Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:24])=[N:4][C:5]([C:8]2[N:9]=[C:10]([CH:21]3[CH2:23][CH2:22]3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:6][CH:7]=1.[N:25]([C@@H:28]([CH3:33])[CH2:29][CH2:30][O:31][CH3:32])=[C:26]=S.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[CH:21]1([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[C:8]([C:5]3[N:4]=[C:3]4[O:24][C:26]([NH:25][C@@H:28]([CH3:33])[CH2:29][CH2:30][O:31][CH3:32])=[N:1][C:2]4=[CH:7][CH:6]=3)[N:9]=2)[CH2:22][CH2:23]1
Reactant: COCC[C@H](C)N=C=S
Reactant: Nc1ccc(-c2nc(C3CC3)[nH]c2-c2ccc(F)cc2F)nc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C4CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 85 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A KIMAX® tube is charged with 3-amino-6-[2-cyclopropyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]pyridin-2-ol (0.7 g, 2.13 mmol) and ethanol (7 mL). (3S)-3-isothiocyanato-1-methoxy-butane (0.46 g, 3.2 mmol) is added, the flask sealed, and the mixture is heated to 85° C. After 16 h, N,N′-dicyclohexylcarbodiimide (0.88 g, 4.26 mmol) is added and the mixture is stirred for 4 h at 85° C. in the sealed tube. After this time, additional N,N′-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) is added to the mixture. Heating is continued at 85° C. overnight. After this time, additional N,N′-dicyclohexyl-carbodiimide (0.88 g, 4.26 mmol) is added to the mixture, and heating is continued at 85° C. for 4 h. The crude reaction is concentrated under reduced pressure, and the residue is purified by normal phase chromatography (120 g silica-gel cartridge, dichloromethane-ethanol gradient). The fractions containing the desired compound are further purified by semi-preparative reverse phase high performance (LC/MS) using an XBRIDGE™ column (5 μm, 19×100 mm) and an isocratic program of 36% of acetonitrile in NH4HCO3 20 mM (pH 9), in 5 min at flow 25 mL/min to afford the title compound (0.15 g, 16%). LCES/MS m/z 440 (M+1); [α]D22+58.60°, (c=0.50, methanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.FC(F)(F)C(O)=O.[NH2:44][CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])=[C:50]([O:60][CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH:49]=1)=[O:47].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([NH:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])=[C:50]([O:60][CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH:49]=2)=[O:47])=[O:18])[CH2:14][CH2:15]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)COc1ccc(C(=O)CN)cc1OCC(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)CNC(=O)[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 877 mg (3.41 mmol) of the compound prepared in (a) (3.41 mmole) in the mixture of 6.8 ml of dimethylformamide and 1.4 ml of pyridine were added 874 mg of N,N'-disuccinimidyl carbonate and a catalytic amount of 4-dimethylaminopyridine, and the resulting mixture was stirred at room temperature for 3 hours, whereafter 1.45 g of the compound prepared in (b) and 0.59 ml of N,N-diisopropylethylamine were added. The mixture was further stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the resulting solid product was purified by column chromatography on silica gel. The solid product thus obtained was washed with ether to give 1.1 g of dimethyl [[4-[[[trans-4-(t-butyloxycarbonylaminomethyl)cyclohexyl]carbonylamino]acetyl]-o-phenylene]dioxy]diacetate as pale yellow crystals (yield, 59%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>O1CCCC1.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.[Cu](I)I>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(O)CON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)c(F)c1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-propoxyimino)-methyl]-benzamide (14.6 mg, 0.025 mmol) prepared in Example 12 was dissolved in anhydrous tetrahydrofuran (2.0 ml). Next, (PPh3)2PdCl2 (20,867-1, Sigma-Aldrich, Inc.) (1.0 mg, 0.00127 mmol), copper iodide (2.0 mg, 0.0094 mmol), N,N-diisopropylethylamine (10 μL, 0.057 mmol), and trimethylsilylacetylene (35 μL, 0.25 mmol) were added thereto at room temperature, and the mixture was stirred at 50° C. overnight.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20].O>CN(C=O)C>[N:15]([C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:18])[CH3:1])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[C:19]=[S:20]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Dimethyl-[1-(4-nitro-phenyl)-piperidin-4-yl]-amine (Example 2, 1.1 g, 5.0 mmol) was dissolved in DMF (5 mL). To the stirred solution, thiocarbonyl diimidazole (Aldrich, 1.18 g, 90%, 6 mmol) was added and the solution was stirred at room temperature for 80 minutes. The mixture was poured into water and extracted with diethyl ether. The extract was dried with sodium sulfate and concentrated to give a pale yellow solid. 1.12 g, 85%. MS (m+H)+: 262.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:18][CH3:19]>>[CH2:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:22][CH:21]=1)[CH2:18][CH3:19]
Reactant: CCCc1ccc(N)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CCCc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 16.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 4-propylaniline (0.10 ml; 0.65 mmol) to provide 243 (23 mg, 15% yield) as a brown solid. LC-MS (M+H (parent)=330, obsd.=330).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[N:26]=[N:27][NH:28][N:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[N:26]=[N:27][NH:28][N:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3nn[nH]n3)cccc21
Product: CC1c2cccc(-c3nn[nH]n3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([S:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CSC[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 77.3 %

Procedure:
To a stirred solution of (3R)-3-(benzylthio)methyl-1-(tert-butoxycarbonyl)pyrrolidine (0.2320 g, 0.755 mmol) in dichloromethane (3 ml), under argon, was added trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 65 minutes before quenching with anhydrous methanol (2 ml) and evaporating in vacuo. More methanol (2 ml) was added to the residue and removed in vacuo. The residual oil was then dissolved in dichloromethane (25 ml) and washed with 2N NaOH solution (10 ml). The aqueous layer was reextracted with more dichloromethane (15 ml) and the combined dichloromethane extracts were washed with saturated NaCl solution (10 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2 /MeOH/NH3, 85:15:1.5) to give 0.1210 g (77%) of the title compound as a colourless oil. δH (250 MHz,CDCl3) 1.41 (1H, m), 1.90-2.00 (1H, m), 2.24 (1H, m), 2.42-2.50 (2H, m), 2.57 (1H, dd, J=6.5 and 11.0 Hz), 2.82-2.99 (2H, m), 3.07 (1H, dd, J=7.3 and 11.0 Hz), 3.72 (2H, s), 7.20-7.36 (5H, m); m/e (ES) 208 (M+ +1).
Reaction SMILES: C(OCC#C)(=O)C=C.C[SiH](C)Cl.C(NCC)C.C(N([CH:23]=[CH:24][C:25]([O:27][CH2:28][CH:29]=[CH:30][Si:31]([CH3:34])([CH3:33])[Cl:32])=[O:26])CC)C.[SiH3]O>>[C:25]([O:27][CH2:28][CH:29]=[CH:30][Si:31]([CH3:34])([CH3:33])[Cl:32])(=[O:26])[CH:24]=[CH2:23]
Reactant: CCN(C=CC(=O)OCC=C[Si](C)(C)Cl)CC
Agent: C#CCOC(=O)C=C
Agent: C[SiH](C)Cl
Agent: O[SiH3]
Solvent: CCNCC
Product: C=CC(=O)OCC=C[Si](C)(C)Cl

Procedure:
Acryloxypropenyldimethylchlorosilane was prepared by a modification of Example 2 of U.S. Patent 3,746,734, to Berger et. al., using propargyl acrylate and dimethylchlorosilane as reactants. This product was then reacted with diethylamine. The resulting N,N-diethylaminoacryloxypropenyldimethylchlorosilane was then condensed with the 12000 MW and 28000 MW silanol terminated silicones utilized in Examples 1-16. The resulting acrylate terminated silicones were designated D and E, respectively.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O)[CH3:12].[Si](OCC)(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:17]3[CH:16]([CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:22])[CH2:20][CH2:19][C:18]=3[C:2]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCCC1=O
Reactant: COc1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Temperature: 135 °C
Reaction time: 5 h

Procedure:
To a solution of 2-iodo-4-methoxyaniline (20.0 g, 80 mmol), ethyl-2-(2-oxocyclopentyl)acetate (20.5 g, 120 mmol, 1.5 eq) and tetraethyl orthosilicate (21.7 g, 104 mmol, 1.3 eq) in anhydrous DMF (100 mL), was added pyridine p-toluenesulfonate (0.807 g, 3.21 mmol, 0.04 eq). The dark brown solution was stirred at 135° C. for 5 h under N2, allowed to cool to 100° C. and then added DIPEA (31.1 g, 241 mmol, 3 eq) followed by Pd(OAc)2 (0.541 g, 2.41 mmol, 0.03 eq). The resulting mixture was stirred at 120° C. for 22 h under N2, concentrated under reduced pressure. The residue was taken up in DCM, filtered through a plug of silica and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound. LCMS m/z=274.4 [M+H]+.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].[CH3:13][C:14](O)([CH3:16])[CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 60 %

Procedure:
To a stirred ice cooled solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (3.0 g, 17.65 mmol) in THF (5 ml), t-BuOH (5.1 ml, 52.94 mmol) and DMAP (0.036 g, 0.176 mmol) in THF (3 ml) were added followed by DCC (4.4 g, 21.2 mmol) in dry THF (2 ml) was added slowly. Then the reaction was stirred at room temperature for about 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and washed with DCM. The filtrate was washed with 5% HCl, water, aqueous NaHCO3 and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (60-120, elution 10% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 2.4 g; Yield: 60%; 1H NMR (300 MHZ, CDCl3): δ 2.84 (m, 1H), 2.70-2.51 (m, 2H), 2.06 (s, 3H), 1.89-1.80 (m, 1H), 1.41 (s, 12H), 0.93 (s, 3H); Mass: [M+Na]+ 249 (100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][OH:22])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][O:22][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC[C@@H](CCO)CCCCOCc1ccccc1
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CC[C@H](CCCCOCc1ccccc1)CCOc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl (S)-8-(benzyloxy)-4-(2-hydroxyethyl)octanoate (1.61 g, 5.2 mmol) in methylene chloride (20 ml) is added 3-hydroxypyridine (0.51 g, 5.4 mmol) and triphenylphosphine (1.82 g, 7 mmol). The mixture is stirred at room temperature for 10 minutes and then diisopropyl azodicarboxylate (1.05 ml, 5.3 mmol) is added slowly. The mixture is allowed to stir for 2 hours and the solvent is evaporated. The residue is purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent to obtain methyl (S)-8-(benzyloxy)-4-[2-(3-pyridyloxy)ethyl]octanoate; IR (CH2CL2): 1732, 1280, 1230, 1102 cm-1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[CH3:11])=[C:4]([C:12]4[O:13][C:14]([CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]5)=[N:15][N:16]=4)[CH:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CCN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4C)o2)CC1
Temperature: 110 °C
Yield: 41 %

Procedure:
6-Bromo-1-methyl-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (45 mg, 0.107 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26.1 mg, 0.107 mmol), sodium carbonate (34.1 mg, 0.322 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (7.85 mg, 10.73 μmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified firstly by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane then by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12]/[C:11](=[CH:15]/[N+:16]([O-])=O)/[NH:10]2)=[CH:5][CH:4]=1>[Ni].O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:19])[NH:10][CH:11]([CH2:15][NH2:16])[CH2:12][O:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COC/C(=C/[N+](=O)[O-])N2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2(C)COCC(CN)N2)cc1
Reaction time: 5 h

Procedure:
A mixture of 50 mmol of 3-(4-methoxyphenyl)-3-methyl-5-[1-nitrometh-(Z)-ylidene]morpholine and 5 teaspoons full of Raney nickel in 500 ml of tetrahydrofuran and 250 ml of methanol is hydrogenated under atmospheric pressure for 5 hours. The reaction mixture is filtered through Hyflo and the filtrate is evaporated. The crude title compound is identified from the residue on the basis of the Rf. The title compound is employed without further purification in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Yield: 82 %

Procedure:
9-(2,5-Dichlorobenzyl)-9H-β-carboline-3-carboxylic acid was prepared as described for the corresponding 9-unsubstituted compound (Hagen et al., Heterocycles 1986, 24:2845). A mixture of methyl 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylate (15.0 g, 0.0389 mol), sodium hydroxide (2.0 g, 0.05 mol), water (75 mL), and 95% ethanol (200 mL) was refluxed for 1 hour. The mixture was concentrated in vacuo, and the residue dissolved in warm water (500 mL), and the pH adjusted to 3 using dilute HCl with vigorous stirring, resulting in the precipitation of a solid. The fine slurry was filtered, washed thoroughly with water, and dried in vacuo overnight at 70° C., and for another day at 85° C., affording 12.60 g (87%) of product. In another run, the product was isolated in 82% yield after recrystallization from hot acetic acid. The product had the following properties: 1H NMR (300 MHz, DMSO-d6) δ9.16 (s, 1H), 9.08 (s, 1H), 8.59 (d, J=8.0, 1H), 7.60-7.69 (m, 3H), 7.39-7.44 (m, 2H), 6.705 (d, J=2.3, 1H), 5.93 (s, 2H), 1.93 (s, 3H); LRMS calcd for C19H10Cl2N2O2 (M+H) 371, found 371.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([NH:18][CH3:19])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].Cl[CH2:23][C:24]1[C:25]([CH3:40])=[N:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([N:18]([CH3:19])[CH2:23][C:24]2[C:25]([CH3:40])=[N:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(NC)c2c1CCCC2
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2

Procedure:
In analogy to the procedures described in example 5C] and 5D], 2-methyl-2-(4-methylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 4G]) to give 2-methyl-2-(4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]([NH:18][NH2:19])=[S:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28]>O1CCCC1.CCOCC>[CH3:14][C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:17][C:27](=[O:28])[NH:19][N:18]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=S)NN)cc(C(C)(C)C)c1O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2n[nH]c(=O)s2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-benzene carbothioic acid, hydrazide (2.0 g, 0.0072 mole) in tetrahydrofuran (10 ml) is added triethylamine (0.39 g, 0.0039 mole) followed by carbonyl diimidazole (0.8 g, 0.0048 mole). The resulting mixture is stirred at 0° C. for one hour. Dilute with ether and extract product with 1M NaOH (2×). The combined aqueous layers are combined and made acidic with aqueous 6M HCl. The product is extracted with 1:1 ether/ethyl acetate. The combined organic extracts are washed with saturated aqueous NaCl and concentration in vacuo provides 1.4 g (2.2 g theor., 64%) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2(3H)-one after recrystallization from ethyl acetate/hexane: mp 229° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].CN(C)C=O.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[OH:26])[CH:22]([CH2:27][CH2:28][NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:21][CH2:20]2>O>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[O:26][CH2:9][C:8]#[CH:7])[CH:22]([CH2:27][CH2:28][NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:21][CH2:20]2
Reactant: CCC(=O)NCCC1CCc2cc(F)c(O)cc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc2c(cc1F)CCC2CCNC(=O)CC
Temperature: 120 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Potassium carbonate (1.37 g, 9.95 mmols) and propargyl bromide (2.4 g, 19.9 mmols) were added to a dimethylformamide (10 ml) solution of N-[2-(5-fluoro-6-hydroxyindan-1-yl)ethyl]propionamide (0.5 g, 1.99 mmols) and stirred at 120° C. for 2 hours. The reaction solution was poured into water, and the organic substance was extracted out with ethyl acetate. The extract was washed with a saturated saline solution and water and then dried with anhydrous magnesium sulfate, and the solvent was removed through distillation under reduced pressure. The resulting residue was purified through silica-gel column chromatography (ethyl acetate) to obtain 0.56 g (yield: 97%) of the target compound.