Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([F:42])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:34]=[C:33]([F:32])[CH:41]=[C:40]([F:42])[CH:39]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc(F)cc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml) was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,5-difluorobenzoyl chloride (0.5 g, 2.8 mmol). The reaction mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was then quenched with MeOH (1 mL) and washed with H2O (40 mL), 1N HCl (40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo, and the resulting mixture was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min) to afford N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3,5-difluoro-benzamide as a white solid (0.5 g, 54%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.4 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.65 (m, 2H), 2.85-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.46-7.84 (m, 6H), 9.33 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.49, 48.86, 106.93, 110.58, 110.69, 110.82, 110.93, 121.99, 127.21, 131.54, 133.20, 134.83, 137.42, 138.62, 160.51, 160.67, 163.78, 163.95, 164.10, 166.92, 167.48, 169.81, 172.73. Anal Calcd for C21H15F2N3O5: C, 59.02; H, 3.54; N, 9.83. Found: C, 58.90; H, 3.15; N, 9.73.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=3)=[N:27][CH:28]=2)O1>>[N:6]1[CH:7]=[CH:8][CH:9]=[N:10][C:5]=1[O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=2)=[N:27][CH:28]=1
Reactant: Brc1ccccc1Oc1ncccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ncccn3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H14N6O, 342.12; m/z found, 343.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.70 (dd, J=2.3, 0.8, 1H), 8.48 (d, J=4.8, 2H), 8.06 (dd, J=8.3, 2.3, 1H), 7.85 (dd, J=8.3, 0.9, 1H), 7.58 (dd, J=7.6, 1.8, 1H), 7.56-7.50 (m, 1H), 7.48-7.41 (m, 1H), 7.30 (dd, J=8.0, 1.2, 1H), 7.10 (t, J=4.8, 1H).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([OH:12])=[CH:9][CH:8]=[CH:7]2.C[O:14][C:15]1C=C[CH:22]=[C:21]2[C:16]=1[CH2:17]CC[C:20]2=[O:25].[CH3:26][Mg]Br>>[CH3:26][C:5]1[C:6]2[CH:7]=[CH:8][C:9]3[C:17]4[O:25][CH:20]=[C:21]([CH3:22])[C:16]=4[C:15](=[O:14])[O:12][C:10]=3[C:11]=2[CH:2]=[CH:3][CH:4]=1
Reactant: COc1cccc2c1CCCC2=O
Reactant: Cc1cccc2cccc(O)c12
Reactant: C[Mg]Br
Product: Cc1cccc2c1ccc1c3occ(C)c3c(=O)oc21

Procedure:
Neo-tanshinlactone (1) was synthesized by a 8-step sequence, as illustrated in Scheme 1. Our synthetic strategy was to first prepare 8-methyl-1-naphthol (6). Accordingly, 5-methoxy-1-tetralone (2) was reacted with methylmagnesium bromide, and without purification, the resulting crude product (3) was dehydrated using concentrated HCl (Y.-G. Suh et al., Chem. Commun., 1203-1204 (2000); P. Mayer et al., Heterocycles, 55(2), 387-392 (2000)). The product 4, after purification, was dehydrogenated over 10% Pd/C in refluxing triglyme to furnish compound 5. Demethylation of 5 with BBr3 gave the desired naphthol intermediate 6 after silica gel chromatography. The total yield over for the four steps (2→6) was 70%. Treatment of 6 with malonic acid in the presence of PPA at 75° C. yielded 7 (H. Kamijo et al., Nippon Kagaku Kaishi, 11, 1257-1262 (1993)). Reaction of 7 with chloroacetone under basic conditions in DMF, followed by reaction with PPA at 110° C. gave the target product 1. (Y.-L. Chen et al., Helvetica Chimica Acta, 79, 651-657 (1996) B. Rajitha et al., Indian J. Chem., 25B, 872-873 (1986))
Reaction SMILES: NC(N)=O.[CH:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])([CH3:7])[CH3:6].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH:5]([CH3:7])[CH3:6])(=[O:11])=[O:10]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CC(C)NS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 29.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-isopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.88 mmol) and 2-chlorophenylisocyanate (135 mg, 0.88 mmol) were coupled to form the desired urea (110 mg, 32%). EI-MS m/z417.1 (M-H)−.
Reaction SMILES: [C:1]([CH:3]=[C:4]([O-:6])[CH3:5])#[N:2].[Na+].[O:8]=[C:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=O)[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C(O)(=O)C.N1CCCCC1>ClCCl>[O:6]=[C:4]([CH3:5])[C:3](=[CH:22][C:17]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:8])[C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:1]#[N:2]
Reactant: CC([O-])=CC#N
Reactant: O=Cc1cccc2c1-c1ccccc1C2=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(C#N)=Cc1cccc2c1-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound from example 11A (5.21 g, 25.0 mmol) is introduced into 180 ml of dichloromethane, and the compound from example 20A (2.89 g, 27.5 mmol), acetic acid (1.72 ml, 30.0 mmol) and piperidine (0.25 ml, 2.50 mmol) are added. The mixture is stirred at the boiling point with a water trap for 4 h. Cooling to RT is followed by dilution with 30 ml of dichloromethane and washing with water (2×50 ml), the organic phase is dried over sodium sulfate and the solvent is removed in a rotary evaporator. The resulting crude product is purified by chromatography on silica gel 60 with dichloromethane as mobile phase. Combining the product fractions and removing the solvent results in 5.40 g (79% of theory) of the title compound as mixture of E/Z isomers.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10](=[S:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=1>CO>[N+:22]([C:19]1[S:18][C:17]([S:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][N:9]=2)=[N:21][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: S=C1N=NC(c2ccccc2)=N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cnc(Sc2n[nH]c(-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
The starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970). 3-Phenyl-1,2,4-triazole-5-thione (E. Hogarth, J. Chem. Soc. (1949) 1163) was prepared by first reacting benzoyl chloride with thiosemicarbazide in pyridine at 0° C. to give benzoyl thiosemicarbazide. Benzoyl thiosemicarbazide was treated with potassium hydroxide in ethanol to give 3-phenyl-1,2,4-triazole-5-thione. 3-Phenyl-1,2,4-triazole-5-thione (1.77 g) was then dissolved in 50 mL of methanol and treated with 0.57 g of 95% sodium methoxide, and then with 2-bromo-5-nitrothiazole (2.09 g). The mixture was stirred at room temperature for 2 hours and the precipitated sodium bromide was removed by filtration. The methanol was evaporated and the product crystallized from ethanol and water to give 1.5 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole, a white solid, MP 155°-157° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[C:16]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.BrC1C=CC=C2C=1C=CN2.Br[CH2:43][C:44]1[O:45][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:48]=1.BrCCCCC>>[O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[C:16]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:43][C:44]1[O:45][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(c2)C2(CO3)C(=O)Nc3ccccc32)C1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(c2)C2(CO3)C(=O)N(Cc3ccc(C(F)(F)F)o3)c3ccccc32)C1

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations using tert-butyl 3-(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl)piperidine-1-carboxylate to replace 4-bromoindole, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 1-bromopentane, the title compound was obtained (10%) as a white solid: mp 59-61° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 2H), 7.12 (d, 1H), 7.04-6.96 (m, 2H), 6.89 (d, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 6.41(s, 1H), 5.10-4.86 (m, 3H), 4.66 (d, 1H), 4.16-3.94 (m, 2H), 2.68-2.38 (m, 2H), 1.90-1.60 (m, 3H), 1.40 (s, 10H), 1.27-1.21 (m, 1H); MS (ES+) m/z 591.2 (M+23).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24]([O:26]C)=[O:25])[N:4]=[N:3]1.[Li+].[OH-].Cl.ClCCl>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)=[C:5]([C:24]([OH:26])=[O:25])[N:4]=[N:3]1
Reactant: COC(=O)c1nnn(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)nnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of methyl 1-methyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-1H-1,2,3-triazole-4-carboxylate (77 mg, 209 μmol) in THF (0.9 mL) and MeOH (0.3 mL) was added LiOH (1M aqueous solution, 418 μL, 418 μmol) at 0-5° C. The ice bath was removed and the mixture was stirred at RT for 4 h. HCl (1M aqueous solution, 0.42 mL, 0.42 mmol) was added and the solution was poured into dichloromethane (40 mL) to result in a suspension. The solid precipitate was filtered, washed with THF/water 4:1 and dried in vacuo to give the product as colorless solid (52 mg, 147 μmol, 70.2%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]1([CH3:33])[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[N:15]1[C:28]2[CH:27]=[CH:26][C:25]([CH:29]=O)=[CH:24][C:23]=2[S:22](=[O:32])(=[O:31])[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.C(OP([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([CH2:55]P(OCC)(OCC)=O)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)(=O)OCC)C>C(Cl)(Cl)Cl>[C:7]1([CH3:33])[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[N:15]1[C:28]2[CH:27]=[CH:26][C:25]([CH:29]=[CH:55][C:52]3[CH:51]=[CH:50][C:49]([C:46]4[CH:45]=[CH:44][C:43]([CH:42]=[CH:1][C:2]5[CH:5]=[CH:27][C:28]6[N:15]([C:8]7[C:7]([CH3:33])=[CH:12][C:11]([CH3:13])=[CH:10][C:9]=7[CH3:14])[C:16]7[C:21]([S:22](=[O:32])(=[O:31])[C:23]=6[CH:3]=5)=[CH:20][CH:19]=[CH:18][CH:17]=7)=[CH:48][CH:47]=4)=[CH:54][CH:53]=3)=[CH:24][C:23]=2[S:22](=[O:32])(=[O:31])[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C)c(N2c3ccccc3S(=O)(=O)c3cc(C=O)ccc32)c(C)c1
Reactant: CCOP(=O)(Cc1ccc(-c2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(N2c3ccccc3S(=O)(=O)c3cc(C=Cc4ccc(-c5ccc(C=Cc6ccc7c(c6)S(=O)(=O)c6ccccc6N7c6c(C)cc(C)cc6C)cc5)cc4)ccc32)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.93 g (8.1 mmol) of potassium tert-butoxide and then 2.70 g (7.16 mmol) of 10-mesityl-5,5-dioxophenothiazine-3-carbaldehyde (example 35b) were added at room temperature with stirring under nitrogen to a solution of 1.63 g (3.58 mmol) of diethyl[4′-(diethoxyphosphorylmethyl)biphenyl-4-ylmethyl]phosphonate (U.S. Pat. No. 3,984,399, example 2, column 29, lines 58-66) in 40 ml of dimethyl sulfoxide which has been dried over a molecular sieve. After stirring at room temperature for 4 h, the reaction solution was diluted with 200 ml of methanol and stirred for a further 1 h. The precipitate was filtered off, washed with 100 ml of methanol, stirred up again in 300 ml of methanol, filtered again and dried at 35° C. under reduced pressure. The crude product (2.90 g) was recrystallized twice from dimethylformamide and once from chlorobenzene. The crystals were filtered off with suction, washed successively with chlorobenzene and ethanol, filtered off with suction and dried at 80° C. under reduced pressure. After the removal of solvent residues under high vacuum (2×10−5 mbar) at 250° C., 0.98 g (30% of theory) of analytically pure luminous yellow microcrystals having an m.p. of >350° C. were obtained, whose solution in chloroform fluoresced at λ=456, 485 (S), 522 (S) nm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23](=[CH2:27])[C:24](O)=[O:25].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:22][C:23](=[CH2:27])[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: C=C(F)C(=O)O
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C=C(F)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.028 g, 0.10 mmol), 2-fluoroacrylic acid (0.013 g, 0.15 mmol), 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one (0.060 g, 0.20 mmol), and DIPEA (0.070 mL, 0.40 mmol) were suspended in DMA (1.0 mL) in a sealed tube. The reaction mixture was purged with argon and the reaction flask was capped and heated to 50° C. for 12 hours. The completed reaction was passed through a syringe filter, and was directly purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% NH4OH modifier to afford ethyl 4-{3-[(2-fluoroacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C18H16FN4O3 [M+H]+: 355, found 355. 1H NMR (600 MHz, DMSO-D6) δ 12.99 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.87 (ddd, J=1.1, 2.1, 8.0 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.40 (dt, J=1.3, 7.7 Hz, 1H), 5.72 (dd, J=3.6, 47.6 Hz, 1H), 5.44 (dd, J=3.7, 15.6 Hz, 1H), 3.85 (q, J=7.1 Hz, 2H), 0.84 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.[Mg].Br[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18]C=CC=2)[CH:16]=1.C1([Mg]Br)C=CC=CC=1.C1C[O:36]CC1>>[C:1]1([C@H:18]([C:17]2[CH:22]=[CH:23][CH:24]=[CH:15][CH:16]=2)[OH:36])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: Brc1ccc2ccccc2c1
Reactant: Br[Mg]c1ccc2ccccc2c1
Agent: Br[Mg]c1ccccc1
Agent: [Mg]
Product: O[C@@H](c1ccccc1)c1cccc2ccccc12

Procedure:
An operation was carried out in the same manner as in Example 14, except that 0.63 mL (0.375 mmol) of 2-naphthylmagnesium bromide (0.60 mol/L) prepared from magnesium and 2-bromonaphthalene was used instead of the anhydrous THF solution of phenylmagnesium bromide. Thus, (S)-1-naphthylphenylmethanol was obtained. The conversion rate of the raw material was 99%, while the enantiomeric excess was 80% ee.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](OCC)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH3:38])[C:27]([CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[O:28].O>CN(C)C=O>[CH3:25][N:26]([CH3:38])[C:27]([CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37]/[C:14](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:33][CH:32]=1)=[O:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccccc1
Reactant: CN(C)C(=O)CNc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CNc1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
6.0 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-chloro-2-indolinone (educt IX) and 3.9 g of N-(dimethylcarbamoylmethyl)-p-phenylenediamine (educt XV.208) are dissolved in 50 ml of dimethylformamide and stirred for 4.5 hours at 120° C. After cooling water is added, the precipitate formed is suction filtered and washed with methanol. The product is purified through a silica gel column with methylene chloride/methanol (100:1) as eluant and finally recrystallised from ether.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH3:10])[CH3:8])[C:3]=1[C:11]#[N:12].[CH3:13][N:14]=[C:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>O1CCCC1>[CH3:13][NH:14][C:15]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH3:10])[CH3:8])[C:3]=1[C:11]#[N:12])=[O:16]
Reactant: CN=C=O
Reactant: CCN(C)c1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCN(C)c1nsc(NC(=O)NC)c1C#N
Yield: 67.9 %

Procedure:
A mixture of 11 g of 5-amino-4-cyano-3-(ethylmethylamino)isothiazole, 6.8 g of methyl isocyanate, 2 ml of dibutyltin diacetate, and 50 ml of tetrahydrofuran was heated under reflux overnight. After cooling, the solution was evaporated under reduced pressure. The residue was recrystallized from toluene to yield 9.8 g of 1-methyl-3-(4-cyano-3-(ethylmethylamino)-5-isothiazolyl)urea, mp 175°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
The present example sets forth a method whereby the benzthiozole compounds may be obtained. However, other methods may be used in the practice of the present invention. A solution of 4.5 g of 2-aminobenzthiazole in 40 mL of dichloromethane and 10 mL of pyridine was cooled in an ice bath. To this cooled solution was slowly added a solution of 2-methoxybenzoyl chloride in 10 mL of dichloromethane. The resulting mixture was stirred for 3 hours while the ice bath slowly warmed to room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with 1 N HCl (2×50 mL), saturated NaHCO3 (1×40 mL), and saturated NaCl (1×50 mL). After drying over Na2SO4, the solution containing the crude product was filtered and evaporated to dryness. The resulting 8.0 g of white solid was recrystalized from ethyl acetate to afford 4.0 g of 2-(2 methoxybenzoylamino)benzthiazole as white crystals, mp 196-197° C., as first crop.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (4.98 g, 0.02 mol), 1-bromo-8-phenyloctane (4.7 g, 0.017 mol) and HMPA (13 ml), at 120° C., was added, dropwise, during 1 h, a mixture of propylene oxide (6 ml) and Et3N (1 ml). The reaction was continued for 3.5 h, allowed to cool and extracted successively with pet ether, Et2O and Me2CO leaving 1 g of insoluble starting material, 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline. The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O), dried (Na2SO4) and concentrated. The residue was dissolved in CHCl3, placed on silica gel column and eluted with CHCl3. Concentration of the eluates left an oil which was triturated with pet ether to give 4.35 g (60%) of 6-methoxy-4-methyl-8-nitro-5-(8-phenyloctoxy) quinoline as yellow solid, mp 39.5°-41° C. Crystallization from hexane (Darco) provided the analytical sample as yellow crystals, mp 41°-42° C.
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:8]=2[O:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[OH-:23].[K+]>CO>[OH:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:22])=[O:23]
Reactant: [OH-]
Reactant: CCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Agent: [K+]
Solvent: CO
Product: CCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O

Procedure:
3-(n-Butyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(o-tolyloxy)-phenyl]-n-hexanoic acid, mp. 83°-84° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[N:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 6-chloronicotinic acid ethyl ester (1.92 g) in N,N-dimethylformamide (1 ml), trimethylsilylacetylene (2.0 g), bistriphenylphosphine palladium dichloride (210 mg), cuprous iodide (60 mg) and triethylamine (1.2 g) were added successively and the mixture was stirred in a sealed tube at 100° C. for 2 hours. After cooling, the reaction solution was poured into a saturated aqueous sodium hydrogencabonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.38 g of the desired product as a brown oil.