Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>>[Cl:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:66][CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccc(Cl)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(Cl)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with 4-chloroaniline (Fluka) (0.054 g, 0.43 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-chloro-phenyl)-amide as a off white solid (Yield 95 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25]>C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]32[O:25][CH2:24][CH2:23][O:11]3)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)C1(CC2)OCCO1

Procedure:
A mixture of Example 3 (13.0 g, 61.8 mmol), p-toluenesulfonic acid (23 mg, 0.12 mmol) and ethylene glycol (27.6 mL, 494.6 mmol) in benzene (140 mL) was heated to reflux for about 24 hours, using a Dean-Stark trap to separate the forming water. The mixture was cooled, poured into excess 5% aqueous sodium bicarbonate and was extracted with toluene. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to provide the desired product. MS (DCI-NH3): m/z 254, 256 (M)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38]([OH:40])=O)[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1.[NH2:42][C:43]1[CH:44]=[C:45]2[CH:51]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[N:49]([CH2:56][CH2:57][OH:58])[C:46]2=[CH:47][N:48]=1.C(N(CC)CC)C>CN(C=O)C>[C:52]([C:50]1[N:49]([CH2:56][CH2:57][OH:58])[C:46]2=[CH:47][N:48]=[C:43]([NH:42][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:25])([F:41])[O:27][C:28]=5[CH:34]=4)[CH2:36][CH2:37]3)=[O:40])[CH:44]=[C:45]2[CH:51]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2cc(N)ncc2n1CCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2n1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (38 mg, 0.10 mmol) was added to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (24 mg, 0.10 mmol), 2-(5-amino-2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (23 mg, 0.10 mmol) and triethylamine (42 μL, 0.30 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and purified by reverse-phase HPLC (10-99% CH3CN—H2O with 0.035% TFA) to yield N-(2-tert-butyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 457.2, found 458.5 (M+1)+. Retention time 1.77 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (br s, 1H), 8.84 (s, 1H), 7.83 (s, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 6.67 (s, 1H), 4.58 (t, J=5.7 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 1.58 (m, 2H), 1.46 (s, 9H), 1.28 (m, 2H).
Reaction SMILES: [O-:1]O.[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:3]([O:22][OH:1])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: [O-]O
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OO
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Measurement of Enzymatic Activity. The activity of the immobilized lipoxygenase was assayed by measurement of hydroperoxide formation (Parra-Diaz, D. et al. [1993] supra). An aliquot of the substrate (5 μmoles of linoleic acid) dissolved in methylene chloride was placed in a 10 mL flask and evaporated to dryness under a stream of nitrogen. The reaction medium containing 0.2 mL of 100 mM deoxychlorate (DOC) and 1.8 mL of sodium borate buffer (0.2 M, pH 9.0) was added to the substrate, and the mixture was then shaken at 250 rpm for 0.5 h at 15° C. The reaction was initiated by adding a suitable amount (approximately 0.15 mg) free or immobilized LOX. Oxidation was conducted at 15° C. with agitation at 250 rpm for two hours. The reaction was quenched by adding 400 μL of 1 M citric add. Linoleic acid hydroperoxide was isolated by extracting the reaction mixture twice with 2 mL chloroform:methanol (2/1, v/v). After removing the solvent under a stream of nitrogen, the hydroperoxide was redissolved in 3 mL ethanol. The amount of hydroperoxide was determined spectrophotometrically by the xylenol orange method (Jiang, T.-Y. et al. [1991] Lipids 26:853-856). Standards were prepared by diluting a commercial cumene peroxide. All results were corrected by subtracting the reading from controls without enzymes. All measurements were in triplicate.
Reaction SMILES: [OH-:1].[Li+].[C:3]([C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=3)[C:23]#N)=[O:17])=[CH:14][CH:13]=2)=[C:8]([CH2:30][CH2:31][CH3:32])[C:7]=1[OH:33])(=[O:5])[CH3:4].[OH2:34]>O1CCOCC1.CCOCC>[C:3]([C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=3)[C:23]([OH:34])=[O:1])=[O:17])=[CH:14][CH:13]=2)=[C:8]([CH2:30][CH2:31][CH3:32])[C:7]=1[OH:33])(=[O:5])[CH3:4]
Reactant: O
Reactant: [OH-]
Reactant: CCCc1c(OCc2ccc(C(=O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: [Li+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCc1c(OCc2ccc(C(=O)c3cncc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 50 %

Procedure:
Add lithium hydroxide (289 mg, 12.06 mmol) to a solution of 5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile (500 mg, 1.21 mmol) in dioxane (10 mL) and water (10 mL) and stir. Heat solution to reflux. After 1 hour cool to ambient temperature, add water (100 mL) and wash with ethyl acetate. Acidify with 10% aqueous hydrochloric acid (15 mL), and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify residue by sonicating in ether for 1 hour. Filter the resulting precipitate to yield the title compound as a beige solid (262 mg, 50%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.48 (sextet, 2H), 2.54 (s, 3H), 2.59 (t, 2H), 5.38 (s, 2H), 6.70 (d, 1H), 7.62 (d, 2H), 7.79 (d, 1H), 7.84 (d, 2H), 8.42 (s, 1H), 9.05 (s, 1H), 9.24 (s, 1H), 12.82 (s, 1H), 13.72 (bs, 1H); MS (esi negative) m/z (rel intensity) 432 (100).
Reaction SMILES: [F:1][C:2]1[C:25]([OH:26])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.C(O)(=O)C>C(O)C.O.[Zn]>[F:1][C:2]1[C:25]([OH:26])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)c(O)cc2[nH]1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: NC1c2ccccc2-c2c(-c3nc4cc(F)c(O)cc4[nH]3)cccc21

Procedure:
The procedure used in stage 4 of Example 216 is followed. In a 30 ml round-bottomed flask under an argon atmosphere, dissolve 667 mg of equimolecular mixture of 4-(5-fluoro-6-hydroxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 3.5 ml of ethanol and 3.5 ml of water and 3.5 ml of acetic acid; at room temperature, add 500 mg of zinc in three stages. Between each addition, stir for approximately one hour to two hours. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (9/1 then 85/15 by volume), in this way we obtain 456 mg of 4-(5-fluoro-6-hydroxy-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][CH:8]([Cl:22])[C:9]([O:11][N:12]=[C:13]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14](O)=[O:15])=[O:10]>C(Cl)Cl>[Cl:7][CH:8]([Cl:22])[C:9]([O:11][N:12]=[C:13]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14]([Cl:2])=[O:15])=[O:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cccs1
Solvent: ClCCl
Product: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1

Procedure:
Phosphorus pentachloride (27.2 g.) was added portionwise during ca. 20 minutes to a stirred and cooled (ice-bath) suspension of 2-dichloroacetoxyimino-2-(thien-2-yl)acetic acid (syn-isomer) (37.0 g.) in methylene chloride (370 ml.). The mixture was stirred at 0° for a further 30 minutes during which time all the solid dissolved. After removal of the solvent under reduced pressure, benzene was evaporated from the residue at 20°, and the process repeated to give 2-dichloroacetoxyimino-2-(thien-2-yl)acetyl chloride (syn-isomer) as an oil that was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O.[Cl:25][C:26](Cl)(Cl)[C:27]([F:30])([F:29])[F:28].C(OC(=O)C)(=O)C>[Zn].CN(C)C=O>[Cl:24][C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:17]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11]/[CH:12]=[C:26](\[Cl:25])/[C:27]([F:30])([F:29])[F:28]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: O=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: FC(F)(F)/C(Cl)=C/COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14 %

Procedure:
To a mixture of 1.21 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde, 0.57 g of zinc dust and 10 ml of N,N-dimethylformamide was added 0.82 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1.5 hours, 0.44 g of acetic anhydride was added. The reaction mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was poured into 20 ml of diluted hydrochloric acid and extracted twice with 50 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.21 g of (Z)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(5-(3-chloro-4,4,4-trifluoro-2-butenyloxy)pentyloxy)benzene [the integrated CF3 signal ratio of Z/E=94/6 as determined by 19F-NMR (CDCl3 /CFCl3)] (yield, 14%), nD26.5 1.5123.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:7]2.C(N(CC)CC)C>C(OCC)C>[O:4]=[C:1]([N:8]1[CH2:9][CH:10]2[CH2:13][CH2:14][CH:6]([CH2:12][CH2:11]2)[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C1CC2CCC1CNC2
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of acryloyl chloride (4.05 ml, 0.05 mole) in 50 ml of ethyl ether was added with stirring to a cold mixture of 3-azabicyclo[3.2.2]nonane (6.26 g, 0.05 mole) and triethylamine (15.3 ml, 0.11 mole) in 250 ml of ethyl ether. The ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 72 hours. The resulting white material was filtered and washed well with ethyl ether and ethyl acetate. The solvent was removed on a rotary evaporator and the residue taken up in ethyl ether, hexane added and the solution chilled. The remaining small amount of insoluble material was filtered and the solvent evaporated, leaving the product as an oil. The structure was confirmed by NMR.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+].Cl>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (6, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 nth). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 N HCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].[OH-].[Na+]>O>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:1][OH:2])[C:5]=1[OH:11]
Reactant: C=O
Reactant: Cc1ccc(O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(O)c(CO)c1
Temperature: 50 °C

Procedure:
A 38% solution of formaldehyde (32.0 grams, 0.4 mol) was added to a stirred solution of 2,4-dimethylphenol (36.6 grams, 0.3 mol) in water (100 ml) containing sodium hydroxide (14 gr., 0.35 mol) and heated at 50° C. for 4 to 5 hours. The reaction was cooled and solid sodium hydroxide added to precipitate the salt of the product. The solid was removed by filtration and dissolved in water. This solution was neutralized with carbon dioxide (dry ice) and the resulting mixture was extracted with methylene chloride. The organic layer was removed, dried, and evaporated to yield a light brown solid. This solid was washed in hexane containing a small amount of toluene to afford a tan solid. The NMR1 and FD/MS2 data support the structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>O>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=3)=[CH:19][C:18]1=2
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(CC#N)c(F)c3)cc21

Procedure:
Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T. Alessi A. H. P. U.S. Pat. No.: 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A grey solid; mp 253-256° C. 1HNMR(DMSO-d6) −δ10.35 (s,1H) 7.67-7.49 (m,5H), 6.97 (d,1H;J=8.6 Hz) 4.09 (s,2H) 1.67 (s, 6H); MS [M−H]− m/z 309. Anal. Calc. For C18H15N2FO2. 0.15 H2O: C,69.07, H, 4.93, N, 8.95. Found C,69.27, H 5.05, N, 8.50
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17](=O)C1)(=O)C1C=CC=CC=1.P(Cl)(OCC)(OCC)=O.[N+:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[C-]>C1COCC1>[CH3:1][C:2]1([CH3:5])[NH:15][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]2[CH:17]=[N:35][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:3]12
Reactant: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)(C)Nc1ccccc1-2
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (1M, 4.54 ml) is added to 1,2,3,4-tetrahydro-3,3-dimethylquinoxalin-2-one (IV, EXAMPLE 2, 0.762 g) in THF (4 ml) at ice/saline temperature. The reaction is stirred for 40 min, at which time diethyl chlorophosphate (0.656 ml) is added. After stirring at ice-saline temperature for 2 hr, ethyl isocyanoacetate (0.562 g) is added, followed by potassium t-butoxide (1M, 4.97 ml). The reaction is stirred for 3.5 hr, allowing it to slowly warm to 20°-25°. The reaction is then quenched with several drops of acetic acid and then partitioned between ethyl acetate, aqueous sodium bicarbonate and saline. The phases are separated and the organic phase is dried over magnesium sulfate, concentrated, and the resulting crude product chromatographed on silica gel (200 ml) eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the title compound, mp 145°-149°; NMR (CDCl3) 1.44, 1.74, 3.79, 4.40, 6.77, 6.82, 7.10, and 7.39 δ.
Reaction SMILES: Br.[OH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:13])[CH:10]=2)[N:5]1C(OCC1C=CC=CC=1)=O.[CH2:24](Cl)Cl.[CH3:27][OH:28]>C(O)(=O)C.C(N(CC)CC)C>[C:27]([O:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:13])[CH:10]=2)[NH:5]1)(=[O:28])[CH3:24]
Reactant: CO
Reactant: O=C(OCc1ccccc1)N1c2ccc(I)cc2CC1CO
Reactant: ClCCl
Agent: Br
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC1Cc2cc(I)ccc2N1
Yield: 84 %

Procedure:
A 30% wt solution containing HBr in acetic acid (25 mL) is added to a flask containing benzyl 2-(hydroxymethyl)-5-iodo-1-indolinecarboxylate (Preparation 8, 6.03 g). All of the solids are dissolved and the solution is concentrated to give a brown solid. The crude product is taken into CH2Cl2 with a small amount of methanol and triethylamine and purified by column chromatography eluting with heptane (250 mL), 20% EtOAc in heptane (500 mL), and 40% EtOAc in heptane to give 3.92 g (84%) of the title compound as a red solid. Physical characteristics: M.p. 64-66° C.; HRMS (FAB) m/z 318.0006 (C11H12INO2+H). Anal. Found: C, 41.91; H, 3.85; N, 4.35.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH:13](O)=O.[OH-].[NH4+]>O>[CH3:12][C:3]1[C:2]2[NH:1][CH:13]=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=CO
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-6-nitrotoluene (11.81 g), formic acid (88%, 390 mL) and 12N HCI (38 mL) is heated to reflux for 1 hour. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with water (200 mL), then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×200 mL). The combined extracts are dried over magnesium sulfate (MgSO4) and evaporated to afford 4-methyl-5-nitrobenzimidazole as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23]COC)=[CH:18][C:17]=3[CH3:27])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31].CS(O)(=O)=O>C(OCC)(=O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:17]([CH3:27])=[CH:18][C:19]([OH:23])=[CH:20][C:21]=3[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: COCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Yield: 9.4 %

Procedure:
3-[2-Fluoro-4-({[4′-(methoxymethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenyl]propanoic acid (1.0 g, 2.29 mmol) was dissolved in ethyl acetate (2 mL) and diethyl ether (4 mL). To this solution was added methanesulfonic acid (0.16 mL, 2.47 mmol) and the solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (85 mg, yield 9%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH:14]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24])([CH2:16][CH3:17])[CH3:15].C(N(CC)CC)C>O1CCCC1.O>[CH:14]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:11]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8])=[O:12])([CH2:16][CH3:17])[CH3:15]
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Reactant: CCC(C)[C@@H]1CCCC[C@H]1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)[C@@H]1CCCC[C@H]1NC(=O)c1sc(C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
At 0° C., 3.4 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic chloride is dripped into a solution of 2.3 g of trans-2-sec.-butylcyclohexylamine and 1.5 g of triethylamine in 15 ml of tetrahydrofuran, and the mixture is stirred for 2 hours at 25° C. The batch is diluted with 300 ml of water, extracted twice with tert-butyl methyl ether and dried, the solvent is evaporated off, and the residue is made into a paste with a small amount of pentane. There is isolated 2.3 g of 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid-trans-2-sec-butylcyclohexylamide of m.p. 112°-113° C.