Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.C(O)(C)C.[CH3:31][N:32]1[CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=2)[CH2:35][CH2:34][CH2:33]1>CO>[N:39]1[CH:38]=[C:37]([C@H:36]2[CH2:35][CH2:34][CH2:33][N:32]2[CH3:31])[CH:42]=[CH:41][CH:40]=1
Reactant: CN1CCCC1c1cccnc1
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: CN1CCC[C@@H]1c1cccnc1
Reaction time: 1 h
Yield: 28.8 %

Procedure:
A mixture of dibenzoyl-l-tartaric acid (58 g, 0.154 mol), 100 ml isopropanol and (R,S)-nicotine (25 g, 0.154 mol) was stirred for 1 hr and heated to reflux. While refluxing, 50 ml methanol was added and continued as in Example 1 to get (R)-nicotine (7.2 g, 57.6% yield) 99.85% GC, optical rotation: +141°, 99.9% chiral purity by HPLC.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:9]1=[O:31])[CH2:5][CH2:6][CH3:7]>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:18])[N:8]([CH:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:32])=[O:2])[C:9]2=[O:31])=[CH:21]1
Reactant: CCCC(C(=O)OC)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(C(=O)O)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (108 mg, 0.25 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (400 μl) and is concentrated. The resulting residue is triturated with MeoH and H2O to afford the title compound. LCMS (ESMS): m/z 420.21 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Cc1ccc(N)c(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c1
Yield: 56 %

Procedure:
Starting from 2-amino-5-methylbenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (130 mg; 56% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])CCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:11]1([CH2:13][C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: C=C(C)CCCc1ccccc1I
Reactant: C=C(C(F)(F)F)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(CC1(C)CCCc2ccccc21)C(F)(F)F
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of 1-iodo-2-(4-methylpent-4-en-1-yl)benzene (Intermediate 2) (8.3 g, 29 mmol), triphenylphosphine (1.57 g, 6 mmol), cuprous iodide (0.572 g, 3 mmol) and palladium acetate (0.673 g, 3 mmol) in anhydrous N,N-dimethylformamide (200 ml) was added tributyl[1-(trifluoromethyl)ethenyl]stannane (Intermediate 3) (14.5 g, 37.7 mmol). The flask was evacuated and filled with nitrogen four times and then placed in a bath preheated to 110° C. and stirred for 3 h. The mixture was allowed to cool, the solution was decanted from the black solid and concentrated to low volume. Heptane (200 ml) and water (200 ml) were added, insoluble material was filtered off, and the layers were separated. The aqueous layer was re-extracted with heptane (100 ml) and the combined organic layers were washed successively with water (2×200 ml), aqueous lithium chloride solution (200 ml), water (200 ml) and saturated brine (200 ml), dried over anhydrous sodium sulphate and evaporated. The resulting oil was purified by flash chromatography on an 800 g Biotage silica cartridge eluted with heptane to give the title compound (5.28 g, 72%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN1CCCC1=O>[Br:8][C:6]1[CH:7]=[C:2]([S:21][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[N:3]=[C:4]([NH:9][CH3:10])[N:5]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CNc1nc(Br)cc(Br)n1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CNc1nc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
0.70 g (0.0026 mol) of (4,6-dibromopyrimidin-2-yl)-methylamine and 0.56 g (0.0026 mol) of 4-nitrothiophenol potassium salt were dissolved in 15 ml of 1-methyl-2-pyrrolidone and stirred at 50° C. for 5 hrs. The solvent was removed and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:9 and subsequently dried in a high vacuum. There was obtained 0.50 g (56%) of [4-bromo-6-(4-nitrophenylsulphanyl)-pyrimidin-2-yl]-methylamine as yellow crystals; m.p.: 204-205° C.
Reaction SMILES: C([Li])CCC.O[CH2:7][CH2:8][CH:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]1.C1C=CC(NC2C=CC(N=NC3C=CC=CC=3)=CC=2)=CC=1.[CH3:37][N:38]([CH2:43][CH2:44][Br:45])[P:39](Cl)([Cl:41])=[O:40]>C1COCC1>[CH3:14][C:11]1([CH3:15])[O:10][CH:9]([CH2:8][CH2:7][P:39]([Cl:41])([N:38]([CH3:37])[CH2:43][CH2:44][Br:45])=[O:40])[CH2:13][O:12]1
Reactant: CN(CCBr)P(=O)(Cl)Cl
Reactant: CC1(C)OCC(CCO)O1
Agent: [Li]CCCC
Agent: c1ccc(N=Nc2ccc(Nc3ccccc3)cc2)cc1
Solvent: C1CCOC1
Product: CN(CCBr)P(=O)(Cl)CCC1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Butyllithium (10.8 ml, 21.60 mmol, 2.0M) was added dropwise at 0° C. to a stirred solution of 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (2.87 g, 19.60 mmol) and a crystal of 4-phenylazodiphenylamine indicator in THF (7 ml) under N2. The resulting solution was added dropwise at -78° C. to a stirred solution of N-methyl-N-(2-bromoethyl) phosphoramidic dichloride (5.00 g, 19.60 mmol) in THF (10 ml) under N2. The mixture was allowed to stir under N2 at -78° C. for 3 hr, at which time the purple mixture turned yellow. The mixture was warmed to room temperature and the solvent removed under reduced pressure. The residue was purified by chromatography (1:4 EtOAc: hexanes) and the product 16a isolated as an oil (4.77 g, 67%): Rf 0.61 (1:1 EtOAc:hexanes); 1H NMR (CDCl3) 4.26(dt, 2H, J= 8.44 Hz), 4.17(t, 1H, J=6.53 Hz), 4.06(t, 1H, J=7.06 Hz), 3.54(t, 1H, J=7.10 Hz), 3.44(m, 4H), 2.76(d, 3H, J=12.76 Hz), 1.95(dt, 2H, J=6.24 Hz), 1.67(d, 6H, 15.63 Hz); 31P NMR (CDCl3) -8.07 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.[ClH:15]>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: COc1ccc(CO)c(OC)c1OC
Reactant: Cl
Solvent: O
Product: COc1ccc(CCl)c(OC)c1OC
Temperature: 0 °C

Procedure:
5.0 g (4.34 mmols) of 2,3,4-trimethoxybenzyl alcohol was dropwise added to 10 ml of conc. hydrochloric acid under stirring at 0° C. The mixture was stirred at 0° C. for further 5 minutes. After the reaction, water was added to the mixture followed by extraction of the solution with diethyl ether. The diethyl ether layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford 4.80 g of 2,3,4-trimethoxybenzyl chloride as a crude product.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCOc1cc(C#N)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCOc1cc(-c2nc(-c3c(F)cccc3Cl)nn2C)ccc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-chloro-3-pentyloxybenzonitrile (0.70 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.50 g of desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13]([NH:25][CH:26]([CH3:28])[CH3:27])[C:14]3[N:15]([C:17](=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl>O1CCOCC1.O>[C:20]([N:18]1[C:17](=[O:24])[N:15]2[CH:16]=[C:11]([C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9][CH2:10]3)[N:12]=[C:13]([NH:25][CH:26]([CH3:28])[CH3:27])[C:14]2=[N:19]1)([CH3:22])([CH3:23])[CH3:21]
Reactant: CCOC(=O)C1(c2cn3c(=O)n(C(C)(C)C)nc3c(NC(C)C)n2)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1nc(C2(C(=O)O)CCCC2)cn2c(=O)n(C(C)(C)C)nc12
Temperature: 60 °C

Procedure:
A solution of 400 mg of the product of Step A in 1,4-dioxane (10 mL) was treated with 6N KOH (2.0 mL) and the mixture was heated at 60° C. for three h. The reaction was cooled to ambient temperature, diluted with water, and the pH adjusted to 2 with 2N HCl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4, filtered, and concentrated to afford 1-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid as a white solid. MS (M+H+)=360.3.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 96.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 32 (0.26 g, 0.69 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 33 (0.19 g, 99%) as a colorless foam.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10](O)=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](C)[CH:15]=[CH:14]2.[CH3:21][O:22][CH2:23]Cl>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[C:10]([CH2:21][O:22][CH3:23])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: Cc1ccc2ccc(O)c(Cl)c2n1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1ccc2cccnc2c1Cl
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Referring to FIG. 20, triethylamine (1.879 mL, 13.49 mmol) was added to a solution of 5c (0.2612 g, 1.349 mmol) in THF (20 mL) under a nitrogen atmosphere. Chloromethyl methyl ether (0.241 mL, 3.17 mmol) was added to the mixture dropwise. After stirring for 2 h, the solution was diluted with EtOAc and washed successively with water (×2) and brine. The organic layer was dried over MgSO4, filtered, and evaporated. The resulting residue was purified by flash chromatography (3:7 EtOAc/hexane) to afford 8c (0.2298 g, 0.9668 mmol, 72%) as a yellow solid (mp 78-79° C.): 1H NMR (CDCl3) δ 8.01 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.26 (1H, d, J=8.8 Hz), 5.40 (2H, s), 3.58 (3H, s), 2.82 (3H, s); 13C NMR (CDCl3) δ 160.9, 153.8, 145.4, 136.6, 126.9, 123.5, 121.4, 116.7, 105.0, 95.7, 56.8, 26.0; FTIR (neat) 2919, 1611, 1508, 1259, 1011, 833, 783 cm−1; MS (ESI) m/z calculated for (C12H12ClNO2+H)+ 238 (35Cl) and 240 (37Cl), found 238 (35Cl) and 240 (37Cl); HRMS (ESI) m/z calculated for (C12H12ClNO2+H)+ 238.0635 (35Cl) and 240.0605 (37Cl), found 238.0623 (35Cl) and 240.0593 (37Cl).
Reaction SMILES: C(=O)([O-])[O-].[Mg+2].[C:6]1([O-:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Na+].Br[C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[CH:19][C:20]=1[F:21]>C1C2C(=CC=CC=2)C=CN=1.[Cu-]=O>[F:21][C:20]1[CH:19]=[CH:18][C:17]([CH3:22])=[CH:16][C:15]=1[O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(F)c(Br)c1
Reactant: [O-]c1ccccc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccc2cnccc2c1
Product: Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 160 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
A mixture of 84.3 g of magnesium carbonate (4MgCO3 .Mg(OH)2.4H2O) and 128 g (1.1 mol) of sodium phenolate was added to a suspension of 189 g (1 mol) of 3-bromo-4-fluoro-toluene and 50 g of copper(I) oxide in 250 ml of isoquinoline at 110° C. The reaction temperature was then increased to 160° C. and the mixture was subsequently stirred at this temperature for 15 hours. Thereafter, the reaction mixture was cooled and filtered. The filtrate was taken up in cyclohexane. The cyclohexane solution was washed with hydrochloric acid and water, dried over sodium sulphate and then concentrated. After distillation of the residue, 170 g (84.1% of theory) of 4-fluoro-3-phenoxy-toluene were obtained in the form of a pale yellow oil of boiling point 105° C./6 mbars.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[C:15]3[C:16]([CH3:24])=[CH:17][N:18]=[CH:19][C:20]=3[CH:21]=[CH:22][CH:23]=2)(=[O:13])=[O:12])[CH2:7]1.C(N(CC)CC)C.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:24][C:16]1[C:15]2[C:14]([S:11]([N:8]3[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:39]([NH:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:40])[CH2:7]3)(=[O:13])=[O:12])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:19]=[N:18][CH:17]=1
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CC[C@H](NCCCN)C3)c12
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cncc2cccc(S(=O)(=O)N3CC[C@H](NCCCNC(=O)Nc4ccccc4)C3)c12
Reaction time: 1 h

Procedure:
A suspension of Intermediate 40a (75 mg) obtained in Step A in 1,2-dichloroethane (3 ml) was cooled on ice, and added with triethylamine (114 μl) and phenyl isocyanate (21 μl, Tokyo Kasei Kogyo), and the mixture was stirred for 1 hour, and then further stirred at room temperature for 10 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (5 ml), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain the title compound (33 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:20][C:21]1[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
Reactant: Cc1noc(C)c1B(O)O
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: COCCOC
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccn1)N(C)C(=O)N2

Procedure:
To a solution of crude 6-Bromo-3-methyl-4-pyridin-2-yl-3,4-dihydro-1H-quinazolin-2-one (600 mg, 0.002 mol) in DME/H2O (12 mL/4 mL) is added 3,5-dimethylisoxazole-4-boronic acid (265 mg, 0.002 mol), Pd(PPh3)4 (77 mg, 0.08 mmol) and Na2CO3 (332 mg, 3.14 mmol). After addition, the mixture is refluxed for 3 h. The mixture is concentrated in vacuum and the residue is purified by preparative HPLC to give the desired product as a yellow solid.
Reaction SMILES: O.[CH2:2]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:17]([O-])(=[O:19])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.C(OCC)C.C(O)(=O)C>[CH2:2]([N:9]1[CH:13]=[C:12]([CH2:17][OH:19])[N:11]=[C:10]1[CH3:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nccn1Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: Cc1nc(CO)cn1Cc1ccccc1
Yield: 12.9 %

Procedure:
A mixture of 8.5 g (0.05 mole) of 1-benzyl-2-methylimidazole monohydrate, 50 ml of 36% formaldehyde, 6 ml of acetic acid and 8.0 g (0.098 mole) of sodium acetate is stirred and heated at reflux for 26 hours. It was then stirred over a weekend (about 65 hours) at room temperature and neutralized with solid sodium carbonate. The neutral solution was extracted with ethyl acetate, the extract dried (MgSO4) and evaporated under reduced pressure to an oil. Water (10 ml) and isopropanol (50 ml) were added to the oil, the solution stirred overnight then evaporated under reduced pressure. The oily residue obtained was taken up in water and the solution made strongly basic by addition of solid sodium hydroxide. It was chilled, layered with diethyl ether, and the white solid which formed removed by filtration and air dried. Yield=1.8 g (18%); m.p. 140°-146° C. It was purified by dissolution in 30 ml of hot (50° C.) ethyl acetate and filtration. Concentration of the filtrate to about two-thirds volume, and chilling, afforded 1.3 g of white solid; m.p. 147°-151° C. Thin layer chromatography in the system ethyl acetate:methanol:diethylamine (80:10:10) gave a single spot.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C-]#N.[Na+].IC1C=CC(C[C:20]#[N:21])=CC=1>>[Br:8][C:6]1[CH:7]=[C:3]([CH2:2][C:20]#[N:21])[S:4][CH:5]=1
Reactant: BrCc1cc(Br)cs1
Reactant: N#CCc1ccc(I)cc1
Agent: [C-]#N
Agent: [Na+]
Product: N#CCc1cc(Br)cs1
Yield: 37 %

Procedure:
A mixture of the above 4-bromothiophen-2-ylmethanol (4.83 g, 25 mmol) and 63 ml of 47% hydrobromic acid was stirred vigorously for 30 minutes at room temperature. The reaction mixture was extracted with pentane to give 5.31 g (yiel: 82.8%) of 2-bromomethyl-4-bromothiophene as a pale yellow oil. Thus obtained 5.12 g of 2-bromomethyl-4-bromothiophene was reacted with sodium cyanide according to the same procedure as in the synthesis of 4-iodophenylacetonitrile of example 5 to give 1.50 g (yield: 37.0%) of 4-bromothiophen-2-ylacetonitrile as a white crystal, removing by-product of α,α-bis[(4-bromothiophen-2-yl)methyl]-4-bromothiopheneaetonitrile by means of recrystalization.
Reaction SMILES: [CH2:1]1[C@@:6]2([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]([C@H:4]([N:11]3[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]3=[O:13])[O:5]2)[O:2]1.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([O:10][CH2:9][C@@:6]23[CH2:1][O:2][C@@H:3]([C@H:4]([N:11]4[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]4=[O:13])[O:5]2)[C@@H:7]3[OH:8])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To Compound 7 (140 mg, 0.53 mmol), anhydrous pyridine was added, followed by performing azeotropy of the mixture 3 times. Then, the product was converted into an anhydrous pyridine solution (1.5 ml), and 4,4′-dimethoxytrityl chloride (210 mg, 0.63 mmol) and DMAP (6.5 mg, 0.053 mmol) were added at room temperature in a stream of nitrogen. The mixture was stirred for 5 hours at room temperature. To the reaction mixture, a saturated sodium bicarbonate solution was added, followed by extraction with CH2Cl2. The organic phase was washed with water and a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvents were distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (CHCl3:MeOH=40:1) to obtain Compound 8 (230 mg, 0.34 mmol, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([NH:1][S:30]([CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:32])=[O:31])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Product: O=S(=O)(Cc1ccccc1)Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with benzenemethanesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [CH3:1][C:2]1[N:3](COCC[Si](C)(C)C)[C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:7][C:5]=2[N:6]=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2COCC[Si](C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2[nH]c(C)nc2s1
Yield: 80.4 %

Procedure:
Ethyl 2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-thieno[2,3-d]imidazol-5-carboxylate (745 mg) was dissolved in ethanol (10 ml) and 6N hydrochloric acid (10 ml) was added, which was followed by reflux under heating for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling until the solution became weak alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the objective compound (370 mg) as white crystals.