Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([CH:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[C:24]([OH:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:17]1([CH:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[C:24]([O:26][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
PS-DCC (1.15 g, 1.44 mmol, loading: 1.25 mmol/g) was suspended in THF (15 ml). 2-Phenyl-2-(o-tolylamino)acetic acid hydrochloride (I22) (200 mg, 0.72 mmol) and HOBT (221 mg, 1.44 mmol) were added, followed by (R)-quinuclidin-3-ol (275 mg, 2.16 mmol), and the mixture was stirred for 16 hours at room temperature. PS-DCC was removed by filtration, and the filtrate was evaporated. The resulting residue was dissolved in EtOAc and washed sequentially with water, sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (260 mg, quantitative yield, mixture of diastereomers).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[CH2:51][CH2:50]1>CN(C=O)C>[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[CH2:51][CH2:50]1
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)CCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.071 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 49% yield: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: CNS(C1C=CC=CC=1)(=O)=O.BrCC1C=CC(C=CC(OCC)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH2:44][C:45]1[CH:57]=[CH:56][C:48]([CH:49]=[CH:50][C:51]([O:53]CC)=[O:52])=[CH:47][CH:46]=1)[S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36]>O.CN(C)C=O>[CH3:33][N:34]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([CH:49]=[CH:50][C:51]([OH:53])=[O:52])=[CH:56][CH:57]=1)[S:35]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:36])=[O:37]
Reactant: CCOC(=O)C=Cc1ccc(CN(C)S(=O)(=O)c2ccccc2)cc1
Agent: CCOC(=O)C=Cc1ccc(CBr)cc1
Agent: CNS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(C=CC(=O)O)cc1)S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
A mixture of 5.1 g. (30 mmol) N-methylbenzenesulphonamide, 8.8 g. (33 mmol) ethyl 4-bromomethyl-cinnamate (m.p. 47° C.), 4.1 g. (30 mmol) potassium carbonate and 50 ml. dimethylformamide are heated, with stirring, for 4 days at 60° C. The reaction mixture is then cooled and stirred into cold water and the organic components extracted with diethyl ether. The ethereal solution is washed with 0.5 N aqueous sodium hydroxide solution, dried with anhydrous sodium sulphate and evaporated. The residue is recrystallized from isopropanol to give 7.9 g. (73% of theory) ethyl 4-(N-methylbenzenesulphonamidomethyl)-cinnamate; m.p. 112°-112.5° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].Cl>C(O)CCC>[I:20][C:18]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:13]([F:12])[CH:19]=1
Reactant: Nc1ccc(I)cc1F
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCCCO
Product: Fc1cc(I)ccc1Nc1nc2ccc(Cl)cc2s1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
A mixture of 2,6-dichlorobenzothiazole (1.0 g, 4.9 mmol) and 2-fluoro-4-iodoaniline (2.32 g, 9.8 mmol) in 20 mL BuOH was stirred at 90° C., and then HCl (4 M in dioxane, 1.0 mL) was added. The reaction mixture was stirred with heating at 90° C. overnight, under argon. NMR analysis then showed little 2,6-dichlorobenzothiazole remaining. After BuOH was removed by rotary evaporation, EtOAc (100 mL) and 1 N aqueous HCl (100 mL) were added. The organic layer was separated and washed with 1 N aqueous HCl (100 mL), saturated Na2O2S3 solution (50 mL), water (100 mL), and then dried over Na2SO4. Removal of solvent under reduced pressure afforded a residue, which was triturated with EtOAc (10 mL) and hexanes (40 mL). The solid was filtered and dried in vacuo to a constant weight, to afford the desired product as a light purple solid (0.75 g, 38%). 1H NMR (DMSO-d6) δ 10.45 (s, 1H), 8.35 (t, 1H), 7.95 (s, 1H), 7.70 (d, 1H), 7.58 (d, 2H), 7.30 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: CC(=O)C#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 119 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (369 mg, 2.09 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (500 mg, 2.3 mmol) in AcCN (7.5 mL) was added DIPEA (0.41 mL, 2.3 mmol). After stirring at room temperature for 5 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give tert-butyl (3R,4R)-4-(6-chloro-5-cyanopyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (880 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][NH2:67])[CH:61]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:67][CH2:66][C:62]4[CH:61]=[N:60][CH:65]=[CH:64][CH:63]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Benzoic acid 29 (150 mg, 0.34 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (0.12 mL, 0.69 mmol) and HBTU (171 mg, 0.45 mmol) were successively added and the reaction mixture was stirred at 20° C. for 10 min. 3-Pyridinylmethanamine (0.14 mL, 1.4 mmol) was subsequently added and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with EtOAc (150 mL), washed with H2O (3×50 mL), washed with brine (50 mL) and dried. The solvent evaporated and the residue was purified by column chromatography, eluting with a gradient (0-10%) MeOH/EtOAc, to afford benzamide 30 (170 mg, 94%) as a white solid: mp (EtOAc) 225-226° C.; spectroscopically identical to the sample prepare above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: NO
Reactant: COc1cccc2c1CCCC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1CCCC2=NO
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of 5-methoxy-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.1 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser. Cooled to room temperature after approximately seventeen hours, transferred to another flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: C[N:2]1[CH2:6]CC[C:3]1=[O:7].[CH3:8]/[C:9](/[S:12][CH3:13])=[N:10]/[OH:11].CN=C=O>C(N(CC)CC)C>[CH3:8]/[C:9](/[S:12][CH3:13])=[N:10]\[O:11][C:3]([NH:2][CH3:6])=[O:7]
Reactant: CS/C(C)=N\O
Reactant: CN1CCCC1=O
Agent: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)O/N=C(\C)SC
Reaction time: 1 h
Yield: 96 %

Procedure:
A 256 g portion of an N-methyl pyrrolidone solution of methomyl oxime (containing 0.4 mole MMO) and 0.5 g triethylamine was charged to a 500 ml 5-necked flask. To this was added 28.7 g (0.5 mole) methyl isocyanate rapidly. The temperature rose to 40° C. for 1.0 hour. The reaction mixture was then transferred to a Kugelrohr apparatus, and the solvent removed at reduced pressure. A yield of 96% Methomyl, assaying >99% was realized.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([C:10]([C:17]([O:19]CC)=O)=[N:11][N:12]=[C:13](Cl)[CH2:14][CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CN(C)C=O>[CH2:14]([C:13]1[N:2]([NH2:3])[C:17](=[O:19])[C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][N:12]=1)[CH3:15]
Reactant: NN
Reactant: CCOC(=O)C(=NN=C(Cl)CC)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2ccccc2)c(=O)n1N
Reaction time: 8 h
Yield: 67.1 %

Procedure:
10.0 g (0.2 mol) of hydrazine hydrate, dissolved in 20 ml of dimethylformamide, were added dropwise to a solution of 26.7 g (0.1 mol) of 1-phenyl-1-ethoxycarbonyl-4-chloro-4-ethyl-2,3-diazabutadiene in 100 ml of dimethylformamide at a temperature of 5°C to 10°C, whilst stirring. After stirring for 3 hours, 250 ml of water were added to the reaction mixture. The whole was left to stand overnight. Thereafter, the solid which had precipitated was filtered off, well rinsed with water and dried. The yellowish-white crude product (17.4 g = 80% of theory) was purified by recrystallization from isopropanol/water. 14.5 g (67.1% of theory) of 3-ethyl-4-amino-6-phenyl-5-H-1,2,4-triazin-5-one of melting point 164°C were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][O:27][CH2:26][C@@H:25]1[NH:29]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:25]([NH2:29])[CH2:26][O:27][CH2:28]1)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4N)ncc3c2)c1Cl

Procedure:
A solution of tert-butyl ((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydrofuran-3-yl)carbamate (1.097 g, 2.049 mmol) in DCM (15 mL, 0.137 M) and TFA (11.7 g, 102 mmol) was stirred about 40 minutes at room temperature. The excess solvents were removed under reduced pressure. The yellow oil was dissolved into DCM (˜60 mL) and washed with aqueous 1N NaOH (˜30 mL). The aqueous layer was then diluted with brine (˜15 mL) and extracted with fresh DCM (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated down, and dried to yield (3S,4R)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydrofuran-3,4-diamine as a very light yellow foam (0.879 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2C=C[CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1.[Li].C(C1N=C(C([O-])=O)[S:34]C=1)(C)C.NC1C(Cl)=C(OC)C=CC=1C(=O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[S:34][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1
Reactant: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Reactant: CC(C)c1csc(C(=O)[O-])n1
Agent: COc1ccc(C(C)=O)c(N)c1Cl
Agent: [Li]
Product: COCCOc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
4,8-Dichloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-methoxy-ethoxy)-quinoline was prepared in a similar fashion as 4,8-Dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline except that the lithium salt of 4-isopropyl-thiazole-2-carboxylate was used instead of 6-isopropyl-pyridine-2-carboxylic acid and 1-(2-Amino-3-chloro-4-methoxy-phenyl)-ethanone was used instead of 1-[2-amino-3-chloro-4-(2-methoxy-ethoxy)-phenyl]-ethanone
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][CH:8]([CH3:11])[CH:9]=[O:10].Cl>>[OH:10][C@@H:9]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH:8]([CH3:11])[CH3:7]
Reactant: CC(C)C=O
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 2-methylpropionaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-1-hydroxy-2-methylpropylphosphonate as a final product in a yield of 95%. The chemical reaction in this Example is shown in chemical formula 41. ##STR35##
Reaction SMILES: C([O:6][CH2:7][C@H:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(=O)CCC.[OH-].[Na+].Cl>CO>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH2:9][C@@H:8]([CH2:7][OH:6])[O:12][N:11]=2)=[N:14][CH:15]=1
Reactant: CCCC(=O)OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl butyrate (Intermediate 10, 16.88 g, 0.051 mol) was dissolved in methanol (110 ml). 50% Aqueous sodium hydroxide (3.6 ml, 0.068 mol) was added. The solution was stirred at RT for 15 minutes, 1M HCl (75 ml) was added, followed by concentration in vacuo to ˜100 ml total volume. Water (˜50 ml) was added, and the white precipitate was collected and rinsed with water. The filtrate was extracted twice with ethyl acetate, the organic layers were pooled, dried over sodium sulfate and evaporated. The solid residue was collected and rinsed with 10:1 hexane:ethyl acetate, then combined with the initial precipitate before drying in vacuo to give the title compound as a white crystalline solid, 12.3 g (93%). Chiral HPLC analysis indicated <0.5% of the (−) isomer was present. [α]D=+139 (c=0.01 g/ml in methanol).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:24][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[C:14]([CH3:15])=[C:13]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(C)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cc2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.5 %

Procedure:
A solution of [6-fluoro-3-methyl-4-(4-methyl-benzyl)-naphthalen-2-yl]-acetic acid methyl ester (140.8 mg, 0.419 mmol) in tetrahydrofuran (14 mL) was treated with a warm solution of lithium hydroxide monohydrate (175.8 mg, 4.19 mmol) in water (3.5 mL). The reaction mixture was stirred at room temperature for 20 hours, diluted with water, acidified with aqueous 3.0 N HCl and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. Purification by reverse phase HPLC gave 81.7 mg (60%) of [6-fluoro-3-methyl-4-(4-methyl-benzyl)-naphthalen-2-yl]-acetic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.43 (br. s, 1 H), 7.91 (dd, J=8.7, 6.3 Hz, 1 H), 7.74 (s, 1 H), 7.62 (dd, J=12.1, 1.8 Hz, 1 H), 7.33 (td, J=8.7, 1.8 Hz, 1 H), 7.03 (d, J=7.8 Hz, 2 H), 6.92 (d, J=7.8 Hz, 2 H), 4.40 (s, 2H), 3.82 (s, 2 H), 2.32 (s, 3 H), 2.21 (s, 3 H). HRMS (ES−) cald. for C21H19FO2 [(M−H)−] 321.1296, obsd. 321.1294.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:9][CH3:10])[C:2]=1[F:1]
Reactant: BrBr
Reactant: COc1c(N)cccc1F
Solvent: CC(=O)O
Product: COc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-fluoro-2-methoxyaniline (2.8 g, 20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) in acetic acid (10 mL) dropwise. The reaction mixture was stirred at rt. for 30 min. Solid was filtered and washed with acetic acid to give the HBr salt. It was then dissolved in water, basified by addition of KOH, extracted with ethyl acetate. The organic layer was dried and concentrated to give a white solid (2.8 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3 H) 6.42 (dd, J=8.6, 1.8 Hz, 1 H) 7.01 (dd, J=8.6, 7.1 Hz, 1 H). [M+H] calc'd for C7H7BrFNO, 222; found 222.
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[C:12]([Si:16]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:17][CH:18]1[CH:22]([CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].[Na]>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.CCCCCCC.O1CCCC1>[C:12]([Si:16]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[O:17][C:18]1([CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH2:19][CH2:20][CH:21]=[C:22]1[CH2:23][O:24][C:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[Si](OC1CC=C(OS(=O)(=O)C(F)(F)F)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Agent: [Na]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCCCCCC
Product: CC(C)(C)[Si](OC1(C[Si](C)(C)C)CCC=C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
Magnesium (turning) (33 g, 5.22 mol) was mixed with anhydrous tetrahydrofuran (2 L). 1,2-Dibromoethane (8 ml) was added thereto and stirred for 15 min. To the resulting solution, a mixture of chloromethyltrimethylsilane (364 ml, 2.61 mol) and anhydrous tetrahydrofuran (0.6 L) was added dropwise for 10 min. The mixture solution thus obtained was heated to 40° C. and cooled slowly to precipitate trimethylsilylmethyl magnesium chloride. A mixture of the compound of formula (X) obtained in Example 2-3 (892 g), tetrakis(triphenylphosphine)palladium (37.7 g, 0.033 mmol) and anhydrous tetrahydrofuran (4.5 L) were added to the resulting solution for 20 min dropwise and stirred at room temperature for 1 to 2 hrs. After completion of the reaction, the resulting solution was cooled to 0° C. and 3% aqueous sodium bisulfonate (8 L) was added thereto. The resulting mixture was filtered through Celite, washed with ethyl acetate (4 L). The organic layer thus separated was condensed under a reduced pressure. The residue thus obtained was mixed with heptane (6 L) and Celite (400 g), stirred for 2 hrs, filtered and washed with heptane (2 L). The organic layer thus separated was washed with a mixture of methanol and water mixed in a weight ratio of 6:1 (5.6 L) twice, dried over anhydrous sodium sulfate, filtered, and condensed under a reduced pressure. The residue was crystallized with a mixture of isopropyl alcohol and water to obtain the title compound as a crystalline solid (786 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21]Cl)=[CH:20][C:14]=2[C:13]=1[CH3:23])=[O:11]>CN(C)C=O>[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[CH:20][C:14]=2[C:13]=1[CH3:23])=[O:11]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1sc2ccc(CCl)cc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(Cc3ncc[nH]3)cc2c1C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a solution of imidazole (0.23 g.) in dry N,N-dimethylformamide (10 ml.) was added sodium hydride (0.17 g. of 50% dispersion in mineral oil) and the mixture was stirred for 30 minutes. A solution of 5-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.82 g.) in dry N,N-dimethylformamide (10 ml.) was then added dropwise with stirring and the resulting mixture was stirred at room temperature for 2.5 hours and then evaporated. The residue was poured into water and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform gave first some impurity followed by pure product. The product containing fractions were combined to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.30 g.), m.p. 136°-138°.