Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]([C:15]2[S:19][C:18]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[O:14])[N:11]=[C:10]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:9]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:10]2[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:12]([C:13]([C:15]3[S:19][C:18]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:22][CH:21]=4)=[CH:17][CH:16]=3)=[O:14])[N:11]=2)[CH:29]=1
Reactant: O=Cc1ccc(-c2ccc(C(=O)N3N=C(c4cccnc4)CC3c3ccccc3O)s2)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2ccc(CN3CCCC3)cc2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.1 %

Procedure:
To a solution of 4-(5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzaldehyde (0.205 g, 0.452 mmol) in THF (72 mL) was added pyrrolidine (0.042 mL, 0.50 mmol) and sodium triacetoxyborohydride (0.105 g, 0.497 mmol). The reaction mixture was allowed to stir at rt for 3 days. The solution was diluted with water and 1N aqueous HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[3-pyridin-3-yl-1-({5-[4-(pyrrolidin-1-ylmethyl)phenyl]-2-thienyl}carbonyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol (I-56) (0.060 g, 0.118 mmol) as a white solid. LCMS: (FA) ES+ 509.4. 1H NMR (400 MHz, d6-DMSO) δ: 10.76-10.86 (bs, 1H), 9.74-9.82 (bs, 1H), 9.11 (s, 1H), 8.71-8.77 (m, 1H), 8.36-8.42 (m, 1H), 8.03-8.08 (m, 1H), 7.84-7.90 (m, 2H), 7.62-7.73 (m, 2H), 7.08 (t, 1H), 6.92-6.97 (m, 1H), 6.82-6.88 (m, 1H), 6.72 (t, 1H), 5.82-5.89 (m, 1H), 4.34-4.39 (m, 2H), 3.86-3.98 (m, 1H), 3.31-3.41 (m, 2H), 3.18-3.25 (m, 1H), 3.00-3.12 (m, 2H), 1.96-2.07 (m, 2H), and 1.82-1.94 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH2:38]=O>C(O)C>[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:38][N:35]1[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])[CH2:33][CH2:34]1
Reactant: O=C1/C(=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)Oc2cc(O)ccc21
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc([N+](=O)[O-])cc24)C3=O)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A solution of (Z)-6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.12 g, 0.37 mmol) in ethanol (3.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.075 g, 0.40 mmol), and 37% aqueous formaldehyde (0.040 g, 0.50 mmol), and the mixture was stirred overnight at 70° C. in a sealed tube. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.090 g, 47%).
Reaction SMILES: C(O[N:5]=[C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Br:15])=[CH:10][C:9]=1[OH:16])[CH3:7])(=O)C.CC(=O)OCC>C(Cl)Cl.CCCCCC>[Br:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[C:6]([CH3:7])=[N:5][O:16][C:9]=2[CH:10]=1
Reactant: CC(=O)ON=C(C)c1cc(C)c(Br)cc1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc2c(C)noc2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Neat 2-(4-bromo-2-hydroxy-5-methylphenyl)-1-azaprop-1-enyl acetate (103) (0.5 g, 1.748 mmol) was heated at 175° C. for 2 h then at 100° C. for 1 h. After cooling down to r.t., the dark brown solid was dissolved in DCM and subjected to silica gel flash chromatography (0-40% B, A: hexane; B: 50% EA in hexane) to give 6-bromo-3,5-dimethylbenz[d]isoxazole (104) (92 mg, yield: 23.3%; purity>95%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NC(C)(C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NC(C)(C)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(1-methyl-1-phenylethyl)-3-piperidinecarboxamide (222 mg, 0.47 mmol), EtOH (5 mL), Hunig's base (0.082 ml, 0.47 mmol), and hydrazine anhydrous (0.089 mL, 2.82 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (101 mg) as a light yellow solid. LC-MS (ES) m/z=485 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.11 (d, J=6.6 Hz, 3H), 1.53 (s, 3H), 1.62 (s, 3H), 1.71 (m, 4H), 2.32-2.44 (m, 2H), 2.84 (m, 1H), 5.38 (s, 2H), 6.09 (s, 2H), 6.57 (s, 1H), 7.11-7.22 (m, 1H), 7.30-7.42 (m, 4H), 7.52-7.60 (m, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.16 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O-:19])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:33]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[N:32]1)[CH3:30]>>[CH2:29]([N:31]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)(=[O:22])=[O:21])[C:9]([C:11]4[CH2:12][CH2:13][N:14]([C:17]([O:19][C:3]([CH3:10])([CH3:4])[CH3:2])=[O:18])[CH2:15][CH:16]=4)=[CH:10][C:3]=23)[C:33]([C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[N:32]1)[CH3:30]
Reactant: O=C([O-])N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 11 with 4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1 (2H)-pyridinecarboxylate and 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound. ESMS [M+H]+: 655.4
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]1[CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.[N:30]1([O:39][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON.Cl.CN1CCOCC1>CN(C=O)C>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]1[CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:30][OH:39])=[O:18]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(CCc2ccccc2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NO)N1C(=O)NC(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of the compound obtained in step e above (109 mg, 0.36 mmol) in DMF (1.8 mL) was added BOP (190 mg, 0.43 mmol) at 0° C. After stirring for 30 min, HONH2×HCl (50 mg, 11.38 mmol) and N-methylmorpholine (0.16 mL, 1.44 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between EtOAc and a saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc, dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (63 mg, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[CH2:23]([NH:30][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][O:4][C:3]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=2[Cl:1])[CH:10]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (68 mg, 0.2 mmol), benzylamine (0.032 ml, 0.3 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtoAC:MeOH=15:3:1) to give N-benzyl-3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzamide as a white solid (12 mg, 14% yield).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[OH:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[N:14][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:6]2[CH2:7][C@@H:3]([NH:2][CH3:1])[C@H:4]([OH:8])[CH2:5]2)=[N:14][CH:15]=1
Reactant: CNC1CNCC1O
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN[C@@H]1CN(c2ccc(Br)cn2)C[C@H]1O
Yield: 39.3 %

Procedure:
Dissolve 4-methylamino-pyrrolidin-3-ol (430 mg, 3.29 mmol) in acetonitrile (10 mL) and add 5-bromo-2-fluoro-pyridine (868 mg, 4.93 mmol) and diisopropylethylamine (0.688 mL, 3.95 mmol). Reflux the mixture for 3 days. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Combine the organic fractions, dry over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-7.5% methanol in dichloromethane with 2N ammonia to give 352 mg (37%) of the title compound as a yellow foam. MS/ES m/z (79Br) 272.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH3:18])[C:11]=1Br)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.CCOC(C)=O.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>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH3:18])[C:11]=1[B:31]1[O:32][C:33]([CH3:35])([CH3:34])[C:29]([CH3:36])([CH3:28])[O:30]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(Br)c(COCC(=O)OC(C)(C)C)c1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(COCC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 192: step d) 1.19 g, 3.45 mmol) in dioxane (10 mL) was treated with PdCl2(PPh3)2 (0.242 g, 0.345 mmol) and triethylamine (2.88 mL, 20.7 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.00 mL, 6.89 mmol) was added slowly and the mixture heated to 80° C. 15 h. The reaction was diluted with EtOAc and washed with brine (2×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% EtOAc in hexanes) afforded the product [5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester (0.793 g, 58%) as a brown oil. The crude material was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=[CH:15][CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH2:8][CH2:15][CH2:14][NH:13][CH3:18])[O:5][CH2:2][CH3:20]
Reactant: c1ccncc1
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCOC(=O)OCCCNC
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., ethyl 3-(methylamino)propyl carbonate hydrochloride (1.18 g) obtained in Reference Example 44 was added. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 3 hrs. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.10 g), triethylamine (0.83 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give the title compound (0.88 g) as a yellow amorphous solid.
Reaction SMILES: [CH2:1](O)[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16](CCC[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH3:29][C:30](C)([O-:32])[CH3:31].[K+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C1(C)C=CC=CC=1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:20])[CH:16]([CH2:29][CH:30]([O:32][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31][CH2:22]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[O-]
Reactant: CC(CO)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
Cholestanol (0.662 g, 1.703 mmol) was dissolved in toluene (13 mL). Potassium tert-butoxide (573 mg, 5.11 mmol) was added in one portion. The mixture was stirred at room temperature for 3 hours. tert-Butyl bromoacetate (503 μL, 3.406 mmol) was added drop-wise and the mixture was stirred overnight at room temperature. Toluene (20 mL) was added and the solution was washed with brine (50 mL). The aqueous phase was extracted with toluene (30 mL) before all organic phases were combined, dried (Na2SO4) and the solvent evaporated. The crude product was purified using column chromatography (SiO2; Hexane:EtOAc, 200:1 to 200:20) to yield the white solid product (0.65 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ: 3.98 (s, 2H, CH2O), 3.30 (m, 1H, CHO), 1.97-0.56 (m, 31H), 1.46 (s, 9H, CH3), 0.89 (d, 3H, J=6.1, CH3), 0.85 (d, 3H, J=2.0, CH3), 0.84 (d, 3H, J=1.4, CH3), 0.79 (s, 3H, CH3), 0.64 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:30][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1
Reactant: Cc1cccc(C=O)c1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: Cc1cccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and m-tolualdehyde (75 ul, 0.633 mmol) similar to Example 6 and isolated as a pale yellow solid (76.2 mg, 29%). 1H NMR (CDCl3): 7.66 (d, J=15.9 Hz, 1H), 7.44 (d, J=15.6 Hz, 1H), 7.42-7.38 (m, 2H), 7.31-7.20 (m, 3H), 7.10 (dd, J=3.2, 8.9 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 4.43-4.32 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]=[C:11](B3CC(C)(C)C(C)(C)O3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](OS(C(F)(F)F)(=O)=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[Li+].[Cl-]>C(COC)OC.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>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:11]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[O:9][CH:10]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1cccc2c(B3CC(C)(C)C(C)(C)O3)coc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12
Temperature: 150 °C
Yield: 104.7 %

Procedure:
To a solution of 2-(7-methoxybenzo[b]furan-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane (1.10 g, 4.0 mmol) in dimethoxyethane (1 mL) was added CsCO3 (0.650 g, 2.0 mmol), H2O (1 mL), 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.480 g, 1.45 mmol), LiCl (0.10 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0.05 mmol). The reaction was heated in the microwave for 5 min at 150° C. The solvent was removed in vacuum, the residue taken up in 300 mL of methylene chloride, washed with 200 mL portions of saturated aqueous sodium carbonate and 1 N NH4OH (aq), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was filtered through 150 mL of silica gel with 15% ethyl acetate/hexane as eluant to give 0.50 g of the title compound. 1H NMR (300 MHz, CDCl3); δ 1.5 (s, 9H), 2.51 (t, 2H), 3.66 (t, 2H), 4.04 (s, 3H), 4.12 (dd, 2H), 6.24 (br s, 1H), 6.91 (d, 1H), 7.17 (t, 1H), 7.39 (d, 1H), 7.59 (s, 1H), MS (ES) m/z (relative intensity): 330 (M+H, 100).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:18][CH2:17]1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Reactant: CN1CCNCC1
Product: CN1CCN(c2nn3ccnc3c3c2CCCC3)CC1
Temperature: 0 °C

Procedure:
A mixture of 15 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine and 36.2 g of 1-methylpiperazine was heated at reflux for 48 hours during which time the reaction mixture turned brown. The reaction was poured into about 150 ml of ice water. The solid which formed was separated by filtration and air-dried to give 6-(4-methyl-1-piperazinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 79.5° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:24][CH2:23]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CC2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with aminomethylcyclopropane according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): 266.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.65 (s, 1H); 8.38 (br s, 1H); 8.23 (d, J=7.8 Hz, 1H); 7.88 (d, J=7.8 Hz, 1H); 7.42 (m, 2H); 6.82 (d, J=5.5 Hz, 1H); 5.30-6.25 (br, 1H); 3.42 (br s, 2H); 1.19 (br s, 1H); 0.62 (m, 2H); 0.35 (m, 2H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[Si:15]([O:22][CH:23]1[CH2:27][C:26](=[O:28])[CH:25]=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[Cl-].[Na+].CC[O:33]CC>>[Si:15]([O:22][C:23]1[C:24](=[O:33])[CH2:25][C:26]([OH:28])([CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:27]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Reactant: Br[Mg]CCCCOc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC1=CC(O)(CCCCOc2ccccc2)CC1=O
Reaction time: 4 h

Procedure:
55 ml (39 mmoles) of a 0.71 M solution of 4-phenoxybutyl magnesium bromide prepared from 10.1 g (44 mmoles) of 4-phenoxy bromide and 1.07 g (44 mmoles) of magnesium in 60 ml of ether was taken, and in an atmosphere of nitrogen, a solution of 7.63 g (36 mmoles) of 4-t-butyldimethylsilyloxy-2-cyclopentenone in 20 ml of ether was added dropwise at -78° C., and the mixture was stirred for 4 hours. A saturated aqueous solution of sodium chloride was added to terminate the reaction. The reaction mixture was extracted with ether, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (hexane:AcOEt=12:1) to give 5.2 g (40%) of a low polarity, 1,2-adduct and 2.9 g (22%) of a high polarity 1,2-adduct. ##STR30##