Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:21])([F:22])[F:9])[CH:12]=2)[C:18]([OH:20])=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (35.32 mL of a 0.31M stock solution, 10.9 mmol) cooled to −78° C. was treated with (3-trifluoromethyl-phenyl)-acetic acid (1.02 g, 5.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.4 mL, 3:1). The resulting solution was stirred at −78° C. for 3 h. Iodomethylcyclopentane (1.16 g, 5.52 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (3×100 mL) and diethyl ether (1×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (2×100 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded 3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (1.16 g, 80.5%) as an off-white solid: mp 64-65° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+Na+) 309.1079, found 309.1084.
Reaction SMILES: [N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][C:14]=2[O:24][CH3:25])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[O:24][CH3:25])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(NC(=O)N2CCc3ccccc32)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1NC(=O)N1CCc2ccccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A mixture of methyl 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl-acetate (5.2 g, Reference Example 6) and sodium hydroxide (20 mL, 1M) in methanol (100 mL) and water (50 mL) was stirred at 50° C. for 4 hours. The mixture was evaporated to low bulk and the aqueous layer was washed with dichloromethane then acidified with hydrochloric acid (1M) to give a tan precipitate. This material was filtered, washed with water, then with ether and then dried to give the title compound (4.3 g) as an off-white solid. HPLC: RT=13.3 minutes (99% by ELS).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B(OC)(OC)OC.O1CCCC1.Cl>O>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: COB(OC)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1CO
Temperature: 65 °C
Yield: 98.1 %

Procedure:
A flask was purged with nitrogen and charged with 2-methyl-4-nitro-benzoic acid (45.3 g, 0.25 mol), trimethyl borate (103.9 g, 1.00 mol), and tetrahydrofuran (906 mL). Neat borane dimethyl sulfide complex (39.9 g, 49.8 mL, 0.525 mol) was added drop-wise at 20-35° C. over at least 30 min. An exotherm and effervescence were observed during this addition. When the addition was complete, the reaction mixture was stirred at 65° C. for at least 2 h or until in-process HPLC analysis showed that conversion was greater than 97%. The batch was quenched with cooling by drop-wise addition of methanol (46 mL), followed by a solution of 12.1 N aqueous hydrochloric acid (97 g, 82.1 mL, 1.00 mol) in water (138 mL) over at least 30 min. Batch temperature was held at 20-35° C. during quench; an exotherm and effervescence were observed during the quench. The mixture was stirred at 50° C. for at least 1 h and concentrated under reduced pressure to a volume of ˜230 mL (to remove tetrahydrofuran). The concentrate was diluted with water (453 mL) and extracted with ethyl acetate (2×453 mL). The organic layer was washed with saturated aqueous sodium chloride solution (230 mL), dried over anhydrous magnesium sulfate (23 g), filtered, and concentrated in vacuo to dryness to give the title compound as a beige solid (41 g, 98% yield).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[N+:20]([C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])([O-:22])=[O:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([N:19]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[N+:20]([O-:22])=[O:21])[C:26]2=[O:27])[CH2:17][CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
15 ml of a chloroform solution containing 500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 540 mg of 3-nitrophthalic anhydride was refluxed for 1 hour. After cooling, 756 mg of carbonyldiimidazole was added to the mixture and the resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain 900 mg of N-tert-butoxycarbonyl-trans-4-(1,3-dioxo-4-nitro-2-isoindolinyl)cyclohexylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]([CH3:30])[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:12]>CO>[CH2:14]([O:13][C:11]([CH:10]([NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[CH3:30])=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCOC(=O)C(C)Br
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC(=O)C(C)Nc1cccc(O)c1
Reaction time: 3 h

Procedure:
Into 25 g of m-aminophenol while heating under reflux in 200 ml of methanol was added dropwise over a period of 3 hours a solution of 37 g of hexadecyl α-bromopropionate in 100 ml of methanol. After completion of the addition, the refluxing was continued for an additional 3 hours, the methanol was then distilled off, the concentrate was dissolved in 300 cc of ethyl acetate, and the solution was washed twice with 300 cc of 10% hydrochloric acid. The ethyl acetate phase was washed with water, dried over sodium sulfate and was then concentrated. The concentrate was cooled with ice, whereby pale yellow crystals were deposited. The yield was 25 g and the melting point was 35°-40° C.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24].CCOCC>CO>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCNC1(C(N)=O)CNC1

Procedure:
Alternatively, a solution of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1g; 9.2 g, 30 mmol) in methanol (150 ml) at 0° C. was added 1 M HCl in ether (75 ml, 75 mmol). The mixture was concentrated to ⅔ volume to remove the ether, in vacuo, and then methanol was added to bring the reaction volume to 150 mL. This was repeated a second time. After the addition of 20% Pd(OH)2 on carbon (50% water; 2.3 g), the mixture was placed on a Parr® shaker and then reduced (45 psi H2) at room temperature overnight. The mixture was diluted with methanol (350 ml) filtered through Celite®, rinsing with additional methanol. The methanol fractions were filtered through a 0.45 μm filter disk, and then concentrated under reduced pressure to give a solid residue that was triturated from diethyl ether, collected by vacuum filtration, washed with ether and then dried, in vacuo, to afford I-(13A-9)f (6.3 g, 91%) as a tan solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[O:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH:43]=[C:42]1[CH2:50][NH:51][CH3:52].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:51]([CH2:50][C:42]2[O:41][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH:43]=2)[CH3:52])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CNCc1cc2ccccc2o1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN1CCN(Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4o3)cnc2N)CC1
Yield: 20 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting benzofuran-2-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (158 mg, 20%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.35-8.33 (m, 2H), 7.99 (br s, 2H), 7.62-7.19 (m, 6H), 6.82 (d, J=12.2 Hz, 1H), 5.01-4.80 (m, 2H), 3.62-3.25 (m, 6H), 3.22 (s, 2H), 3.10-2.92 (m, 5H), 2.73 (s, 3H);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:29])[N:11]([CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:29])[N:11]([CH:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCC(O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution (5 mL) of 6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-4-(4-oxocyclohexyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.1 g) in methanol was added sodium borohydride (0.014 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.046 g, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:14][C:13]([C:7]1[C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[CH:8]=1)=[O:15])[CH3:22]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)c2cccc(Br)c2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 8-bromo-2-methylquinoline4-carboxylic acid (7.2 g), ethanol (150 ml) and conc. sulfuric acid (3 ml) was boiled for 6 h. After cooling to room temperature solvent was removed at reduced pressure, the residue treated with water and neutralised with solid potassium carbonate. The neutralised mixture was extracted with ethyl acetate, the extracts dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel (30% diethyl ether/60-80 petroleum ether) to give the ester (2.5 g). m/z (API+): 294, 296 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C([O-])(=[O:19])C.[K+].[OH-].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:16][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2][OH:19]
Reactant: CC(=O)[O-]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCO
Yield: 94 %

Procedure:
For the verification of the optical purity the compound obtained is hydrogenated on pre-hydrogenated platinum dioxide to (3R,7R)-1-chloro-3,7,11-trimethyldodecane; boiling point at 0.07 mm; 90°; = -1.2° (4.08% in CHCl3), which is converted by heating with dry potassium acetate in dimethylformamide (4 hours at 170°). This ester is purified by adsorption on silicagel (elution agent: n-hexane/ether 4+1), then further reacted to (3R,7R)-3,7,11-trimethyl-1-dodecanol by stirring with 4-N aqurous caustic potash (30 min. at room temperature). The mixture is extracted, washed neutral, dried, concentrated, distilled in the bulb-tube (115°, 0.20 Torr) and there is obtained 3R,7R)-3,7,11-trimethyl-1-dodecanol in 94% yield (based on (3R,7R)-1-chloro-3,7,11-trimethyl-dodecane employed). The product has an optical rotation value of [α]D20 = +3.7° (4.14% in n-octane) and is accordingly identical with authentic material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH:15](SC1C=CC=CC=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Ni].C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1C(Cc1ccccc1)Sc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=c1oc(-c2ccccc2)cc(O)c1CCc1ccccc1

Procedure:
The title compound was prepared by Method F using Raney-Nickel (Grace 3100), ethanol (20 mL), 4-hydroxy-6-phenyl-3-[2-phenyl-1-(phenylthio)ethyl]-2H-pyran-2-one (0.425 g, 1.06 mmol). m.p. dec. >255° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.65 (dd, 2 H), 2.71 (dd, 2 H), 6.68 (s, 1 H), 7.23 (m, 3 H), 7.52 (m, 3 H), 7.76 (m, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1.[CH:10](OCC)(OCC)OCC.C1(OC2C=CC=CC=2)C=CC=CC=1.C>CO.C(O)C>[C:6]1(=[O:7])[NH:8][N:9]=[CH:10][N:3]2[CH:2]=[N:1][CH:5]=[C:4]12
Reactant: NNC(=O)c1c[nH]cn1
Reactant: CCOC(OCC)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: CCO
Product: O=c1[nH]ncn2cncc12
Temperature: 240 °C

Procedure:
A mixture of 6.30 gm. of imidazole-4-carboxylic acid hydrazide [Jones et al., J.A.C.S. 71, 2444 (1949)], 63 ml. of triethyl orthoformate and 500 ml. of ethanol is stirred and refluxed for 81/2 hours. The mixture is concentrated in vacuo to a solid. A 100 ml. portion of diphenyl ether is added and the mixture is heated at 240° C. for 15 minutes. The mixture is cooled to room temperature, petroleum ether is added and a solid is collected. This solid is boiled with 150 ml. of methanol. The insoluble portion is collected by filtration and saved. The filtrate is evaporated to give a solid which is heated with 100 ml. of diphenyl ether at reflux for 15 minutes. Cooling to room temperature and the addition of petroleum ether produces a solid. This solid is combined with the above solid, boiled with 600 ml. of methanol and treated with charcoal. The mixture is filtered. The filtrate is boiled down to 35 ml. and cooled giving a solid. This solid is boiled with 50 ml. of ethanol and the hot mixture is filtered. The solid is boiled with 200 ml. of methanol and the insoluble solid is collected by filtration and saved. The filtrate is boiled down to 75 ml. and cooled giving a second solid. These two solids are combined giving the desire product, m.p. 294°-305° C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][O:1][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: CI
Reactant: CC(O)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of 4.05 g of 1-hydroxyethylbenzimidazole in 25 ml of dimethylformamide was added 1.2 g of 50% sodium hydride in oil, and the mixture stirred for 30 minutes. Methyl iodide (3.55 g) was added and the reaction mixture stirred at room temperature overnight. Water (200 ml) was added and the product extracted with ethyl acetate. The extracts were combined, dried and concentrated to an oil which was chromatographed on 130 g of silica gel using 5% methanol in chloroform as the eluent to give 2.36 g of brown oil.
Reaction SMILES: [Na].[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH3:11].Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1>C(OCC)(=O)C.[Cu]>[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1cccc(Br)n1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [Cu]
Agent: [Na]
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2cc(C)c(Br)c(C)c2)n1
Temperature: 185 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of sodium hydroxide (0.23 g, 5.81 mmol) in methanol (50 mL) was added 4-bromo-3,5-dimethylphenol (1.17 g, 5.81 mmol) and the mixture was left standing at room temperature for 10 min. and concentrated to dryness to give 4-bromo-3,5-dimethylphenol sodium salt (1.30 g). Then, a mixture of the obtained 4-bromo-3,5-dimethylphenol sodium salt (1.30 g), 2-bromo-6-methylpyridine (1.0 g, 5.81 mmol) and copper powder (11 mg, 0.17 mmol) was stirred at 185° C. for 1 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=5/1) to give the title compound (1.25 g, yield 74%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>CCCCCCC>[Br:19][C@@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Br
Solvent: CCCCCCC
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 179.8 %

Procedure:
Under an argon atmosphere, a suspension of (S)-1-[3,5-bis(trifluoromethyl)-phenyl]ethanol (1.0 g, 3.87 mmol, >99.5% ee) in heptane (2 mL) was added dropwise with phosphorus tribromide (0.52 g, 1.94 mmol) at 0 to 5° C., and the mixture was stirred at 0 to 5° C. for 30 minutes. The reaction mixture was added dropwise with hydrogen bromide (30% solution in acetic acid, 0.76 mL, 3.87 mmol) at 0 to 5° C., and the mixture was stirred at 10° C. for 17 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (15 mL×2). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL×1) and then with saturated brine (15 mL×1), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 8 g; developing solvent, n-hexane) to obtain 1.12 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.C1(C)C=CC=CC=1.C(OO)(=[O:26])C>O>[OH:26][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Reactant: CC(=O)OO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
While stirring a mixture of 22.5 g of ethyl 2-(4-formylphenoxy)propionate ([α]D25 =+51.5°) and 60 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After stirring at 20° to 30° C. for 2 hours and at 50° C. for 2 hours, 0.2 g of water was added, and the mixture was stirred for 2 hours. After cooling the reaction mixture to room temperature, 40 g of water was added. The aqueous layer was separated. The organic layer was washed with 40 g of water, followed by washing twice with 40 g of a 5% sodium hydrogen carbonate aqueous solution, then with 40 g of a 5% sodium hydrogen sulfite aqueous solution and further with 40 g of water. Then, the reaction mixture was concentrated by distilling off toluene under reduced pressure, and subjected to distillation under reduced pressure, whereby 16.5 g of (+)-ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:5]2[C:4](=[O:7])[N:3]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=3)[C:2](=[O:1])[NH:6]2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(N2C(=O)CNC2=O)c2ccccc12
Reactant: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(N2C(=O)NC(=Cc3ccc(O)cc3)C2=O)c2ccccc12

Procedure:
The title compound was obtained as an off-white solid (37.3 mg, 17.6%), mp>275° C. from compound 1C and 4-hydroxybenzaldehyde in the same manner as that used in the preparation of Example 1 by acidifying the aqueous washings and recrystallization of the crude product from MeOH. LC/MS m/z 356 [M+H]+.