Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.ClCCl.[CH3:31][NH:32][C:33]([NH2:35])=[O:34].N1C=CC=CC=1>FC1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:35][C:33]([NH:32][CH3:31])=[O:34])=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)O)cc1Cl
Reactant: CNC(N)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Fc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)C(OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A cooled (0° C) solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid (Example 6; 100 mg, 0.30 mmol) in fluorobenzene (2.5 mL) and N ,N-dimethylfor m namide (1.8 μL). was treated with a 2.0 M solution of oxalyl chloride in dichloromethane (0.18 mL, 0.36 mmol). Immediately a vigorous gas evolution was observed, and the mixture was stirred at 25° C. for 1 h and became light yellow in color. Methyl urea (97 mg, 0.90 mmol) was then added and after the reaction was heated at 70° C. for 10 min, pyridine (0.048 mL, 0.60 mmol) was added and the reaction was maintained at 70° C. for 1 h. The cooled mixture was diluted with ethyl acetate (5 mL) then was filtered through Celite to remove insoluble materials and the filtrate concentrated in vacuo. The concentrate was washed with 3N hydrochloric acid (1×20 mL), saturated sodium bicarbonate (1×15 mL) and brine (1×15 mL), then was dried over sodium sulfate, filtered and evaporated under reduced pressure. The product was purified by chromatography (Biotage Flash 40S column, 50/50 hexanes/ethyl acetate) to provide rac-1-[(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetyl]-3-methyl-urea (78 mg, 67% yield) as a white foam: FAB-HRMS m/e calculated for C16H21N2O5SCl (M+H)+389.0938, found 389.0943.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C1([Li])C=CC=CC=1.C1CCCCC1.[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.CCOCC>[C:29]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([OH:28])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccncc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: OC(Cc1ccncc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A flame-dried, 12-L flask equipped with a mechanical stirrer, thermometer, and dropping funnel was charged under argon with 252.5 g of 4-picoline and 2.50 L of tetrahydrofuran. The solution was cooled in an ice bath to below 20° and maintained at 15°-20° during the addition over 15 minutes, of 1.315 L of 1.85M phenyllithium in 70:30 cyclohexane:ether solution. The mixture was stirred at 15°-20° for 30 minutes and then cooled to -5°-0° in an acetone-ice bath. The temperature was maintained in this range during the rapid addition of a solution of 494.2 g of benzophenone in 1.50 L tetrahydrofuran. A bright blue color persisted after the addition of just a little of the benzophenone solution. The cooling bath was removed and the mixture was stirred at ambient temperature for 3 hours. To the flask was added 1.0 L of deionized water and 2.0 L of tetrahydrofuran. The mixture was warm gently on a steam bath to dissolve all the solids. The aqueous phase was separated and extracted with 2.0 L of tetrahydrofuran. The combined organic solutions were dried over sodium sulfate and stripped of solvent on a rotary evaporator at 45°. The resulting solid was triturated at reflux with 1.60 L of hexanes. The suspension was stored at 4° overnight and filtered. The solids were washed with a total of 1.0 L of boiling point 35°-60° petroleum ether and dried in a forced air oven at 75° to give 699.6 g (94% yield) of alpha,alpha-diphenyl-4-pyridineethanol as a pale-yellow solid, mp 154°-155°.
Reaction SMILES: [I:1][C:2](=[CH2:5])[CH2:3][OH:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>ClCCl>[C:14]([Si:11]([O:4][CH2:3][C:2]([I:1])=[CH2:5])([CH3:13])[CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(I)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C(I)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2-iodoprop-2-en-1-ol (24 g, 130.4 mmol) in dry dichloromethane (500 mL) was cooled to 0° C. Imidazole (17.75 g, 260.9 mmol) was added in several portions, and the mixture was stirred for 10 minutes. Tert-butyldimethylsilyl chloride (29.49 g, 195.9 mmol) was added in several portions at 0° C., and the reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water (100 mL), and the organic phase was separated. The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (water bath temperature <25° C.). The residue was purified by column chromatography using 100% petroleum ether as eluent to afford tert-butyl((2-iodoallyl)oxy)dimethylsilane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:4]([F:22])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:4]=1[F:22])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 124.5 %

Procedure:
To a stirred solution of 1-bromo4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzene (549.4 mg, 1.468 mmol) in DMSO (6 mL) and MeOH (5 mL) was added Et3 N (448 ul, 3.229 mmol), Pd(OAc)2 (36.2 mg, 0.161 mmol), and 1,3-bis(diphenylphosphino)propane (66.4 mg, 0.161 mmol). To the mixture was induced CO gas for 10 min. The resulting mixture was stirred at 70° C. for 2 days under a current of CO. After the mixture was concentrated, the residue was diluted with EtOAc. The solution was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel eluting with n-hexane:EtOAc (5:1, v/v) as eluent to afford 323.0 mg (62%) methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzoate as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.87 (br s, 1H), 1.95–2.10 (m, 3H), 3.34–3.44 (br m, 2H), 3.89 (s, 3H), 3.94 and 4.11–4.26 (br m each, 3H), 7.03–7.11 (m, 1H), 7.75–7.80 (m, 2H); MS (FAB) m/z 354 M++1).
Reaction SMILES: [CH:1]([S:4][C:5]1[C:6](/[CH:11]=[N:12]/[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]([S:4][C:5]1[C:6]([CH:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][NH:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC/N=C/c1ncccc1SC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCNC1c1ncccc1SC(C)C
Reaction time: 3 h

Procedure:
To 65C (10 mmol) in CH2Cl2 (100 mL) at −15° C. was added Et3N (1.4 mL, 10 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 20 mL, 20 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (100 mL) at 0° C. and stirred at rt for 1.0 h. Methylene chloride was removed under vacuum and the crude was diluted with EtOAc. The mixture was filtered through a pad of wet Celite®, extracted with EtOAc (3×40 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(3-(isopropylthio)pyridin-2-yl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:3 ratio. LC-MS 295 (M+H). To the above ethyl 2-(3-(isopropylthio)pyridin-2-yl)pyrrolidine-3-carboxylate in THF (10 mL) was added Et3N (1.4 mL) and di-tert-butyl dicarbonate (1.0 M in THF, 10 mL, 10 mmol). The mixture was stirred at rt over night before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (gradient ethyl acetate in hexanes) to provide a major product trans 65D (1.8 g, 45% yield) and a minor product cis 65E (900 mg still contaminated with 65D, 20% yield). 65D: 1H NMR (400 MHz, CDCl3) δ ppm two rotomers: 1.07-1.16 (m, 6H) 1.25 (t, J=6.81 Hz, 3H) 1.30 and 1.39 (s, 9 H) 2.12-2.20 (m, 1H) 2.22-2.32 (m, 1H) 2.93-3.04 (m, 1H) 3.32-3.44 (m, 1H) 3.60-3.70 (m, 1H) 3.73-3.83 (m, 1H) 4.17 (q, J=7.18 Hz, 2H) 5.61 and 5.75 (d, J=3.95 Hz, 1H) 7.11 (dd, J=7.47, 4.83 Hz, 1H) 7.62 (d, J=7.91 Hz, 1H) 8.38 (d, J=3.52 Hz, 1H); LC-MS 395 (M+H). 65E: 1H NMR (400 MHz, CDCl3) δ ppm two rotomers: 0.93 (t, J=6.81 Hz, 3H) 1.12-1.33 (m, 15H) 2.48-2.58 (m, 1H) 3.35-4.12 (m, 6H) 5.67 and 5.88 (d, J=7.91 Hz, 1H) 7.08 (dd, J=7.47, 4.39 Hz, 1H) 7.53-7.65 (m, 1H) 8.36 (d, J=3.08 Hz, 1H). LC-MS 395 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[NH:25][C:26](=[N:29][C:30]([O:32][C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:31])[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1.[OH-].[Na+].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:23])[C:24]4[N:25]=[C:26]([NH:29][C:30]([O:32][C:33]([CH2:36][CH3:37])([CH3:34])[CH3:35])=[O:31])[S:27][CH:28]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Reaction time: 0.17 h

Procedure:
To a solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.36 g.) in methanol (35 ml.) was added 1N sodium hydroxide aqueous solution (5.5 ml.) under ice-cooling, and to the mixture was dropwise added an aqueous solution of sodium borohydride (91 mg.) in water (2.5 ml.) over 2 minutes at 10° to 15° C. The mixture was stirred for 10 minutes at the same temperature, and the methanol was distilled off from the mixture below 40° C. under reduced pressure. The remaining aqueous solution was washed with a small amount of ethyl acetate, adjusted to pH 5 to 6, with 10% hydrochloric acid, further washed with a small amount of ethyl acetate. The solution was adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then treated with an activated charcoal. The solvent was distilled off from the extract till the volume of the extract became a smaller amount. The precipitates were collected by filtration, washed with a small amount of ethyl acetate, and then dried to give 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (1.69 g.). On the other hand, the mother liquor and the ethyl acetate washing were combined together and concentrated under reduced pressure, and then the precipitates were similarly treated as aforementioned to give the same object compound (0.80 g.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: COCc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COCc1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of 2.800 g of 4-(4-methoxymethyl-phenyl)-1-trityl-1H-imidazole in 50 ml of TFA is stirred at room temperature for 3 hours. The reaction mixture is concentrated, taken up into ethyl acetate and the organic phase washed with sat. NaHCO3-solution and brine and dried over Na2SO4. Evaporation of the solvent gives a residue which is purified by flash chromatography on silica (40-63 μm particle size) with dichloromethane/methanol 93:7, yielding 1.169 g of 4-(4-methoxymethyl-phenyl)-1H-imidazole as a beige powder. Rt=2.906 min by HPLC on a nucleosil C18HD column with acetonitril+0.05% TFA/water+0.05% TFA, 20/80 to 100/0 over 6 min, 1.0 ml/min solvent flow. MS (API-ES, pos. scan): e/m=189 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20](O)=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:6][CH:5]=2.Cl.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]([NH:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([OH:25])=[O:35])=[CH:28][CH:29]=2)=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)O
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)NCc1ccc(C(=O)O)cc1

Procedure:
Same procedure as Example 82 except (2-Methyl-5-trifluoromethanesulfonylamino-indol-1-yl)-acetic acid and methyl-4-(aminomethyl)benzoate hydrochloride was used. 1H-NMR (400 MHz, DMSO-d6) δ 12. 84 (s, 1H, COOH), 11.45 (s, 1H, SNH), 8.75 (t, J=6.4 Hz, 1H, NHCO), 7.89 (d, J=8.6 Hz, 2H, ArH), 7.3 (m, 4H, ArH, H-7, & H-4), 6.93 9dd, J=2, 8.5 Hz, 1H, H-6), 6.27 (s, 1H, H-3), 4.86 (s, 2H, CH2N-2), 4.37 (d, J=6.6 Hz, 2H, NCH2Ar), 2.35 (s, 3H, CH3), MS m/z 468 (M−H).
Reaction SMILES: [F:1][CH:2]([F:28])[S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH:19]C(=O)C3C=CC=CC=3)[CH2:17][OH:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[NH2:19][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH:2]([F:28])[F:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH2:17][OH:18]
Reactant: O=C(NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 5.14 g of N-[1-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]-2-hydroxyethyl]benzamide, 9.5 mL of sodium hydroxide solution (1.54 g, 38.5 mmol in 9.5 mL water), and 36 mL of ethanol was boiled for ~40 h. The mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in water, and the aqueous mixture was extracted with 3×70 mL of ethyl acetate. The combined extracts were dried and the solvent was removed under reduced pressure. The white solid obtained was washed with a little ether to give the product 2.69 g (70% yield); m.p. 107.5-110.5° C. IR(Nujol): 3333, 3281, 1597 1313, 1073, 1042, 895, 820 cm-1. 1H-NMR(CDCl3): δ3.56-3.63 (m, 1H), 3.76-3.81 (m, 1H), 4.09-4.13 (m, 1H), 6.86 (t, J=57.0 Hz, 1H), 7.41-7.65 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](O)([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[CH:15]=2)[C:6]1=[O:25].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClC(Cl)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[CH:15]=2)[C:6]1=[O:25]
Reactant: COc1c(C)cc(C2(O)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: COc1c(C)cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Temperature: 50 °C
Yield: 77.5 %

Procedure:
Dissolve 1-(2-chloro-benzyl)-3-hydroxy-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (430 mg, 1.05 mmol) in dichloroethane (15 mL) and treat with triethylsilane (0.503 mL, 3.15 mmol) and boron trifluoride diethyl etherate (0.038 mL, 0.3 mmol) under nitrogen. Heat at 50° C. for 24 h. Add more triethyl silane (0.250 mL, 1.57 mmol) and boron trifluoride diethyl etherate (0.030 mL, 0.24 mmol) and continue for 6 h. at which time reaction complete. Concentrate in vacuo and purify by flash chromatography (gradient of 5% EtOAc/hexanes to 25% EtOAc/hexanes) to obtain 319 mg (78%) of the title compound as a white solid. MS (ES): m/z=392 (M+1), 390 (M−1); 1H NMR(DMSO-d6): δ7.54 (m, 1H), 7.36-7.29 (m, 2H), 7.25 (t, J=7.9, 7.6 Hz, 1H), 7.18-7.13 (m, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.85 (s, 2H), 5.02 (s, 2H), 4.90 (s, 1H), 3.65 (s, 3H), 2.20 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1[NH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2>O1CCOCC1>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]1[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: c1ccc2c[nH]cc2c1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(c1)CN(CCc1c[nH]c3ccccc13)C2

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.48 g, 20 mmol) and isoindole (4.76 g, 40 mmol) in abs. dioxane (50 ml) was stirred at 80° C. for 6 h. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCOCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
36.6 g (170 mmol) of pyridinium chlorochromate are placed at room temperature in 120 ml of dichloromethane under N2, and a solution of 20.4 g (113 mmol) of 4-benzyloxybutanol in 20 ml of dichloromethane is added. The reaction mixture rapidly becomes dark and the reaction is slightly exothermic. The reaction mixture is stirred at room temperature for 31/2 hours. The supernatant dichloromethane phase is decanted off and concentrated by evaporation in a rotary evaporator. The residue is filtered over 100 g of silica gel. The product fractions are concentrated by evaporation in a rotary evaporator and distilled under a high vacuum over a 10 cm Vigreux column. 4-benzyloxybutanal is obtained, b.p.0.1 =72°-73°.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:41])=[C:10]([CH:40]=2)[C@@H:11]([C:28]2[C:37]([CH3:38])=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][C:29]=2[CH3:39])[O:12]C(=O)[C@@H](NS(C2C=CC(C)=CC=2)(=O)=O)C)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C)C=O>[OH:12][C@H:11]([C:28]1[C:29]([CH3:39])=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][C:37]=1[CH3:38])[C:10]1[CH:40]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:41]
Reactant: COC(=O)c1cc(C)c([C@@H](OC(=O)[C@H](C)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)cc1[C@H](O)c1c(C)cc(C(=O)O)cc1C

Procedure:
The compound obtained in Example 7 was treated in the same manner as in Example 2 to give 10.5 g of (S)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 -261.5° (c=1.0, dimethylformamide).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@:4](C1C=CC(Br)=CC=1)([NH:6][C:7]([C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH3:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:7]([NH:6][C@@H:4]([CH2:5][C:12]2[CH:17]=[CH:16][C:15]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:14][CH:13]=2)[C:3]([OH:2])=[O:26])=[O:8])[N:10]=1
Reactant: COC(=O)[C@@](C)(NC(=O)c1cc2ccccc2cn1)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C[C@H](NC(=O)c3cc4ccccc4cn3)C(=O)O)cc2)cc1
Yield: 164.1 %

Procedure:
3-(4-Bromo-phenyl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.24 mmol) prepared as in example 2 was reacted with 4-methoxyphenyl boronic acid (76 mg, 0.5 mmol) as described in general procedure D yielding the title compound (84 mg, 82%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[F:7][C:8]([F:36])([F:35])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:6])[C:30](=[O:32])[CH2:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:8]([F:7])([F:36])[F:35])=[N:10][N:11]=4)[N:14]=3)[CH2:19][CH2:20]2)=[CH:34][CH:33]=1
Reactant: O=C(O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CNCCOC
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: COCCN(C)C(=O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
N-(2-methoxyethyl)methylamine (25 mg, 0.28 mmol) was added to 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (100 mg, 0.24 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (0.124 mL, 0.71 mmol) in DMF (2 mL). The resulting solution was stirred at ambient temperature for 3 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give N-(2-methoxyethyl)-N-methyl-2-[4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetamide (26 mg, 22%).