Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[CH:9]=2)=[C:4]([CH3:28])[CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH2:37]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:28][C:4]1[CH:3]=[C:2]([O:1][CH2:37][CH2:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)[CH:9]=1
Reactant: OCCCc1ccccn1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(O)cc3C)c2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OCCCc4ccccn4)cc3C)c2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution of methyl 3-{4-[(4′-hydroxy-2′-methylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.602 g, 1.60 mmol), 3-(pyridin-2-yl)propan-1-ol (0.822 g, 6.00 mmol) and triphenylphosphine (1.57 g, 6.00 mmol) in tetrahydrofuran (20 mL) under ice-cooling was stirred and diethyl azodicarboxylate (40% toluene solution, 2.72 mL, 6.00 mmol) was added. The mixture was warmed to room temperature and stirred for 42 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) and preparative HPLC to give the title compound as a yellow viscous oil (0.446 g, yield 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15]/[CH:16]=[C:17]2\[C:18](=[O:29])[NH:19][C:20](=[O:28])[C:21]3[C:26]\2=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.BrC1C=C2C(=CC=1)[C:37](=[O:41])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[I:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:28])[NH:19][C:18](=[O:29])/[C:17]/2=[CH:16]/[O:41][CH3:37].[F:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2F)CC1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CN1CCN(c2ccc(N)cc2F)CC1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.27 g (90.0% yield) of light brown solid is obtained from 0.2 g (0.61 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 0.15 g (0.73 mmol) of [3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amine: mp 211-212° C.; MS (ESI) m/z 507.1 (M+H)+1
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH3:10])[C:7]([C:11]2[N:15]3[N:16]=[C:17](Cl)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].O1CCOCC1.O.[NH2:28][NH2:29]>CO>[N+:1]([C:4]1[N:8]([CH2:9][CH3:10])[C:7]([C:11]2[N:15]3[N:16]=[C:17]([NH:28][NH2:29])[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: NN
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(NN)nn12

Procedure:
3 g. 3-(5-nitro-1-ethyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were dissolved in 30 ml. of a mixture of dioxan and methanol (1:1) and 3 ml. hydrazine hydrate were added thereto at 20° - 25° C., while stirring. The reaction mixture was further stirred for 45 minutes and the separated crystals were filtered off with suction, washed with a mixture of dioxan and methanol (1:1) and dried in a vacuum at 120° C. There was thus obtained 0.66 g. of the desired 3-(5-nitro-1-ethyl-2-imidazolyl)-6-hydrazino-s-triazolo[4,3-b]pyridazine which melts, with foaming up, at 216° - 223° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[NH:14][C:15](=[O:22])[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[N:18][CH:17]=4)[CH:5]=1.Cl[CH2:24][C:25]1[N:26]=[N:27][N:28]([CH3:30])[CH:29]=1.O>CN(C=O)C>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:24][C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[N:18][CH:17]=4)[CH:5]=1
Reactant: Cn1cc(CCl)nn1
Reactant: Cc1cc(-c2nnc3c4ccncc4c(=O)[nH]n23)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4ccncc4c(OCc4cn(C)nn4)nn23)no1
Temperature: 60 °C
Yield: 14.3 %

Procedure:
Sodium hydride (42 mg of a 60% dispersion on oil, 1.1 mmol) was added to a stirred solution of 3-(5-methylisoxazol-3-yl)-1,2,3a,4,7-pentaazacyclopenta[a]naphthalen-5(4H)-one (200 mg, 0.75 mmol) in DMF (6 ml) at room temperature under nitrogen, and the mixture was heated at 60° C. for 0.5 h. The reaction mixture was allowed to cool to room temperature, treated with 4-chloromethyl-1-methyl-1,2,3-triazole (108 mg, 0.82 mmol) and heated at 60° C. for 1.5 h. On cooling to room, water was added. The mixture was extracted with ethyl acetate, the organics separated, dried (MgSO4), and evaporated in vacuo. The residue was recrystallised from methanol to afford the title product as a white solid (39 mg, 14%), 1H NMR (360 MHz, d6 DMSO) δ 2.60 (3H, s, Ar—CH3), 4.08 (3H, s, N—CH3), 5.73 (2H, s, OCH2), 7.21 (1H, d, J=0.8 Hz, Ar—H), 8.45 (2H, m, Ar—H), 9.15 (1H, d, J=5.3 Hz, Ar—H)), 9.41 (1H, s, Ar—H); MS (ES+) m/e 364 [MH]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C([NH:16][C:17]1[N:26]=[C:25]([NH:27]C(C(C)(C)C)=O)[C:24]2[CH2:23][C:22](=O)[CH2:21][CH2:20][C:19]=2[N:18]=1)=O)(C)C>>[NH2:16][C:17]1[N:26]=[C:25]([NH2:27])[C:24]2[CH2:23][C:22](=[N:9][O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][CH2:20][C:19]=2[N:18]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Product: Nc1nc(N)c2c(n1)CCC(=NOCc1ccccc1)C2

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:7]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:34][OH:35].[H-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:6]1[C:5]2[C:4](=[O:31])[N:3]([CH3:32])[C:2]([O:35][CH2:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])=[N:10][C:9]=2[N:8]=[C:7]1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)CO
Reactant: Cn1c(Cl)nc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1nc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 210.3 %

Procedure:
10 mg of t-butyl 4-[2-chloro-7-(2-chlorophenyl)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl glycolate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was dissolved in ethyl acetate, and the mixture was washed with 1N hydrochloric acid. Thus, 24 mg of t-butyl 4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was obtained. 8 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.11 mg of the title compound.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]3[O:25]C(C)(C)C(C)(C)[O:18]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CC(C)=O.O>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]([OH:25])[OH:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(B(O)O)ccc21
Reaction time: 48 h
Yield: 67.5 %

Procedure:
To N-Boc-indazole-5-boronic acid pinacol ester (S46) (390 mg, 1.13 mmol, 1.00 equiv) in acetone/H2O (5.0 mL/5.0 mL) at 23° C. was added NH4OAc (436 mg, 5.65 mmol, 5.00 equiv) and NaIO4 (1.21 g, 5.65 mmol, 5.00 equiv). After stiffing for 48 hr at 23° C., the reaction mixture was concentrated in vacuo to remove acetone. To the residual solution was added EtOAc (5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×5 mL). The combined organic phases are washed with brine (10 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was triturated with Et2O to afford 200 mg of the title compound as a colorless solid (68% yield).
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: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)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: N([O-])=[O:2].[Na+].N[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9](=[O:18])[NH:8][C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[N-]=[N+]=[N-].[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[OH:2][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9](=[O:18])[NH:8][C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2O)cc1
Reaction time: 0.5 h

Procedure:
At 0° C., a solution of sodium nitrite (24.8 mg, 0.36 mmol) in water (0.5 mL) is added slowly to a solution of 4-amino-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (100 mg, 0.33 mmol) dissolved in acetic acid (1 mL) and sulphuric acid (0.5 mL). The mixture is left under stirring under cold conditions for 30 minutes then sodium azide (25.7 mg, 0.39 mmol) dissolved in a minimum amount of water (0.2 mL) is introduced slowly. Stirring, still under cold conditions, is maintained for another 3 hours, then water (10 mL) is poured onto the reaction mixture and the solid residue formed is collected by filtration. Silica gel column chromatography using a gradient of ethanol (0 to 2%) in CH2Cl2 as eluent makes it possible to isolate the compound possessing the greatest mobility which corresponds to the expected compound 41 (31 mg, 31%) in the form of a white solid, 1H NMR (CDCl3) 7.91 (1H, d), 7.74 (1H, d), 7.41 (2H, d), 7.16 (1H, dd), 6.85 (2H, d), 6.75 (1H, br s), 4.60 (1H, br s), 3.98 (3H, s), 3.78 (3H, s); MS 295 (M−2H).
Reaction SMILES: [C:1]1([N:7]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1C[O:48][CH2:47]C1>>[CH:4]1[CH:3]=[CH:2][C:1]([NH:7][C:47]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:48])=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: Nc1ccccc1
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: O=C(Nc1ccccc1)Nc1ccccc1
Temperature: 120 °C

Procedure:
In a capped vial (1 mL) containing a solution of phenylazide (6.6 mg, 55 μmol) in dry THF (300 μL), was added [RhCl(cod)]2 (0.27 mg, 0.55 μmol), and 1,2-bis(diphenylphosphino)ethane (0.44 mg, 1.1 μmol) and was shaken until the solution was homogeneous. After addition of aniline (10 μL, 110 μmol), the resulting mixture was transferred to the micro-autoclave, which was pre-charged with [11C]CO. The autoclave (250 μL) was heated at 120° C. for 5 min under 35 MPa and the crude product was transferred to a reduced pressure vial. The radioactivity was measured before and after the vial was flushed with N2 (the [11C]CO-trapping efficiency of 82% was determined based on these values). A small amount of crude product was collected and analyzed by the reversed phase HPLC. Yield of product: 82%. The product was identified by HPLC with an added authentic reference compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH3:14][NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[ClH:1].[CH3:14][N:15]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Product: CN(C(=O)COc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@H]1N1CCCC1
Product: Cl

Procedure:
The title compound was prepared according to the method described in Example 2, using 3,4-dichlorophenoxyacetic acid (2.34 g, 11 mmol) and (±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]amine prepared in Example 1 (2 g, 11 mmol). The crude product, which started to precipitate before the addition of the diethyl ether, was recrystallised from hot dichloromethane. Yield 2.9 g (62%).
Reaction SMILES: CCO[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.Cl>C(O)C>[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[C:20]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])=[CH:10][CH:9]=1)=[O:12]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a mixture of terephthalaldehyde mono-(diethyl acetal) (3.96 mL, 20.0 mmol) and 2,4-thiazolidinedione (2.81 g, 24.0 mmol) in ethanol (40 mL) was added piperidine (2.0 mL, 20.0 mmol). The reaction mixture was heated to reflux for 4 h. After cooling on an ice-bath, hydrochloric acid (0.2 mol/L, 100 mL) was added and the precipitated products were collected by filtration. The cake was washed with water and dried. To a solution of this product (5.50 g) in tetrahydrofuran (180 mL) was added hydrochloric acid (1 mol/L, 18 mL) and the mixture was stirred at room temperature for 2 h. Water was added, and the precipitated products were collected by filtration to give 5-(4-formylbenzylidene)-2,4-thiazolidinedione (3.91 g, 94%).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=3)=[CH:13][N:12](CC3C=CC(OC)=CC=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]1([NH:7][C:8]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=3)=[CH:13][NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Cn2cc(-c3cccc(CO)c3)c(C(=O)Nc3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Nc1ccccc1)c1n[nH]cc1-c1cccc(CO)c1
Temperature: 120 °C
Yield: 35.2 %

Procedure:
A mixture of 4-(3-hydroxymethyl-phenyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide (20 mg) and anisole (20 μl) in trifluoroacetic acid (1 ml) was heated at 120° C. (50 W) for 15 minutes in a CEM Discover microwave synthesiser. The reaction was evaporated then purified by flash column chromatography eluting with 2:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 5 mg of product. (LC/MS: Rt 2.55 [M+H]+ 294).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]#[N:30])[CH:21]=[CH:20]3)=[CH:15][N:16]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1
Reactant: N#CCOc1ccc2cc(-c3cnc(Cc4ccc5ccccc5c4)o3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2cc(Cc3ncc(-c4ccc5cc(OCc6nnn[nH]6)ccc5c4)o3)ccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of ({6-[2-(2-naphthylmethyl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (99 mg, 0.252 mmol), prepared in the previous step, sodium azide (50.2 mg, 0.772 mmol) and ammonium chloride (40.7 mg, 0.761 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for three hours. Following the reaction by MS, starting material remained. Additional sodium azide (51.1 mg, 0.75 mmol) and of ammonium chloride (45.7 mg, 0.85 mmol) were added and the reaction stirred at 100° C. for two more hours. This procedure was repeated two additional times until the MS showed that the reaction went to completion. The reaction was filtered, acidified with 5 mL of 1N HC1 and then diluted with 10 mL of H2O. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (75.4 mg, 69%) as a tan solid, mp 179-182° C. Elemental Analysis for C26H19N5O2+0.31 mol H2O Calc'd: C, 71.13; H, 4.50; N, 15.95. Found: C, 70.44; H, 4.51; N, 14.98.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.Br[CH2:37][CH:38]1[O:42][CH2:41][CH2:40][O:39]1>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:37][CH:38]2[O:42][CH2:41][CH2:40][O:39]2)[C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2
Reactant: BrCC1OCCO1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC3OCCO3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
NaH (1.5 eq, 60% dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available methyl indole-6-carboxylate) in DMF (0.1 M) and once effervescence had subsided the solution was stirred at RT for a further 30 min. 2-bromomethyl-1,3-dioxolane (4 eq) and catalytic (0.025 eq) KI were then added and the mixture heated at 50° C. for 36 h. The reaction mixture was then allowed to cool to RT, quenched with aqueous HCl (1 N) and extracted with EtOAc. The organics were washed with aqueous HCl (1 N) (3×), water and brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. Purification was by flash chromatography (10% EtOAc/PE) to give a pale yellow solid that was triturated with Et2O/PE) to afford the title compound as a white solid (69%); MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[N:8][C:4]=2[CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]3[N:23]=[N:24][NH:25][N:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(Br)ccc21
Temperature: 110 °C
Reaction time: 48 h
Yield: 84.6 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (200 mg, 0.565 mmol) in DMF (3 mL), follow by the addition of NaN3 (48 mmol, 0.738 mmol) and NH4Cl (39 mg, 0.729 mmol). The reaction mixture is stirred at 110° C. for 48 hours. The reaction mixture is diluted with EtOAc/water. The organic layer is separated, washed with water then brine, dried with Na2SO4, filtered and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (190 mg, 85%) as a solid product. LCMS (ESMS): m/z 397.49, 399.40 (M++1)
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10]2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1ccc(CC[C@H]2CCCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCC[C@H](CCc2ccccc2)C1)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 0 %

Procedure:
A solution of (S)-3-phenethyl-piperidine (4.23 mmol, 801 mg), 2-bromo-4′-chloroacetophenone (1.5 equiv, 6.35 mmol, 1.48 g) and K2CO3 (2.0 equiv, 8.46 mmol, 1.17 g) in CH3CN (10 mL) was heated to 60° C. and stirred for 12 h. The reaction mixture was quenched with H2O (25 mL) and then extracted with EtOAc (2×50 mL). The combined organics were dried with NaCl(sat) and Na2SO4(s). The solvents were removed in vacuo and chromatography (Isco Combi-Flash, 110 g cartridge, 9:1 Hexane-EtOAc) provided the desired product (0.556 mg, 1.45 mg theoretical, 38%) as a colorless oil: Rf0.37 (SiO2, 5:1 hexane-EtOAc); LRMS m/z 342 (M++1, C21H24ClNO, requires 342).