Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(=O)(O)[O-].[Na+].[CH3:22][C:23]1[NH:24][C:25]2[CH:31]=[C:30]([C:32](=[O:41])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH:29]=[CH:28][C:26]=2[N:27]=1>O.C(Cl)(Cl)Cl>[CH3:22][C:23]1[N:27]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[C:26]2[CH:28]=[CH:29][C:30]([C:32](=[O:41])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:31][C:25]=2[N:24]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
N,N-dimethylformamide (10 ml), 4-nitrobenzyl bromide (3.24 g), and sodium bicarbonate (2.52 g) are added to 2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (3.56 g), and the solution is heated for two hours at 80° C. Chloroform and water are added to the reaction solution and layers are separated. After the organic layer is concentrated under reduced pressure, it is purified through silica gel column chromatography (eluate: ethyl acetate/methanol=4/1), and a mixture of 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole is obtained. Further, the position isomers in this mixture are separated through medium pressure silica gel column chromatography (eluate: ethyl acetate/methanol=85/15). Each is recrystallized in a mixed solvent of chloroform and diethylether, and thus, 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.37 g) (191) and 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.19 g) (192) are obtained.
Reaction SMILES: [Fe:1].[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:17]1[C:18]2[C:13](=[CH:19][CH:3]=[CH:2][CH:6]=2)[CH2:14][CH2:15][CH2:16]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Fe+2:1]
Reactant: Cc1ccccc1
Reactant: [Fe]
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: c1ccc2c(c1)CCCC2
Temperature: 375 °C

Procedure:
An iron containing ZSM-5 catalyst was prepared by the following method: about 10 g of the same HZSM-5 as that of Example 1 was heated in a stream of dry air to 375° C. for 4 hours and then was cooled to room temperature. A solution of 0.3331 g of ferrocene (dicyclopentadienyliron) in 30 g dry toluene was then added to the dried zeolite and the slurry was mixed at room temperature overnight. The slurry was filtered and washed once with 100 ml of Tetralin® to remove excess ferrocene from the external surface of the zeolite. Excess Tetralin® was allowed to evaporate at room temperature to give a Tetralin®/ferrocene wetted zeolite. The recovered solid was then calcined in a stream of dry air at about 538° C. for about 6 hours to produce the desired iron containing catalyst, Catalyst C. The iron loading of this catalyst is about 0.66 wt. %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][N:27](S(C5C=CC(C)=CC=5)(=O)=O)[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO>CO.O.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ccc23)C1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)azepan-1-yl)ethanone (800 mg, 1.36 mmol) in MeOH:H2O (4:1, 5 mL) was added K2CO3 (656 mg, 4.77 mmol) and the reaction mixture was heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo to give a residue which was triturated with 10% MeOH in EtOAc (20 mL), filtrated, the filtrate was evaporated in vacuo to give the crude compound that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (393 mg, 66%) the titled compound. 1H NMR (DMSO-do, 400 MHz): 11.53 and 11.47 (2s, 1H), 8.15 and 8.07 (2s, 1H), 7.30 and 7.17 (2d, J=4 Hz, 1H), 7.07 (2t, d=2.4 Hz, 1H), 6.74 (s, 1H), 6.68 (m, 1H), 6.62 (s, 1H), 6.38-6.33 (m, 1H), 4.54-4.46 (m, 1H), 4.36-4.27 (m, 1H), 4.12-3.96 (m, 2H), 3.94-3.86 (m, 1H), 3.52-3.42 (m, 1H), 3.24-3.12 (m, 1H), 2.02-1.78 (m, 3H), 1.74-1.52 (m, 3H). LC-MS: m/z [M+1]=433.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=2[NH2:9])[CH2:3][CH2:2]1.[C:18](Cl)(Cl)=[S:19]>O1CCOCC1.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:8]=2[N:9]=[C:18]=[S:19])[CH2:5][CH2:6]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 2-morpholino-5-trifluoromethylaniline (12 g) with thiophosgene (8.6 g) in dioxan (30 ml) and water (100 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 2-morpholino-5-trifluoromethylphenyl isothiocyanate as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:14]=2)[C@H:9]([N:29]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[CH2:8][C@@H:7]1[CH3:49])=[O:5])[CH3:2].[OH-].[Li+]>C1COCC1.CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=2)[C@H:9]([N:29]([CH2:34][C:35]2[CH:36]=[C:37]([C:45]([F:47])([F:48])[F:46])[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=2)[C:30]([O:32][CH3:33])=[O:31])[CH2:8][C@@H:7]1[CH3:49])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc2c(cc1OC)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)C[C@H](C)N2C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(OCCCCCC(=O)O)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
Prepared by treating a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-(5-ethoxycarbonyl-pentyloxy)-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 163) (27 mg, 0.04 mmol) in 0.6 mL THF and 0.2 mL methanol with an aqueous 1M lithium hydroxide solution (0.2 mL, 0.2 mmol) at room temperature. After 45 minutes, acidification with 1N HCl and extraction with ethyl acetate, drying the organic extracts over sodium sulfate, and concentration under reduced pressure provided 25 mg of the title compound. MS m/z 697 (M++19), 378 (M+−300); 1H NMR (CDCl3) δ6.39 (C5, s, 1H), 3.79 (C6-OMe, s, 3H), 1.16 (Me, d, 3H, J=6.1 Hz).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:33]([OH:35])=[O:34])=[N:25][C:26]2[N:27]([N:30]=[CH:31][CH:32]=2)[C:28]=1[F:29]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:33]([OH:35])=[O:34])=[N:25][C:26]3[N:27]([N:30]=[CH:31][CH:32]=3)[C:28]=2[F:29])=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)c1nc2ccnn2c(F)c1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of i-Pr2NH (3.50 equivalents) in THF at 0° C. is added n-BuLi (3.50 equivalents, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture is cooled to −78° C. 4-Bromo-2-fluorophenylamine (2.50 equivalents) is added. After vigorous stirring for 10 minutes, a mixture of the 6-chloro-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent) in THF is added. The dry-ice bath is removed after 30 minutes, and the reaction mixture is stirred for 17 hours at room temperature. The reaction mixture is treated with a 10% aqueous HCl solution, extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride give desired product.
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(OCC)OCC)[P:4](=[O:11])([O:8]CC)[O:5]CC.O>CC1C=CC=CC=1>[PH:4](=[O:5])([O-:11])[O-:8].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[C+4:3].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8].[PH:4](=[O:5])([O-:11])[O-:8]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[PH]([O-])[O-]
Product: [C+4]
Temperature: 12.5 °C
Yield: 86.1 %

Procedure:
1.1 g (0.0275 mol) sodium hydride (60% content) is added to a 100 ml three-necked bottle under the protection of nitrogen, paraffin oil is removed by rinsing twice with 10 ml n-hexane each time; then, 10 ml methylbenzene is added, 8.6 g tetraethyl methylenediphosphonate (0.03 mol) is dropwise added to the solution of 20 ml methylbenzene under magnetic stirring, the temperature of cold water bath is maintained within a range from 10 to 15° C. while addition, a large amount of gas is discharged, the addition can be finished about half an hour later, and stirring is continued for reaction for half an hour; afterwards, 5.1 g C-14 aldehyde (3B) (prepared in the embodiment 3, 0.025 mol) is dropwise added and dissolved in the solution of 20 ml methylbenzene, the temperature of cold water bath is maintained within a range from 10 to 15° C. while addition, the addition can be finished about half an hour later, and stirring is continued for reaction for half an hour. 20 ml water is added to the reaction mixture solution, which is followed by stirring for 10 minutes and layering, organic layer is rinsed by 20 ml sodium hydride aqueous solution with the concentration of 10%, dried by magnesium sulfate and filtered, and the solvent is dried by evaporation under reduced pressure to obtain 7.3 g 1,3,6,10-tetra-double bond pentadec-carbon phosphonate (4) crude product, which is light brown liquid and has the gas phase content of 93.5% and the yield of 86.1%. The product's NMR spectroscopy is consistent with the embodiment 4.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16].Cl.[CH:19](N)=[NH:20]>C(O)C>[Cl:15][CH2:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:20][CH:19]=[N:16]2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: N=CN
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1N
Agent: Cl
Solvent: CCO
Product: COc1cc2c(O)ncnc2cc1OCCCl
Temperature: 130 °C
Yield: 95.6 %

Procedure:
To a solution of 2-amino-4-(2-chloro-ethoxy)-5-methoxy-benzoic acid methyl ester (2.4 g, 9.24 mmol) in ethanol was added formamidine hydrochloride (2.97 g, 36.96 mmol). The mixture was heated at 130° C. in sealed tube for 8 h. The precipitate formed was filtered and washed with ethanol and dried to afford the pure compound 7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol (2.25 g, 96%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.45 (s, 2H), 7.15 (s, 1H), 4.40 (t, 2H), 4.00 (t, 2H), 3.88 (s, 3H), LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [CH2:1]([Zn][CH2:4][CH3:5])[CH3:2].ICI.[C:9]([C:13]1[C:27]([OH:28])=[CH:26][C:16]2[CH2:17][C:18]3([O:25][C:15]=2[CH:14]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:9]([C:13]1[C:27]([OH:28])=[C:4]([CH3:5])[C:16]2[CH2:17][C:18]3([O:25][C:15]=2[CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)([CH3:12])([CH3:10])[CH3:11].[C:9]([C:13]1[C:27]([OH:28])=[C:26]([CH2:1][CH3:2])[C:16]2[CH2:17][C:18]3([O:25][C:15]=2[CH:14]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ICI
Product: CCc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Product: Cc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Reaction time: 0.08 h
Yield: 13 %
Yield: 15 %

Procedure:
Under a nitrogen stream, 1.64 ml of diethylzinc (1M in n-hexane) was added dropwise into a solution of 0.18 ml of diiodomethane in 4 ml of anhydrous toluene at 0° C. Further to this solution was added dropwise 0.30 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 7 and dissolved in 4 ml of anhydrous toluene. After stirring for 5 minutes, the solution was refluxed for 1.5 hours. The reaction solution was allowed to cool down, and then combined with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1%-2% ethyl acetate) to give 0.04 g of 6-t-butyl-5-hydroxy-4-methyl-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane (yield 13%) and 0.05 g of 6-t-butyl-4-ethyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane (yield 15%) both as white solids.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1cccc(Cl)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(c2cccc(Cl)c2)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-benzyl-3-(3-chlorophenyl)-4-piperidone (75 mmol) in anhydrous THF (250 mL) is cooled to −30° C., then treated with a solution of freshly prepared lithium diisopropylamide (2.0 M in THF/heptane, 45 mL). After stirring for 15 min, a solution of methyl iodide (80 mmol) in THF (40 mL) is rapidly added. The mixture is then stirred for 1 hour at −30° C., warmed quickly to room temperature, and quenched with a saturated aqueous solution of ammonium chloride. The organic layer is collected, washed with water, brine, and dried (MgSO4). After filtering, the filtrate is concentrated in vacuo to afford the desired intermediate.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:2][C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CNC(=O)COc1ccc(C(C)=O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CNC(=O)COc1ccc(C(=O)CBr)cc1

Procedure:
The product of step (i) (3.00 g) and N-bromosuccinimide (2.02 g) in carbon tetrachloride (50 ml) was heated at reflux temperature for 64 hours. The solvent was evaporated and the black residue dissolved in methanol/ethyl acetate, treated with charcoal, filtered and then evaporated. The resulting brown oil was purified by flash chromatography on silica, eluting with dichloromethane. Trituration with hexane gave methyl N-[4-(bromoacetyl)phenoxyacetyl]glycinate, 0.85 g, as a solid: mp softens 109°-111° C.; NMR (d6DMSO) δ8.60 (1H, bt), 7.99 (2H, d), 7.09 (2H, d), 4.84 (2H, s), 4.69 (2H, s), 3.91 (2H, d), 3.64 (3H, s).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18])([O-:7])=[O:6].C(Cl)(Cl)Cl>N1C(C)=CC=CC=1C>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17]([O:4][CH2:3][CH2:2][F:1])(=[O:19])=[O:18])([O-:7])=[O:6]
Reactant: OCCF
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCF)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoroethanol (1.28 g, 20 mmol) in 2,6-lutidine (20 mL) at −10° C. was added 2,4-dinitrobenzene-1-sulfonyl chloride LVI (4.91 g, 18.7 mmol) in portions. A precipitate formed so CHCl3 (50 mL) was added to the reaction mixture in order to ensure efficient stirring. After 10 min, the mixture was washed with cold 10% aqueous HCl (150 mL) and water (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1:2 EtOAc:hexane) to afford 2-fluoroethyl 2,4-dinitrobenzenesulfonate LVII (1.44 g, 4.90 mmol, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:13][C@H:14]([OH:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O[C@H]1C[C@@H](c2nc(I)c3c(Cl)nccn32)C1
Reaction time: 4.5 h

Procedure:
3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14 mmol) was dissolved in a 1:1 mixture of MeOH (35.0 mL) and CH2Cl2 (35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0 mmol) was added slowly, gas evolution was observed. After 4.5 h at rt under nitrogen, the reaction was concentrated in vacuo. The crude mix was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using HPFC Jones 50 gram silica gel column eluting with 50% EtOAc in Hexane to 100% EtOAc, to yield the title compound as a light yellow solid; MS (ES+): m/z 349.81 (100) [MH+], 351.50 (30) [MH+++]; HPLC: tR=2.49 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.41-2.54 (m, 2H) 2.78-3.05 (m, 1H) 3.12-3.32 (m, 1H) 4.08-4.75 (m, 1H) 5.30 (s, 1H) 7.31 (d, J=5.05 Hz, 1H) 7.57 (d, J=4.80 Hz, 1H)
Reaction SMILES: [CH2:1]([C:11]12C[CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23].[I-].C([Al+][CH2:28][CH3:29])C.C(CN)O>C1(C)C=CC=CC=1>[CH2:4]([CH:5]1[CH2:6][CH:7]2[CH2:28][CH:29]1[CH:9]=[CH:8]2)[CH2:3][CH2:2][CH2:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC[Al+]CC
Reactant: CCCCCCCCCCC12C=CC(CC1)C2
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Solvent: NCCO
Product: CCCCCCCCCCC1CC2C=CC1C2
Reaction time: 1 h

Procedure:
50 ml dry toluene cosolvent, 7 ml decylnorbornene, 0.8 ml of the 1-hexene solution, and 0.9 ml of the diethylaluminum iodide solution were charged to a dry, nitrogenpurged 7 oz. bottle. 1.1 ml of the MoCl5 solution was charged last, and the bottle was shaken. After 1 hour the reaction was shortstopped using a mixture of 0.1 ml ethanolamine and 0.5 ml Solution A. No antioxidant was added. The polymer cement was coagulated using excess Solution A in a Waring blender. About 4.5 grams of a solid, ring-opened 5-decyl-2-norbornene/1-hexene copolymer was recovered by filtering and vacuum drying.
Reaction SMILES: [ClH:1].Cl.Cl.C1(NC(C2C3C=C(C4C([Cl:25])=CN=C(NCCCN5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:37]1([NH:40][C:41]([C:43]2[C:51]3[CH:50]=[C:49]([C:52]4[C:57]([Br:58])=[CH:56][N:55]=[C:54]([Cl:59])[N:53]=4)[S:48][C:47]=3[CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:39][CH2:38]1.[CH3:60][N:61]1[CH2:67][CH2:66][CH2:65][N:64]([CH2:68][CH2:69][CH2:70][NH2:71])[CH2:63][CH2:62]1>>[ClH:25].[ClH:59].[ClH:1].[CH:37]1([NH:40][C:41]([C:43]2[C:51]3[CH:50]=[C:49]([C:52]4[C:57]([Br:58])=[CH:56][N:55]=[C:54]([NH:71][CH2:70][CH2:69][CH2:68][N:64]5[CH2:65][CH2:66][CH2:67][N:61]([CH3:60])[CH2:62][CH2:63]5)[N:53]=4)[S:48][C:47]=3[CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:39][CH2:38]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CN1CCCN(CCCN)CC1
Agent: Cl
Product: CN1CCCN(CCCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized as a yellow solid from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 3-(4-methyl-[1,4]diazepan-1-yl)-propylamine. ES+(m/z) 543 (79Br) and 545 (81Br) [M(free base)+H].
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[C:11](=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[Si:1]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]([CH3:19])[N:15]=2)[C:11](=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (2.07 g) in acetic anhydride (21 mL) was added a solution of fuming nitric acid (0.58 mL) in acetic anhydride (21 mL), and the mixture was stirred under for 1.5 hr under ice-cooling. To the reaction mixture were added ice water and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.9 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][CH:12]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CN(C)c1ccc(C2(O)CCC(=O)CC2)cc1
Product: CN(C)c1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-dimethylamino-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.