Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19](B(O)O)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>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>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1
Reactant: Brc1cncc2cccnc12
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nn3c(c2-c2cncc4cccnc24)CCC3)nc1
Temperature: 60 °C
Yield: 65.1 %

Procedure:
Add 8-bromo-[1,6]naphthyridine (Spec; 32 mg, 0.152 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 35 mg, 0.153 mmol), and potasium phosphate (97 mg, 0.458 mmol) to DMF (1 mL) and water (0.5 mL). De-gas the solution with argon and add tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mol). Heat the mixture at 60° C. for 18 h under an argon atmosphere. Cool the mixture to room temperature and dilute with water. Filter the mixture, and separate the filtrate. Extract the aqueous layer with dichloromethane. Dry the combined organic layers over sodium sulfate, filter, and concentrate. Purify the crude residue by column chromatography (12 g Redisep column, gradient dichloromethane through CMA over 40 min, 20 mL/min) to provide the title compound (31 mg, 64%) as an off white solid. Mp 180-184° C. MS (APCI) m/e=314 (M+1). 1H NMR (CDCl3) δ 8.88 (dd, J=1.6, 4.2 Hz, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.73-7.68 (m, 3H), 7.58 (dd, J=4.2, 8.5 Hz, 2H), 4.30 (t, J=7 Hz, 2H), 3.30 (t, J=7 Hz, 2H), 2.73 (p, J=7 Hz, 2H). HPLC: >99%, Rt=7.1 min.
Reaction SMILES: C(O)C.C[O-].[Na+].[C:7]([O:12]CC)(=O)[CH:8]([CH3:10])[OH:9].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=1[OH:22]>CO.C(Cl)(Cl)Cl.O>[OH:22][C:21]1[CH:20]=[C:19]([CH3:23])[CH:18]=[CH:17][C:16]=1[NH:15][C:7](=[O:12])[CH:8]([OH:9])[CH3:10]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCOC(=O)C(C)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)C(C)O)c(O)c1
Yield: 6.4 %

Procedure:
To 20 ml of ethanol, there were added 6.72 g of sodium methoxide, 20.0 g (169 mmol) of ethyl lactate and 6.95 g (56.5 mmol) of 6-amino-m-cresol, followed by heating under reflux for 3 hours. After cooling, 100 ml of water was added to the mixture and the crystals thus precipitated were filtered. The filtrate was extracted with 200 ml of ethyl acetate, washed with a saturated aqueous solution of common salt and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the solid thus obtained was subjected to silica gel column chromatography (Si60 manufactured by Merck; 230-400 mesh; 300 g; eluent: 2% methanol-chloroform). After distilling off the solvent from the 2,000-3,200 ml fraction under reduced pressure, the obtained solid was dissolved in 200 ml of ethyl acetate, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the residue was dried and thus 0.70 g (3.6 mmol) of N-(2-hydroxy-4-methylphenyl)-2-hydroxypropionamide was obtained as brown crystals. The yield was 6%.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:12]=2[CH:11]=1>>[OH:9][C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([S:17](=[O:19])(=[O:20])[NH2:18])=[CH:16][C:12]=2[CH:11]=1
Reactant: COc1ccc2sc(S(N)(=O)=O)cc2c1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc2cc(O)ccc2s1
Temperature: 190 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Pyridine hydrochloride (50 g) was heated to 190° C. and to the melt was added 5-methoxy-2-sulfamoylbenzo[b]thiophene (12.78 g, 0.053 m). The mixture was stirred at 190° C. for 2 hours and then poured into ice and extracted with ethyl acetate (3×200 ml). The combined extract was washed with 3N HCl, dried over Na2SO4 and filtered through a pad of filter aid and charcoal. The filtrate was concentrated under reduced pressure and the residue was crystallized from nitromethane to yield 7.83 g (64%) of product melting at 197°-198.5° C. An analytical sample melted at 192.5°-193.5° C. after recrystallization from nitromethane and treatment with decolorizing carbon.
Reaction SMILES: [CH2:1]([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]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:43]([O:47][C:48](=[O:56])[NH:49][CH2:50][CH2:51][C:52]([NH:54][NH2:55])=[O:53])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.C(N(CC)CC)C>[C:43]([O:47][C:48](=[O:56])[NH:49][CH2:50][CH2:51][C:52]([NH:54][NH:55][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:53])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 in methylene chloride (14.1 mL) were added triethylamine (393 μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg), 1-hydroxybenzotriazole.monohydrate (324.6 mg), and tert-butyl(3-hydrazinyl-3-oxopropyl)carbamate (430.8 mg, prepared following a procedure analogous to Reference Example 2), followed by agitating at room temperature overnight. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to afford 347.3 mg of the title compound (yield 53.3%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:28])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.2 %

Procedure:
A solution of diisopropylamine (1.5 mL, 10.67 mmol) in dry tetrahydrofuran (24 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (4.3 mL, 10.67 mmol). The resulting reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.40 g, 10.16 mmol) in a small amount of tetrahydrofuran. The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.24 g, 10.67 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warn to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (10 mL) and then partitioned between water (75 mL) and ethyl acetate (75 mL). The layers were shaken and separated. The aqueous layer was further extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (2.69 g, 83%) as a colorless oil: EI-HRMS m/e calcd for C16H18F4O2 (M+) 318.1243, found 318.1250.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:20]1([S:26]([NH2:29])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([NH:15][S:12]([C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:26]([NH:29][C:6]([CH3:10])([CH3:7])[CH3:5])(=[O:28])=[O:27])[CH:21]=2)[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=1)(=[O:14])=[O:13])[CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCCNS(=O)(=O)c1cc(Br)c(OC)c(C=O)c1
Product: CCCCNS(=O)(=O)c1cc(C=O)c(OC)c(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)c1
Yield: 178.3 %

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide (0.65 g, 1.72 mmol) and N-tert-butyl-3-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (0.64 g, 1.90 mmol, 1.1 eq.), gave N-butyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (0.74 g) as on orange oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][C:6]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:7][OH:8])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[CH2:15]([N:4]1[CH2:1][CH:2]2[C:6]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)([NH:7][O:8][CH2:3]2)[CH2:5]1)[CH:16]=[CH2:17]
Reactant: C=CCN(CC=C)CC(=NO)c1cccnc1
Solvent: Cc1ccccc1
Product: C=CCN1CC2CONC2(c2cccnc2)C1
Yield: 54.2 %

Procedure:
A solution of 2-(diallylamino)-1-(3-pyridyl)ethanone oxime (3.95 g, 17.08 mmol) in toluene (56 mL) is heated at 120° C. for 18 hours. The solvent is removed under reduced pressure. The crude product is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (2.14 g, 43%). ES/MS (m/e): 232 (M+1).
Reaction SMILES: [C:1]([C:23]([NH2:25])=O)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[C:1]([C:23]#[N:25])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:20])([F:21])[F:22])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Yield: 85 %

Procedure:
Monoamidines were synthesized in accordance with the method of the invention as follows. In a four-neck flask, provided with a mixer, thermometer, back-flow condenser and a dropping funnel, 41.1 g (0.01 mole) of dry C7F15COOH were added and blended with 32.0 g methanol and 19. ml of concentrated H2SO4. The mixture was boiled for 6 hours, then washed with water and dried with MgSO4. The product, an ester, was distilled (Tboiling of 158° C.). The yield was 90-95% (39.2 g) using the procedure as described in U.S. Pat. No. 2,570,116 (1951). In a four-neck flask, provided with mixer, thermometer, condenser and the tube for introduction of gas, 39.2 g of C7F15COOCH3 and 100 ml diethyl ether were added. Additionally, ammonia gas was provided, and ice was used as necessary to cool the flask. The completion of the reaction was checked by gas-liquid chromatography by noting the absence of C7F15COOCH3 in the ether solution. The ether was distilled off, and the solid product was dried in air. 37.0 g of C7F15CONH2 were obtained (a yield of 97.9%) and the product had a Tboiling of 90° C. In a round-bottom flask, 37.0 g of C7F15CONH2 (0.0896 mol) that had been ground into a fine powder and 63.6 g of P2O5 were added. The materials were thoroughly mixed, and a reflux condenser was placed on the flask and heated at 100-200° C. The product C7F15—CN was obtained in an amount of 30.1 g (a yield of 85%), and had a Tboiling of 90° C. The reaction scheme as noted above appears representatively below:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NS(C)(=O)=O)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39.4 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), methanesulfonyl chloride (88 mg), triethylamine (234 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→4:1→1:0 as the eluant and the product was recrystallized from ethyl acetate to afford the title compound (159 mg, mp 224.8-226.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([OH:12])=[C:4]([O:13][CH3:14])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[O:12][C:9]([CH2:11][OH:20])([CH3:10])[CH2:8][C:6]=2[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1cc(Cl)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Cl)cc2c1OC(C)(CO)C2
Yield: 74.4 %

Procedure:
Treatment of 4-chloro-2-methoxyphenol (15.00 g, 0.10 mol) with sodium hydride (4.4 g, 0.11 mol, 60 wt. %) and 3-chloro-2-methylpropene (12.00 g, 0.12 mol) generally according to the procedure described for Intermediate 13 provided 19.3 g (91%) of 4-chloro-2-methoxy-1-[(2-methylprop-2-enyl)oxy]benzene as a colorless oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 afforded 15.5 g (78%) of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol as a pale yellow oil. Treatment of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol (10.00 g, 0.047 mol) with 3-chloroperoxybenzoic acid (20.00 g, 0.089 mol, 77%) followed by potassium carbonate (20.00 g, 0.145 mol) generally according to the Procedure described for Intermediate 9 provided 8.00 g (74%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a light yellow oil. Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (10.8 g, 0.047 mol) with p-toluenesulfonyl chloride (13.5 g, 0.071 mol), diisopropylethylamine (12.15 g, 0.094 mol), and 4-(dimethylamino)pyridine (0.35 g, 2.83 mmol) generally according to the procedure described for Intermediate 45 gave 13.8 g (76%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 113-115° C.; Anal. calcd. for C18H19ClO5S: C, 56.47; H, 5.00. Found: C, 55.82; H, 4.94.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[C:14]([C:8]1[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:17])=[O:3])(=[O:16])[CH3:15]
Reactant: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
Ethyl bromoacetate (0.619 mL) was added to a mixture of 5-bromo-2-hydroxyacetophenone (1.0 g) and potassium carbonate (0.964 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl(2-acetyl-4-bromophenoxy)acetate as a crude product. The crude ethyl(2-acetyl-4-bromophenoxy)-acetate was dissolved in ethanol (5 mL). A 2 mol/L aqueous solution of sodium hydroxide (5 mL) was added to the solution, and the mixture was stirred for 1 hr. The reaction mixture was made acidic with an addition of 2 mol/L hydrochloric acid (7 mL), and then ethyl acetate and brine were added. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate and n-hexane to afford the title compound (0.851 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12]/[C:13](/[CH3:27])=[CH:14]/[C:15]1[C:20]2[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[C:19]=2[CH:18]=[CH:17][CH:16]=1.O>CO>[CH3:27]/[C:13](=[CH:14]\[C:15]1[C:20]2[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[C:19]=2[CH:18]=[CH:17][CH:16]=1)/[CH2:12][CH2:11][CH2:10][C:9]([OH:28])=[O:8]
Reactant: COC(=O)CCC/C(C)=C/c1cccc2c1NCCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C/C(=C\c1cccc2c1NCCNC2=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (43.32 mmol, 5.987 g) was added to a solution of Example 161 (7.22 mmol, 2.066 g) in 200 mL MeOH (gently heated with a heat gun to get it in solution) and 100 mL H2O. The reaction mixture was stirred at rt for 24 h. The MeOH was removed in vacuo and the residue was taken up in H2O and extracted with EtOAc. The aqueous layer was made acidic (pH 0-1) using 2N HCl when the product precipitates out of solution as a white solid. The solid was filtered, washed with H2O and dried (1.878 g; 96%). The product was used without further purification: mp=257-259° C.; 1H NMR (DMSO-d6) δ 1.83-1.93 (m, 2H), 2.33 (t, 2H, J=6.0 Hz), 2.75 (t, 2H, J=6.0 Hz), 3.52-3.56 (m, 2H), 4.22 (br s, 2H), 6.34 (s, 1H), 7.07 (t, 1H, J=6.0 Hz), 7.65 (d, 1H, J=6.0 Hz), 7.75 (d, 1H, J=6.0 Hz), 8.23 (t, 1H, J=6.0 Hz), 11.98 (br s, 1H); HRMS calcd. for C15H16N2O3 (M+) 272.1161, found (M+) 272.1151.
Reaction SMILES: ClCCCl.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]2.[O-:33]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S@:17]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]2)=[O:33]
Reactant: Cc1ccccc1-n1ccnc1SCCCOc1ccc2c(c1)CCC(=O)N2
Reactant: [O-]O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)c1ccccc1
Solvent: O
Solvent: ClCCCl
Product: Cc1ccccc1-n1ccnc1[S@@](=O)CCCOc1ccc2c(c1)CCC(=O)N2
Temperature: -5 °C
Yield: 3.2 %

Procedure:
To 1 l of 1,2-dichloroethane were added 56.8 g of titanium tetraisopropoxide, 168 g of D-(-)-diethyl tartarate, 0.91 ml of water and 80 g of 6-{3-[1-(2-methylphenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril. The mixture was stirred and then cooled to -5° C. Thereto was added 124 g of cumene hydroperoxide slowly. After the completion of the addition, the mixture was stirred at 5° C. for 18 hours. The reaction was repeated. The reaction mixtures from the two reactions were combined and purified by a silica gel column chromatography (eluant: dichloromethane/ethyl acetate/methanol=3/1/0→30/10/1), followed by recrystallization from ethanol-ethyl acetate. The mother liquor was concentrated to obtain crystals. This procedure was conducted 14 times. The resulting crystals were purified by a silica gel column chromatography (eluant: dichloromethane/ethyl acetate/methanol=30/10/1), followed by recrystallization from ethanol to obtain 2.7 g of (S)-(+)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril. White powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH:10]1[CH2:12][CH2:11]1>>[CH:10]1([CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: ClCC1CC1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CC2CC2)CC1

Procedure:
1-(Cyclopropylmethyl)-4-piperidone is prepared from 4-piperidone and (chloromethyl)cyclopropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([Si:17]([CH3:29])([CH3:28])[O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)([CH3:16])([CH3:15])[CH3:14].CI>O1CCCC1>[C:13]([Si:17]([CH3:29])([CH3:28])[O:18][CH:19]1[CH2:24][CH2:23][C:22]([CH3:1])([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)O)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a cold (−78° C.) of diisopropylamine (3.44 mL, 24.5 mmol) in tetrahydrofuran (49 mL) was added n-butyl lithium (2.5 M in hexanes, 9.81 mL, 24.5 mmol) dropwise over 10 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to 0° C. and then cooled back to −78° C. A solution of Example 45B (3.3 g, 12.3 mmol) in tetrahydrofuran (10 mL) was then added. The ice bath was removed and the reaction mixture was heated at 50° C. for 2 hours. The reaction mixture was then cooled back to −78° C. and methyl iodide (0.84 mL, 13.5 mmol) was added followed by stirring for 2 hours. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was then poured into diethyl ether (200 mL) and 1M HCl (200 mL). The layers were separated and the aqueous layer was further extracted with diethyl ether (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a crude yellow oil. The crude oil was purified by flash chromatography with 15% ethyl acetate/84% hexane/1% methanol to afford the titled compound (2.37 g) as a light yellow oil. MS (CI) m/z 273 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:16].[CH3:17][O:18][CH2:19]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: Oc1c(Br)c(C(F)(F)F)cc2ccccc12
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c(Br)c(C(F)(F)F)cc2ccccc12
Yield: 91 %

Procedure:
2-Bromo-3-(trifluoromethyl)-1-naphthalenol (179) (0.23 g, 0.79 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.24 g (91%) of the title compound (180) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 5.29 (s, 2H), 7.59-7.65 (m, 1H), 7.65-7.71 (m, 1H), 7.91 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 8.22 (d, J=8.4 Hz, 1H). LCMS (ESI): m/z 335 (M+H)+.