Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15]COC)[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:28]([O:29]COC)=[C:27]([O:33][CH3:34])[CH:26]=[C:25]([O:35]COC)[C:24]=1[O:39][CH3:40].Cl.C(=O)([O-])O.[Na+].O=O>C(O)(C)C.O1CCCC1.O1CCCC1.C(O)(C)C.CO.C1C=CC=CC=1>[CH3:40][O:39][C:24]1[C:25](=[O:35])[CH:26]=[C:27]([O:33][CH3:34])[C:28](=[O:29])[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5](=[O:15])[C:6]([O:13][CH3:14])=[CH:7][C:8](=[O:9])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC1=CC(=O)C(OC)=C(CCCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
355 Milligrams of 2,2'-tetramethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 8 ml of isopropanol with 4 ml of tetrahydrofuran, to this solution was added 1.2 ml of solution prepared by dissolving 10% (by weight/weight) of hydrogen chloride in a mixed solvent of tetrahydrofuran-isopropanol (1:1), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, to the residue obtained was added benzene, and further concentrated under reduced pressure. The residue thus obtained was dissolved in 5 ml of methanol, and a catalytic amount of sodium hydrogen carbonate was added thereto and oxygen gas was blown thereinto. 2 Hours later, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by means of a silica gel chromatography (diameter 2 cm×length 5 cm, eluent: 30%-ethyl acetate-n-hexane mixed solvent, adsorbent: "Wakogel C-200") to obtain 120 mg of 2,2'-tetramethylenebis(3,6-dimethoxy-1,4 -benzoquinone). Yellow needles crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:20][OH:21])([CH2:18][CH3:19])[CH2:13]1.[OH-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:29]([O:28][CH2:26][CH2:25][O:21][CH2:20][C:14]1([CH2:18][CH3:19])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:13]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC1(COCCOC(C)(C)C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol (0.40 g, 1.37 mmol) in DCM (1.5 ml) was added 50% NaOH (6 ml), tetrabutylammonium hydrogensulfate (0.46 g, 1.37 mmol) and tert-butyl bromoacetate (5.35 g, 27.45 mmol). The reaction mixture was stirred at RT for 24 h. Water was added, the reaction mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give 3-(2-tert-butoxy-ethoxymethyl)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine. This crude intermediate (0.20 g, 0.50 mmol) in dry THF (2 ml) was then added to a suspension of LiAlH4 (0.19 g, 5.00 mmol) in dry THF (4 ml). The reaction mixture was refluxed for 1.5 h. Water was slowly added and the reaction mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the crude product, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([Li])CCC.[Cl-:14].[Cl-].[Cl-].[CH3:17][C:18]1[C:22]([Ti+3:24])([CH3:23])[C:21]([CH3:25])=[C:20]([CH3:26])[C:19]=1[CH3:27]>C1(C)C=CC=CC=1>[Cl-:14].[Cl-:14].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][Ti+2:24][C:22]1([CH3:23])[C:18]([CH3:17])=[C:19]([CH3:27])[C:20]([CH3:26])=[C:21]1[CH3:25]
Reactant: Cc1ccccc1O
Reactant: CC1=C(C)C(C)([Ti+3])C(C)=C1C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti+2]Oc2ccccc2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 165.1 %

Procedure:
0.86 g (5.1 mmol) of 2-methylphenol (Aldrich, 99%) was dissolved in 40 ml of toluene, and 2.4 ml of butyllithium (2.5 M hexane solution) was slowly added dropwise thereto. The mixture solution was allowed to react at room temperature for 12 hours, and a solution of (pentamethylcyclopentadienyl)titanium(IV) trichloride (1.64 g, 5.5 mmol) in 10 ml of toluene was slowly added dropwise to the reaction solution at 0° C. The reaction solution was stirred at room temperature for 12 hours, filtered, treated to remove volatile material, and recrystallized with a mixed solution of toluene and hexane at −35° C., thus obtaining 1.64 g of a red solid. The cyclic voltammogram of the catalyst thus prepared is shown in FIG. 2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH2:5][CH:6]([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[NH:7]2.CS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>O>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH2:5][CH:6]1[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[N:7]12
Reactant: O=C(O)CCCC1CC(=O)c2c(O)cc(O)cc2N1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC2CCCC(=O)N2c2cc(O)cc(O)c21
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of 26 g. (0.098 mole) 4-[2,3-dihydro-5,7-dihydroxy-(1H)-quinolin-4-one-2-yl]butyric acid and 260 ml. methanesulfonic acid was heated under a nitrogen atmosphere at 140° C. for two hours. The reaction mixture was cooled to room temperature and poured onto 1000 ml. ice. To this was added 4 liters ethyl acetate, 1 liter water, 250 g. sodium chloride and the resulting mixture stirred at room temperature overnight. The layers were separated, the aqueous phase extracted with 4×500 ml. ethyl acetate and the combined organic layers washed with saturated sodium bicarbonate solution until the pH was 7 and no effervescence was observed. The extract was then washed with water (1000 ml.), brine (1000 ml.) and dried (MgSO4). The solvent was evaporated in vacuo, the residue redissolved in a small amount of hot ethyl acetate, diluted with ethyl ether and cooled to 0° C. The precipitated solid was collected by filtration and dried in vacuo to afford 9.4 g. (38.8%) of the title compound, M.P. 259°-268° C. (decomp.). 1H--NMR [(CD3)2SO] ppm (delta): 1.75-3.25 (m, 11H), 6.1 and 6.95 (2H, split doublets, meta aryl). Mass spectrum (m/e): 247 M+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=2[CH3:19])=[N:6][CH:7]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:15]([CH3:17])=[CH:14][C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=3[O:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(C(=O)COc2cc(C)cc(C)c2C)nc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2coc3c(C)c(C)cc(C)c23)nc1
Yield: 87 %

Procedure:
Using 1-(5-methylpyridin-2-yl)-2-(2,3,5-trimethylphenoxy)ethanone obtained in Reference Example 168, the title compound was synthesized in the same manner as in Reference Example 191. Yield 87%. Melting point: 134-135° C. (ethyl acetate-hexane).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC.CCO.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCCC[C@@H]12
Temperature: 90 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (109 mg, 0.472 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was then cooled to room temperature, diluted with EtOH (3 ml) and water (˜300 ul), then filtered. The solids were collected and refluxed in ethanol (5 mL) for 2 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (75.1 mg, 43%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.47 (s, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.40-7.48 (m, 2H), 7.34-7.40 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (s, 1H), 4.45-4.55 (m, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.42 (s, 2H), 3.01 (d, J=2.8 Hz, 2H), 2.56-2.66 (m, 3H), 2.44 (br. s., 2H), 1.98-2.08 (m, 1H), 1.80-1.89 (m, 1H), 1.59-1.68 (m, 1H), 1.34-1.57 (m, 3H). [M+H] calc'd for C23H25ClN4O, 409. found, 409. MP: 201.6° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:15]([O:8][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Oc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium carbonate (63.6 g) was added to a solution of pyrocatechol (55 g) in water (230 mL), and to the resulting mixture was added dropwise benzoyl chloride (58 mL) over a period of 2 hours with vigorous stirring. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified carefully by dropwise addition of 2N hydrochloroic acid (350 mL) and then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate (100 mL) and n-hexane (400 mL) to give the title compound (64.6 g) having the following physical data.
Reaction SMILES: C(C1C=CC(CN)=CC=1)(C)(C)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]=[C:40]=[O:41])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([CH3:57])[CH:45]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:38][NH:39][C:40](=[O:41])[NH:42][CH2:43][C:44]2[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([CH3:57])[CH:45]=2)=[CH:36][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: C=Cc1cc(CN)cc(C)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(C)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 23.9 %

Procedure:
4-tert-Butyl-benzylamine (1.5 eq, 71.91 μl, 0.44 mmol) was added in CH2Cl2 and then BOC2O (1.5 eq, 0.44 mmol, 101.19 μl) and DMAP (0.2 eq, 0.06 mmol, 7.08 mg) were slowly added. After confirming the synthesis of the 1-tert-Butyl-4-isocyanatomethyl-benzene, N-(4-Aminomethyl-2-methyl-6-vinyl-phenyl)-methanesulfonamide (1 eq, 0.29 mmol, 70.5 mg) and TEA (2 eq, 0.58 mmol, 80.84 μl) were added into the reaction mixture. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to step 9 of example 7 to obtain N-{4-[3-(4-tert-Butyl-benzyl)ureidomethyl]-2-methyl-6-vinylphenyl}methanesulfonamide (29.75 mg, 23.9%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.O1CCCC1>O>[C:35]1([S:41]([N:16]2[CH2:17][CH2:18][C:19]3[C:10]4[C:11]([S:13][C:14]=3[CH2:15]2)=[N:12][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]=4[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(S(=O)(=O)c1ccccc1)C3
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.5 %

Procedure:
A mixture of the compound obtained in Example 5A (0.96 g), benzenesulfonyl chloride (0.43 g), triethylamine (0.42 ml) and tetrahydrofuran (20 ml) was stirred at room temperature for 14 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 7-benzenesulfonyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (0.96 g, 76%), which was then recrystallized from ethyl acetate-hexane to yield colorless needle crystals having a melting point of 161 to 162° C. ##STR49##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[C:2]1([NH:1][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Nc3ccccc3)cccc21
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Aniline (328 μl, 3.6 mmol) was added to a room temperature mixture of 4-bromo-1-triisopropylsilanyl-1H-indole (1.06 g, 3 mmol), tris(dibenzylideneacetone)dipalladium 2-(dicyclohexylphosphino)-2,4,6-triisopropyl-1,1′-biphenylphosphine (Pd2(dba)3, 27.5 mg, 0.03 mmol), (72 mg, 0.05 mmol) and K2CO3 (1.04 g, 7.5 mmol) in t-BuOH (14 ml). The reaction mixture was stirred at 110° C. for 4 hours. The reaction was cooled, and the solid was filtered off. The filtrate was concentrated and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording the compound XXI as a yellow oil in quantitative yield (1.09 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O:22]CC)[NH2:21]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:7][C:6]3[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=3[C:4]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:21][C:20]1=[O:22]
Reactant: CNc1sc2c(c1C(=O)c1ccccc1)CCCC2
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cn1c(=O)nc(-c2ccccc2)c2c3c(sc21)CCCC3
Temperature: 200 °C

Procedure:
A mixture of 1.5 g of 2-methylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 1.5 g of ethyl carbamate and 0.11 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The chloroform extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure and residue is recrystallized from ethanol to give 1-methyl-4-phenyl-1,2,5,6,7,8-hexahydrobenzothieno[ 2,3-d]pyrimidin-2-one as crystals having a melting point of 215° - 216°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
4-Bromophenol (5.0 g, 29.0 mmol) was dissolved in N,N-dimethylformamide (150 ml), and imidazole (4.09 g, 60.0 mmol, 2.0 eq.) was added to the mixture, tert-Butyldimethyl silyl chloride (4.36 g, 29.0 mmol, 1.0 eq.) was slowly added to the above mixture and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with aqueous ammonium chloride solution and ethyl acetate, and dried over magnesium sulfate. The crude product was purified on silica flash column. The solvent was evaporated under reduced pressure to thereby yield 8.15 g of the title compound (yield: 97.8%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[CH:19]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (8 mg, 0.033 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (8.9 mg, 0.0367 mmol) in DMF (1 mL) at rt was added TEA (5.1 μL, 0.0367 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (9.5 mg; yield 64%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1 H), 7.66-7.85 (m, 6 H), 4.32-4.96 (m, 2 H), 1.51 (s,6 H) ppm; MS: m/z=444 (M+1, ESI+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]O.C(O)CCCCO.C(O)CCCCCO.C(O)(=O)/C=C/C(O)=O.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54]CC=CCCCC=C)=[CH:50][CH:49]=2)([CH3:47])[CH3:46])=[CH:41][CH:40]=1)C=CCCCC=C>[Pd].C=CC=C.[Ni+2]>[CH2:1]=[CH:2][CH:3]=[CH2:4].[OH:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([C:48]2[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=2)([CH3:47])[CH3:46])=[CH:43][CH:44]=1
Reactant: C=CCCCC=CCOc1ccc(C(C)(C)c2ccc(OCC=CCCCC=C)cc2)cc1
Reactant: OCCCCO
Agent: [Ni+2]
Agent: [Pd]
Agent: C=CC=C
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
The use of low levels of palladium catalyst in 1,3-butadiene telomerizations is disclosed in British patent No. 2,114,974. This patent teaches that when 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol telomerized with butadiene, about a 61% yield of monoether based on butadiene can be realized by using a molar ratio of catalyst/diene equal to about 1/20,600. The patent also discloses that a large stoichiometric excess of diol is also necessary in order to obtain high yields of the desired monoether product. For best yields of monoether, the above patent also teaches that the optimum catalytic effect is obtained by combining the palladium catalyst with a nickel(II) compound and a base such as a quaternary ammonium hydroxide. The patent also discloses a method of removing the palladium catalyst with ion exchange resins from the reaction mixture after the reaction has been completed. The palladium levels are obviously not low enough to preclude the recovery step; an operation which the present invention eliminates. U.S. Pat. No. 3,746,749 discloses that octadienyl esters of adipic acid can be prepared in 86% yield by employing a molar ratio of Pd/Acid/Butadiene equal to 1/12,300/56,000 and octadienyl esters of fumaric acid can be prepared in 67% yield by employing a molar ratio of Pd/Acid/Butadiene equal to 1/60,000/28,000. However, these low palladium levels are used in conjunction with from 0.1 to 10 moles of an alkali metal salt of a carboxylic acid/mole of carboxylic acid. U.S. Pat. No. 3,518,315 teaches that 2,2-bis(4-(2,7-octadienyloxy)phenyl) propane is formed by the telomerization of 1,3-butadiene with 2,2-bis(4-hydroxyphenyl) propane (bisphenol A) using a palladium (II) catalyst wherein the palladium (II)/bisphenol A/butadiene ration is 1/39/295 at a temperature of 100° C. for 48 hours.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.II.[I:21](O)(=O)(=O)=O>C(O)(=O)C.O>[I:21][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)NCCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)NCCc1ccc(I)cc1
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 300.1 %

Procedure:
To a stirring room temperature solution of N-(methylsulfonyl)-N-(2-phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95% sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85%, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15° C. and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH2Cl2 (1 L) and extracted with additional water (2×200 mL). The organic phase was concentrated under reduced pressure to provide N-(2-(4-iodophenyl)ethyl)-N-(methylsulfonyl)amine, (201 g, 60.2%) as a white powder. 1H NMR (300 MHz) 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1), 4.37 (br t, 1H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:8]=3[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:10][CH:11]([CH2:12][CH2:13][CH3:14])[C:5]2=[N:4][N:3]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>>[F:25][C:22]1[CH:23]=[CH:24][C:7]2[N:6]3[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]4)=[N:3][N:4]=[C:5]3[CH:11]([CH2:12][CH2:13][CH3:14])[N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:21]=1
Reactant: CCCC1N=C(c2ccccn2)c2cc(F)ccc2-n2c(Br)nnc21
Reactant: CCN1CCNCC1
Product: CCCC1N=C(c2ccccn2)c2cc(F)ccc2-n2c1nnc2N1CCN(CC)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-fluoro-4-propyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-ethylpiperazine to give 8-fluoro-4-propyl-1-(4-ethylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.