Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[C:11]4[CH:12]([CH2:13][NH:14][CH2:15][C:16]=4[CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([N:14]1[CH2:13][CH:12]2[C:7]3[CH:6]=[CH:5][C:4]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[C:8]=3[O:9][C:10]3[C:11]2=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH2:15]1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1OC)Oc1cccc3c1C2CNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Tetrahydroisoquinoline 7a (1.273 g; 4.5 mmol) was dissolved in 150 ml of acetone. Potassium carbonate (0.613 g; 4.5 mmol) and 0.4 ml (4.6 mmol) of allyl bromide were added. The reaction was stirred at room temperature for four hours. The solid was then removed by filtration and washed on the filter several times with ether. The filtrate was concentrated and purified by flash chromatography (silica gel, 50% ethyl acetate:hexane) to give 1.033 g (71%) of a yellow oil that was used without further purification: 1H NMR: (300 MHz, CDCl3): 7.15 (t, 1H, J=9 Hz); 7.04 (d, 1H, J=9 Hz); 6.83 (m, 2H); 6.65 (d, 1H, J=6 Hz); 5.98 (m, 1H); 5.27 (m, 2H); 4.10 (m, 3H); 3.95 (s, 3H); 3.86 (s, 3H); 3.46 (d, 1H, J=15 Hz); 3.30 (d, 2H, J=6 Hz); 2.56 (t, 1H, J=12 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:20])=[C:4]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C:3]=12
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.0 g, 30 mmol) in CHCl3 (80 mL) at 0° C. was treated with m-CPBA (12 g, 53 mmol) in portions. The reaction was stirred at about room temperature overnight. The reaction was cooled to 0° C. and to this was added Na2SO3 (25 g, 200 mmol) in water (100 mL) (slurry), followed by dropwise addition of Na2CO3 (14 g, 130 mmol) in water (100 mL). The mixture was stirred for about 30 minutes. The aqueous phase was extracted with CHCl3. The organic phase was dried with MgSO4 and concentrated under reduced pressure at low temperature (<25° C.) to afford the crude (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (5.5 g, 100%) which was not purified further. 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)=[CH:19][CH:18]=1>[Pd]>[CH:1]1([N:6]2[C:10]3=[N:11][C:28]([C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH2:23][C:20]5[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=5)[CH:26]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccc(OCc2ccncc2)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Pd]
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCc4ccncc4)c3)nc(=O)c1-2
Yield: 21.6 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.7 g, 0.124 mol), 3-(4-pyridinylmethoxy)benzaldehyde (3.95 g, 0.0185 mol) and xylenes (100 ml) was refluxed overnight. Additional carboxamide (1 g) was added and the mixture was refluxed for another 2 days. 10% palladium on carbon (1 g) was added and the mixture was refluxed for another 3 hours. The catalyst was removed by filtration, the filtrate was concentrated in vacuo and the solid residue was collected by filtration. Additional product was obtained by concentration of the mother liquors and the combined product fractions were recrystallized from ethyl acetate to afford 1.66 g of 1-cyclopentyl-3-ethyl-6-[3-[4-pyridinylmethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 230-232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:24]1[S:28][C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)=[N:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc(Br)s2)CC1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole [Intermediate 1] (132 mg, 0.441 mmol) and tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (140 mg, 0.401 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (23 mg, 20 μmol) followed by a solution of Na2CO3 (85 mg, 0.802 mmol) in water (0.5 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL), washed with water (10 mL), then the organic phase was separated and concentrated in vacuo to afford the crude product as a pale brown solid. The crude material was purified by flash chromatography using a 12 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a pale yellow/off-white solid (138 mg, 78% yield). LC-MS: Rt 1.34 min; MS m/z 443.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=2.53 Hz, 1H), 8.21 (d, J=8.59 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.66 (d, J=2.02 Hz, 1H), 7.60 (dd, J=8.59, 2.02 Hz, 1H), 6.59-6.62 (m, 1H), 4.05 (s, 3H), 3.51 (s, 8H), 1.43 (s, 9H).
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH2:16][CH:17]=[CH2:18])(=O)C.[CH3:19][OH:20]>>[OH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH2:16][CH:17]([O:20][CH3:19])[CH3:18]
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1OC(C)=O
Reactant: CO
Product: COC(=O)c1cc(C)c(O)c(CC(C)OC)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of methyl 4-acetoxy-3-allyl-5-methylbenzoate (175 mg, 0.75 mmol) in methanol (2 mL) was cooled in an ice-bath under a nitrogen atmosphere and treated with mercuric trifluoroacetate (322 mg, 1 equivalent). The reaction was stirred in the ice-bath for one hour by which time TLC analysis showed complete consumption of staring material. The reaction was then treated with 1 mL of 3 N NaOH and after vigorous stirring for 2 minutes, a solution of sodium borohydride (0.5 M, 1 mL) in 3 N NaOH was added. The back suspension was stirred for 5 minutes in the ice-bath and then ethyl acetate (25 mL) was added. After stirring for an additional 5 minutes, the ethyl acetate solution was decanted and then washed twice with saturated aqueous ammonium chloride. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product (141 mg, oil) was purified by preparative TLC on silica using 15% ethyl acetate/hexanes. Purified Yield=82 mg (˜50%), MALDI-TOF 239 obs.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]([CH3:64])[C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][N:50]([CH3:64])[C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1
Reactant: CN(C)c1ccc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-dimethylamino-pyridin-3-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.011 g of product in 42% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]1>>[CH3:26][O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:1][C:2]2[C:3]([C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=2)=[O:24]
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C1CC1
Product: COC(=O)c1c(C2CC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-4,5-dichloro-phenyl)-phenyl-methanone and methyl 3-cyclopropyl-3-oxopropanoate. Yellow solid. MS (ESI): 372.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CCOCC>[Si:28]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (5.00 g, 0.0198 mol) was dissolved in anhydrous DMF (30 mL, 0.4 mol) under an atmosphere of nitrogen. To this solution was added 1H-imidazole (3.2 g, 0.046 mol) followed by tert-butyldimethylsilyl chloride (3.92 g, 0.0260 mol). The resulting mixture became translucent. After stirring for 16 h at RT, the reaction mixture was diluted with ether (100 mL) and washed with water (3×20 mL), and brine (2×10 mL), then dried (Na2SO4), filtered, concentrated and purified by CombiFlash chromatography (120 g column, eluting with 0-25% EtOAc/hexanes). LC/MS: 260.2 (M−Boc+2H).
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].Cl[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:11]=[CH:10][N:9]=1>O.O1CCOCC1>[OH:6][CH2:5][CH2:4][S:3][C:8]1[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2SCCO)CC1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
Sodium hydroxide (0.92 g, 23 mmol) was dissolved in water (9 mL) and dioxane (15 mL). 2-Mercaptoethanol (0.54 mL, 7.7 mmol) was added while stirring and 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (2.3 g, 7.7 mmol, from Example 52, step 1) in dioxane (10 mL) was added. The reaction mixture was heated at 100° C. for 22 h. After cooling to room temperature, it was extracted with EtOAc. The organic layer was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) as eluent to give 1.71 g (65%) of the title compound as an orange oil. MS m/z 341 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:19])([CH3:18])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:22]=1[C:23]#[N:24]>>[NH2:20][C:21]1[C:22]([C:23]#[N:24])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:1][CH2:2][C:3]([CH3:19])([CH3:18])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)=[O:7]
Reactant: COc1ccc(CNC(=O)NCC(C)(C)CO)cc1
Reactant: N#Cc1c(N)cccc1F
Product: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(N)c2C#N)cc1
Yield: 60 %

Procedure:
Prepared as in Example 197b (Method B) from 1-(3-hydroxy-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 218c) and 2-amino-6-fluorobenzonitrile in 60% yield. MS 383 (MH+).
Reaction SMILES: [CH3:1][C:2]12[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][C:7]1=[CH:6][C:5](=[O:16])[CH2:4][CH2:3]2.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:17]1[CH2:18][O:19][CH:4]2[CH:5]([CH2:6][C:7]3[C:2]([CH3:1])([CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]=3)[O:16]1
Reactant: CC12CCC(=O)C=C1CCc1ccccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC12CC3OCCOC3CC1=CCc1ccccc12

Procedure:
A solution of 4a-methyl-4,4a,9,10-tetrahydro-2(3H)-phenanthrone 1 (7 g, 33 mmol; prepared by the method of A. L. Campbell and J. D. McChesney, Syn. Commun. 1979, 9, 471-479) is dissolved in anhydrous benzene (300 mL) and ethylene glycol (16 mL) and p-toluenesulfonic acid (0.7 g, 4 mmol) added. The solution is refluxed with the removal of water in a Dean-Stark trap according to the method of A. J. Vila, R. A. Spanevello, A. C. Olivieri, M. G. Sierra, and J. D. McChesney, Tet. Lett. 1989, 45, 4951-4960 to form the ketal, 2-ethylenedioxy-4a-methyl- 1,2,3,4,4a,9-hexahydrophenanthrene 2.
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:21]=3)[CH:10]=2)=CC=1.C1(OC)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[Br:15][C:14]1[C:9]([SH:8])=[CH:10][C:11]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=2)=[N:12][CH:13]=1
Reactant: COc1ccc(CSc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Sc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 75 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
4-(4-methoxybenzylthio)-5-bromo-N-(4-phenethylthiazol-2-yl)pyridine-2-amine (1.23 g, 2.4 mmol) was dissolved in TFA (10 mL):anisole (2 mL) (5:1). The reaction mixture was stirred at 75° C. overnight, then neutralized with solid NaHCO3, extracted with EtOAc, dried, and concentrated. The crude material was triturated in MeOH and filtered. The filtrate was further concentrated and triturated again with MeOH. The solids were combined and dried to give the desired product (0.68 g, 72% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:17]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:20][C:9]2=3)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reactant: C1CCNCC1
Product: c1ccc2c(c1)c1c(N3CCCC3)nc(N3CCCC3)nc1n2CCN1CCCCC1

Procedure:
A mixture of 9-(2-methanesulfonyloxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (IX, EXAMPLE4, 50 g) and piperidine (200 mL) is heated at reflux for 16 hr. Excess piperidine is removed under reduced pressure and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is washed with saline, dried over sodium sulfate and concentrated to give the title compound, NMR (CDCl3) 7.88, 7.28, 7.20, 7.10, 4.46-4.40, 3.94-3.90, 3.66-3.62, 2.74-2.68, 2.57, 1.98-1.94, 1.64-1.58 and 1.45 δ.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:6]=12.C1C(=O)N([Br:36])C(=O)C1>C(#N)C>[Br:36][C:13]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=2[F:1])[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[2,3-b]pyridine (2.40 g, 5.96 mmol) in 20 mL of acetonitrile at 0° C. was added a solution of NBS (1.01 g, 5.69 mmol, Aldrich) in 10 mL of acetonitrile. The reaction mixture was stirred at 0° C. for 30 min, quenched by the addition of cold water (50 mL), and extracted with EtOAc (3×120 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with dichloromethane) to afford the desired product (2.70 g, 94%) as a light yellow oil. MS(ESI+) m/z 482.9 (M+H)+.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:18]([C:19]([NH:21][CH3:22])=[O:20])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CNC(=O)c1cccc(O)c1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: CNC(=O)c1cccc(OCc2ccc(Cl)cc2C(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-hydroxy-N-methylbenzamide (WO 2003018566):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:2].[CH:15]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1)([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:22]2[CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Product: CCOC(=O)/C=C/c1ccc(-c2cc(C(C)C)ccc2OC)cc1

Procedure:
(E)-3-(4-Bromo-phenyl)-acrylic acid ethyl ester (450 mg, 2.0 mmol) was reacted with 5-isopropyl-2-methoxy-benzene boronic acid (776 mg, 4.0 mmol) by a procedure described in example 52 a, to give (E)-3-(5′-Isopropyl-2′-methoxy-biphenyl-4-yl)-acrylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:25])[CH2:14][CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH3:25][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCCNC1
Yield: 72.3 %

Procedure:
Benzyl 3-(tert-butoxycarbonylamino)-3-methylpiperidine-1-carboxylate (1.4 g, 4.0 mmol) and 10% Pd/C (0.21 g, 0.2 mmol) in MeOH (20 mL) were stirred under H2 atmosphere (1 atm) for 1 hour. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated to give tert-butyl 3-methylpiperidin-3-ylcarbamate (0.62 g, 72% yield) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.[I-].[K+].[CH3:30][NH2:31].O1CCCC1>C(OCC)(=O)C>[CH3:30][NH:31][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (0.30 g, 0.76 mmol), potassium iodide (0.13 g, 0.76 mmol) and 2M methylamine-tetrahydrofuran solution (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=7/3) and recrystallized from hexane/diisopropyl ether to give the title compound (0.20 g, yield 67%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.O1CCOCC1.[Cl:18][C:19]1[C:31](I)=[CH:30][C:22]2[NH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:18][C:19]1[C:31]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:30][C:22]2[NH:23][C:24]([C:26]([F:28])([F:29])[F:27])=[N:25][C:21]=2[CH:20]=1
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound number 260 (i.e., 6-chloro-5-(2,4-dichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. (2,4-dichlorophenyl)boronic acid (229 mg, 1.20 mmol, 2.00 equiv), dioxane (30 mL), 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.58 mmol, 1.00 equiv), sodium carbonate (191 mg), water (8 mL) and Pd(PPh3)4 (34.7 mg) was placed in the flask. The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 87.8 mg (42%) of 6-chloro-5-(2,4-dichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.