. for 1 h and 1N HCl was then added to neutralize the base. The mixture was then extracted with EtOAc, the organic layer was dried over MgSO4, and the solvent was removed in vacuo to yield the title compound. LRMS (M+H)+=607.1.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([CH3:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([CH3:43])[CH:36]=2)=[CH:9][C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(C)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(C)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.3 mL, 8.3 mmol) in THF (20 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.3 mL, 8.3 mmol) dropwise. The mixture was stirred at room temperature for 40 min. A solution of (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl)-methanone from above in THF (10 mL) was added to the mixture. The mixture was refluxed for 4 h. The solution was poured into ice water (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3-ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-methyl-phenyl)-acrylonitrile as a white solid (0.97 g, 75% yield) (isomer ratio is 1:0.8 by HNMR): mp: 86-88° C.; 1H NMR (DMSO-d6) δ 1.30 (t, J=7 Hz, 3H, CH3), 2.13 (s, 3H, CH3), [2.17 (s)], 3.78 (s, 3H, CH3), 3.82 (s, 3H, CH3), [3.83 (s), 3.86 (s)], 3.93-4.04 (m, 2H, CH2), 6.01 (s, 1H, CH), [6.08 (s)], 6.72-7.26 (m, 6H, Ar); 13C NMR (DMSO-d6) 14.56, 14.59, 15.98, 63.77, 92.10, 92.42, 110.04, 110.18, 111.35, 111.51, 112.27, 113.83, 118.92, 122.27, 122.35, 125.61, 125.86, 128.05, 128.60, 128.92, 129.44, 130.14, 130.35, 130.82, 131.29, 147.36, 147.78, 150.15, 151.02, 158.44, 159.28, 161.47, 161.53; Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.16; H, 6.48; N, 4.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[N:19][OH:20]
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(O)c(F)c2)cc1Cl
Agent: Cl
Product: ON=Cc1ccc(-c2ccc(O)c(F)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 3-chloro-3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (1.52 mmol) with hydroxylamine hydrochloride (233 mg, 3.34 mmol) according to Method C to yield 260 mg (66%) of yellowish solid: mp 198-200° C.; 1H NMR (DMSO-d6): δ 7.03 (1H, t, J=8.79 Hz), 7.41-7.43 (1H, m), 7.60 (1H, dd, J=12.91 Hz, J=2.20 Hz), 7.64-7.66 (1H, m), 7.77 (1H, d, J=1.92 Hz), 7.84 (1H, d, J=8.24 Hz), 8.36 (1H, s),10.16 (1H, bs), 11.68 (1H, bs); MS (ESI) m/z 264/266 (M−H)−, 266/268 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Al].Cl[CH:16](Cl)[CH2:17][Si:18]([Cl:21])([Cl:20])[Cl:19]>C(=S)=S.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:16]([CH2:17][Si:18]([Cl:21])([Cl:20])[Cl:19])[C:6]=2[CH:7]=1
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Al]
Solvent: S=C=S
Solvent: CCCCCC
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccc(Br)cc21
Yield: 15 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of 4-bromobiphenyl and 0.08 g (11.1 mmol) of aluminum foil were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)-trichlorosilane 6.68 g (21.7 mmol) for 24 hr. at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, the reaction products were vacuum distilled to give 1.28 g of 2-bromo-9-(trichlorosilyl)methylfluorene (yield; 15%).
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:31]=[C:32](I)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:27]([C:30]1[CH:35]=[C:34]([NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([CH:1]=[CH:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[N:10][N:11]3[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])=[CH:16][CH:15]=2)[CH:33]=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc([N+](=O)[O-])c3)cc21
Temperature: 80 °C
Yield: 74 %

Procedure:
To 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine (1.1 g, 3 mmol, m-nitro-iodobenzene (0.9 g, 3.6 mmol), BINAP (0.07 g, 0.133 mmol), Pd2(dba)3 (34 mg, 0.0375 mmol) and Cs2CO3 (1.37 g, 4.2 mmol) under an atmosphere of argon was added toluene (6 mL). The resulting heterogeneous mixture was heated to 80° C. After 46 h the reaction was cooled to 23° C. diluted with ethyl acetate (EtOAc) (20 mL) and filtered. Water (5 mL) was added, the phases were separated, and the organic was extracted 2×50 mL EtOAc. The pooled organic material was washed with brine, then dried with Na2SO4, filtered and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (eluting with 9:1 hexane:EtOAc) to give (3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine as a yellow solid (7.65 g, 74%): TLC (Hexane:EtOAc 7:3) Rf sm 0.16, Rf p 0.30 (ethyl acetate:hexane 3:7); FITR (KBr) 3391, 3059, 2952, 2894, 1614, 1530, 1483, 1346, 1248, 1076, 836, 734 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.83 (s, 1H), 7.65 (dt, 1H, J=2.21, 5.13 Hz), 7.15-7.41 (m, 5H), 6.93 (dd, 1H, J=1.87, 8.67 Hz), 5.56 (s, 2H), 3.51 (t, 2H, J=8.17 Hz), 0.81 (t, 2H, J=7.96 Hz), −0.15 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 149.6, 144.8, 143.5, 142.4, 140.9, 137.3, 131.8, 130.3, 129.0, 128.2, 126.7, 122.8, 122.6, 120.1, 119.3, 116.1, 115.6, 111.4, 98.5, 77.9, 66.7, 18.0, −1.2; MS (ESI) [M+H]/z Calc'd 487, found 487. Anal. Calc'd: C, 66.64; H, 6.21; N, 11.51. Found: C, 66.91; H, 6.21; N, 11.44.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:35])(=[O:32])=[O:31]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 10 of Example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1) and 2-chlorobenzenesulfonyl isocyanate.
Reaction SMILES: ClC1C=CC(C2C3CN([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])CC3ON=2)=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[CH3:53][O:54][C:55]1[N:60]=[CH:59][C:58]([C:61]2[C@@H:65]3[CH2:66][NH:67][CH2:68][C@@H:64]3[O:63][N:62]=2)=[CH:57][CH:56]=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:67]3[CH2:68][CH:64]4[CH:65]([C:61]([C:58]5[CH:59]=[N:60][C:55]([O:54][CH3:53])=[CH:56][CH:57]=5)=[N:62][O:63]4)[CH2:66]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Reactant: COc1ccc(C2=NO[C@H]3CNC[C@@H]23)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=NOC3CN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5-c4ccc(F)cc4F)CC23)cn1

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using TFA salt 4c. Acid 102 was isolated as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](/SC)=[CH:9]\[C:10]([CH:12]2[CH:17]3[CH:13]2[CH2:14][CH:15]([O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]3)=O)=[CH:4][C:3]=1[O:38][C:39]([F:42])([F:41])[F:40].O.[NH2:44][NH2:45].C(OCC)(=O)C>C(O)C>[Si:19]([O:18][CH:15]1[CH2:14][CH:13]2[CH:17]([CH:12]2[C:10]2[NH:45][N:44]=[C:8]([C:5]3[CH:4]=[C:3]([O:38][C:39]([F:41])([F:42])[F:40])[C:2]([NH2:1])=[N:7][CH:6]=3)[CH:9]=2)[CH2:16]1)([C:32]([CH3:34])([CH3:33])[CH3:35])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS/C(=C/C(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21)c1cnc(N)c(OC(F)(F)F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CC2C(C1)C2c1cc(-c2cnc(N)c(OC(F)(F)F)c2)n[nH]1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 76 %

Procedure:
A solution of (E)-3-(6-amino-5-(trifluoromethoxy)pyridin-3-yl)-1-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-(methylthio)prop-2-en-1-one (0.70 g, 1.1 mmol) and hydrazine hydrate (5 mL) in ethanol (5 mL) was sealed in a microwave vessel and heated at 100° C. by microwave irradiation for 1 h. The reaction mixture was concentrated, and the resulting residue was purified by flash column chromatography (60% ethyl acetate in petroleum ether) to product as a white solid (0.50 g, 76% yield). LCMS (ESI) [MH]+=579.1.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[Br:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20]C(=O)C=2[S:15][CH:14]=1.O>ClCCl>[Br:12][C:13]1[C:17]2[N:18]=[CH:19][N:20]=[C:6]([Cl:11])[C:7]=2[S:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2c(Br)csc12
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ncnc2c(Br)csc12
Yield: 81.5 %

Procedure:
Dimethylformamide (25.8 mL, 0.33 mol) and dichloromethane (150 mL) were added to a reactor. Oxalyl chloride (46.4 mL, 0.53 mol) diluted with dichloromethane (150 mL) at room temperature was added to the reactor for about 30 minutes. 7-bromothieno[3,2-d]pyrimidin-4(3H)-one (35 g, 0.15 mol) was added thereto, and then, the reaction solution was heated to reflux for 3 hours. The temperature of the reaction solution was lowered and water was carefully added thereto. The organic layer was separated, and the aqueous layer was subjected to extraction using dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and distilled under reduced pressure, and dried with nitrogen gas to obtain the title compound (30.5 g, 85%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:28])[CH:34]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2cccc(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-methylphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.29 g, 99%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[CH2:36]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([CH:43]1[CH2:48][CH2:47][N:46]([C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: NCCSC(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and 4-benzylpiperidine (327 μl) were subjected to similar reactions to those described in References 2 and 4 to give 2-(4-benzylpiperidino)carbonylthioethylamine (crude formate: 210 mg). The product was dissolved in anhydrous methanol (3.5 ml). Triethylamine (432 μl) and mitocyin A (151 mg: 0.7 molar equivalent) were added to the solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 41 (300 mg) in the form of grayish blue powders with a yield of 81%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[C:23]([CH2:26][C:27](=O)[CH3:28])(=O)[CH3:24].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]2[C:2]3=[N:1][C:23]([CH3:24])=[CH:26][C:27]([CH3:28])=[C:3]3[C:4]([C:21]#[N:22])=[CH:5]2)=[CH:19][CH:18]=1
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1cc(N)n(C(c2ccccc2)c2ccc(F)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(C(c3ccccc3)c3ccc(F)cc3)c2n1

Procedure:
To a solution of 5-amino-1-[(4-fluorophenyl)(phenyl)methyl]-1H-pyrrole-3-carbonitrile (13.7 g, 47.0 mmol) in ethanol (200 ml) was sequentially added acetylacetone (5.66 g, 56.6 mmol) and concentrated hydrochloric acid (2.0 ml). The mixture was heated under reflux for 3 hours, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH:20]=[CH:21][CH2:22]Br>>[C:1]1([N:7]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:19][CH:20]=[CH:21][CH2:22][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC=CCBr
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Product: C(=CCN(c1ccccc1)c1cccc2ccccc12)CN(c1ccccc1)c1cccc2ccccc12
Temperature: 70 °C
Yield: 17.5 %

Procedure:
A mixture of N-phenyl-l-naphthylamine (63 g, 0.29 mol) and 1.4-dibromobut-2-ene (12 g, 0.056 mol) is heated to 70° C. for three days. The resulting reaction mass is allowed to cool and is then extracted with 3×100 ml of hot hexane. The combined hexane extracts are concentrated in vacuo to an oil which is chromatographed (silica gel. 95/5 cyclohexane/diethyl ether) to give an oil. Said oil is then crystallized from ether to give 4.8 g (17.5% yield) of the title compound as a tan solid melting at 140°-142° C.