Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1CCC2C(=C(C(=O)C)C=CC=2[Cl:14])C1=O)(=O)C.[C:19]([NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([NH:33]C(=O)C)[CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:37])(=[O:21])[CH3:20]>>[C:19]([NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([NH2:33])[CH:27]=[CH:28][C:29]=2[Cl:14])[C:24]1=[O:37])(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(Cl)c2c1C(=O)C(C(C)=O)CC2
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: CC(=O)NC1CCc2c(Cl)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 270 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 160 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cccc(-c2ncc(Br)cc2N)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(3-methoxyphenyl)pyridin-3-amine (0.156 g, 0.56 mmol) in dry DMF (10.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.0454 g, 1.14 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.25 g, 0.86 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 3 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as mostly N-(5-bromo-2-(3-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=533.0 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][OH:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1>CN(C)C=O.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][O:21][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(CO)c3ccccc3)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(1-benzenesulfonyl-1H-indol-5-yl)-2-phenyl-ethanol CCLXVII (1.06 g, 2.707 mmol), tert-butyldimethylchlorosilane (0.45 g, 2.978 mmol) and imidazole (200 mg, 2.978 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 4 hours. The resulting mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 10/90) to give 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole CCLXVIII as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C1C=CC=CC=1)(=O)=O)[CH:7]=[CH:6]2)#[N:2].[CH2:23]([OH:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>CCCCCCC.CCOC(C)=O>[OH:29][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]2
Reactant: N#Cc1ccc2cc(OS(=O)(=O)c3ccccc3)ccc2c1
Reactant: C#CCCCCO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(C#CCCCCO)ccc2c1

Procedure:
This product was prepared from benzenesulfonic acid 6-cyano-naphthalen-2-yl ester and hex-5-yn-1-ol following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 6:4; yield (90 mg, 72%); 1H NMR δ (CDCl3): 8.2 (s, 1H), 7.93 (s, 1H), 7.88-7.76 (m, 2H), 7.65-7.52 (m, 2H), 3.73 (t, J=7.20 Hz, 2H), 2.50 (t, J=7.22 Hz, 2H), 1.87-1.68 (br m, 5H); LCMS m/z: 249.
Reaction SMILES: C(O[C:9](=O)[N:10](C)[CH:11]([C:13](=[O:36])[NH:14][CH:15]([C:19]([N:21]1[CH2:25][CH2:24][CH:23]2[NH:26][CH2:27][CH:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:22]12)=[O:20])[CH:16]([CH3:18])[CH3:17])[CH3:12])C1C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:48][S:49]([N:26]1[CH:23]2[CH:22]([N:21]([C:19]([CH:15]([NH:14][C:13](=[O:36])[CH:11]([NH:10][CH3:9])[CH3:12])[CH:16]([CH3:18])[CH3:17])=[O:20])[CH2:25][CH2:24]2)[CH:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27]1)(=[O:51])=[O:50]
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccccc3)C21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(Oc1ccccc1)CN2S(C)(=O)=O)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 18 (150 mg, 0.28 mmol) in DCM (3 mL) was cooled to 0° C. DIPEA (74 mg, 0.57 mmol) and DMAP (4 mg, 0.03 mmol) were added followed by the addition of MsCl (36 mg, 0.32 mmol). After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude sulfonamide which was used without further purification. Mass spectrum, m/z [601] (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:28]3[CH2:29][CH2:30][N:25]([C:22]4[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=4)[CH2:26][CH2:27]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Product: N#Cc1ccc(N2CCC(N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)CC2)cc1

Procedure:
2.5 g of 1-(4-cyanophenyl)-4-piperidone [cf. Taylor et al., Synthesis (1981) 606] and 5.2 g of 1-(4-nitrophenyl)piperazine were reacted as in Example 1.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (3S)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (3.43 g, 11.6 mmol) (obtained as described in Reference Example 52(3)) in acetonitrile (103 ml) was added triphenylphosphine (3.19 g, 12.2 mmol), and the mixture was stirred in an oil bath (70° C.) for 2 hours. After checking the completion of the reaction, sodium sulfate decahydrate (3.93 g, 12.2 mmol) was added thereto and the reaction mixture was stirred for 5 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give (3S)-3-amino-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (2.83 g, yield 92%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][CH:13]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC(NC(c1ccc(OC)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCC(NC(c1ccc(OC)cc1)c1cccc(N)c1)c1ccc(F)c(F)c1

Procedure:
Following a similar procedure to that described in Example (1b), 3.17 go N-[1-(3,4-difluorophenyl)propyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.66 g, of nickel chloride hexahydrate and 1.17 g of sodium borohydride were reacted, to obtain 2.76 of the title compound as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.Cl>CO.O1CCCC1>[CH3:36][C:33]([CH3:34])([CH3:35])[C:32](=[O:37])[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:12][CH:11]=3)=[C:14]([CH3:39])[CH:15]=2)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:25][C:26]=1[CH3:38]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.296 mL, 0.296 mmol) was added to a solution of (4′-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 50-(1); 50.7 mg, 0.099 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for two hours. The reaction mixture was then poured into 0.5 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (43.3 mg, 87%).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH2:13]([NH:20][CH:21]([CH2:25][CH2:26][CH:27]1[O:32][CH2:31][CH2:30][CH2:29][O:28]1)C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH:21]([CH2:25][CH2:26][CH:27]2[O:28][CH2:29][CH2:30][CH2:31][O:32]2)[CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)C(CCC1OCCCO1)NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC(CCC3OCCCO3)N(Cc3ccccc3)C2C1
Yield: 70.5 %

Procedure:
A mixture of N-allyl-N-(2-oxoethyl)carbamic acid, ethyl ester (Schenke, T.; Peterson, U. Eur. patent EPO393424A2, 1992) (0.203 g, 1.19 mmol) and 2-benzylamino-4-(1,3-dioxan-2-yl)butyric acid (0.330 g, 1.18 mmol) in anhydrous toluene (5 mL) was heated at reflux under argon for 24 h. After cooling, the solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 50% EtOAc/petroleum ether) to give 0.3234 g (71%) of the title compound as a yellow oil. δH (360 MHz, CDCl3) 1.26 (3H, m), 1.28-1.40 (2H, m), 1.48-1.89 (5H, m), 2.05 (1H, m), 2.69 (1H, m), 2.94 (1H, m), 3.10 (1H, m), 3.30-3.47 (4H, m), 3.58 (1H, m), 3.74 (2H, td), 3.92 (1H, d, J=13.6 Hz), 4.07-4.14 (4H, m), 4.48 (1H, t, J=5.0 Hz), 7.22-7.34 (5H, m). m/e (ES+) 389 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1)[CH:7]=2)([O-:3])=[O:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=3)[C:7]([C:16]3[CH:15]=[CH:14][CH:6]=[CH:5][C:4]=3[NH2:1])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH2:21])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C2=Cc3cc([N+](=O)[O-])ccc3C2=CC=C1[N+](=O)[O-]
Reactant: Nc1ccccc1
Product: Nc1ccccc1C1(c2ccccc2N)c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21

Procedure:
2,7-Bis(diarylamino)-9,9-bis(diarylaminophenyl)fluorene, a compound of this invention, can be synthesized according to the above synthetic route as follows: A mixture of a 2,7-dinitrofluorenone and an aniline is refluxed in the presence of an acid catalyst to give an intermediate 2,7-dinitro-9,9-bis(aminophenyl)fluorene. The two nitro groups are then converted to two amino groups by a reduction reaction with Fe/NH4Cl. Finally, the reduced intermediate is reacted with aryl halides (Ar—X and Ar′—X, stepwise) in the presence of a catalyst such as palladium to produce the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][O-:26].[Na+]>CO.O>[OH:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:26][CH3:25])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1

Procedure:
(4S,5S)-Tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.560 mmol) was dissolved in a 25% solution of SODIUM METHOXIDE (12.8 ml, 56.0 mmol) in methanol and refluxed for 12 hrs and cooled. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate, MS m/z: 353.3 (100%, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:8]2[S:7][C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:9]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: COc1ccc2sccc2c1
Product: COc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Methoxybenzo[b]thiophene (see WO 97/25033) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 367/369 (M+H).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(OCC)(=O)C.CCCCCC>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:17]3[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c2c(c1)OC(=O)C2c1ccc(C(C)C)cc1
Yield: 45 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 and 3,5-dimethylphenol, the title compound was synthesized in the same manner as in Reference Example 2. Yield 45%. Melting point: 76-77° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29]Br)=[CH:25][CH:24]=1>CN(C)C=O>[F:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][O:8][C:4]2[C:3]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2N)cc1
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (5 g) in dimethylformamide (30 ml) at room temperature was added potassium carbonate (24.8 g) and 4-fluorophenoxyethylbromide (5.6 g), the mixture was stirred for 16 hrs. The reaction was partitioned between water (100 ml) and diethyl ether (100 ml). The aqueous layer was separated and extracted with further diethyl ether (4×100 ml). The organic fractions were combined, washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure azeotroping with xylene. The residue was purified by column chromatography on silica gel eluting with a solvent gradient, pentane:ethylacetate (7:3 to 0:1, by volume) to yield the title compound as a white solid (4.95 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[C:37]([O:41][C:42](=[O:46])[C@H:43]([CH3:45])[NH2:44])([CH3:40])([CH3:39])[CH3:38]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:46])[CH3:45])[CH2:30][CH2:29]1)=[O:27]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](C)C(=O)OC(C)(C)C)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-alanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.19 (3H, m), 2.95 (2H, t, J=12.0 Hz), 2.60 (2H, m), 1.78 (4H, m), 1.50 (9H, m), 1.27 (3H, d, J=6.9 Hz), 1.23 (2H, m), 1.18 (6H, d, J=6.9 Hz). LC/MS: purity 98%, m/z 435 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(Cl)c1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 5.0 g (19 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 3.6 mL (26 mmol) trimethylsilylethyne using 352 mg (1.9 mmol) CuI, 485 mg triphenylphosphine (1.9 mmol), 1.3 g (1.9 mmol) PdCl2(PPh3)2 and 26 mL (185 mmol) triethylamine in 100 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by RP-MPLC (ACN/H2O gradient). Yield: 1.6 g (38%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].I[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([CH2:26][CH2:25][CH2:24][S:7][C:8]2[C:9]([C:10]([NH:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[O:11])=[CH:19][CH:20]=[CH:21][N:22]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Reactant: ICCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1cccnc1SCCCc1ccccc1
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
227 mg (1.65 mmol) of K2CO3 were added to a solution of 375 mg (1.5 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (3.5 ml), and stirring was carried out for 30 min at RT. 369 mg (1.5 mmol) of 1-iodo-3-phenylpropane were then added and stirring was carried out for a further 3 d at RT. The mixture was then concentrated in vacuo and the residue was taken up in an EA/water mixture. The organic phase was separated off and the aqueous phase was extracted again with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 1:1), yielding 382 mg (1.0 mmol, 69%) of 2-(3-phenyl-propylsulfanyl)-N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 369.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[Br:1][CH2:2][C:3]1[C:4]([C:9]([Cl:14])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1CBr
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1CBr

Procedure:
--A solution of α-bromotoluic acid (1.08 g) in dry benzene (10 ml) was stirred for 2 hours with thionyl chloride (0.73 ml) and dry DMF (five drops). The reaction mixture was evaporated to dryness, taken up in toluene and evaporated again. The crude product was crystallized from n-hexane (10 ml, charcoal) thereby obtaining pure α-bromotoluic acid chloride (0.95 g) as white flakes.
Reaction SMILES: [N+:1]([C:4]1[C:5](CC(OC(C)(C)C)=O)=[N:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-])=O.[C:25](O)(=[O:27])[CH3:26]>[Fe]>[C:11]1([S:10][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][N:6]=2)[NH:1][C:25](=[O:27])[CH2:26]3)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)Cc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Product: O=C1Cc2cc(Sc3ccccc3)ncc2N1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of t-butyl (3-nitro-6-phenylthio-2-pyridyl)acetate (1.04 g, 3.0 mmol) in glacial acetic acid containing iron powder (600 mg, 10.7 mmol) was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice/water and extracted with chloroform. The combined chloroform extracts were washed with brine, dried (MgSO4) and concentrated to leave 5-phenylthio-6-azaoxindole as a light yellow solid (560 mg, 77%); m.p. 186°-189° C.