Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: O=C(O)Cc1ccccc1F
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccccc1F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-fluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.46-7.49 (m, 1H), 7.35 (tdd, J=7.7, 5.7, 1.9 Hz, 1H), 7.18-7.23 (m, 2H), 3.81-3.84 (m, 5H), 3.44-3.59 (m, 1H), 3.05-3.14 (m, 4H); MS (ESI+) M/Z 383 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[O:8]1[CH2:11][CH2:10][C:9]1=[O:12]>C1COCC1.II>[OH:8][CH2:11][CH2:10][C:9]1([OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: O=C1CCO1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.2 %

Procedure:
1,4-dibromobutane (10 g, 46.3 mmol) in THF (100 mL) was treated with magnesium (2.81 g, 116 mmol) and I2 (100 mg) as initiator. The mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise oxetan-2-one (3.34 g, 46.3 mmol) in THF (25 mL). The reaction was stirred at room temperature for 12 hours, quenched with saturated NH4Cl, and the mixture was extracted with isopropanol/CH2Cl2 (1:3) (2×100 mL). The organic layers were combined and dried over MgSO4, filtered and concentrated. The residue was purified by distillation at 95-100° C. (0.6 torr) to provide the title compound (1.1 g, 18%) MS (DCI/NH3) m/z 148 (M+NH4)+.
Reaction SMILES: [C:1]([S:3][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[N:7]([CH3:9])[CH:8]=1)#N.CI.C[O-].[Na+]>CO>[CH3:13][O:12][C:10]([C:6]1[N:7]([CH3:9])[CH:8]=[C:4]([S:3][CH3:1])[CH:5]=1)=[O:11]
Reactant: COC(=O)c1cc(SC#N)cn1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1cc(SC)cn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
4-Cyanothio-2-methoxycarbonyl-1-methylpyrrole (2.8 g, 14.3 mmol) is dissolved in 50 ml of methanol under nitrogen. Methyliodide (1.25 ml, 20 mmol) is added followed by 1.08 g (20 mmole) of sodium methoxide. After stirring for about 30 minutes at room temperature, the reaction mixture is concentrated to a paste and then diluted with 100 ml of ethylether. The resulting precipitate is filtered off and the filtrate concentrated to give an oil which is distilled at 100° to 104° at 0.25 mm-Hg to afford 2.2 g (86%) of 2-methoxycarbonyl-4-methylthio-1-methylpyrrole.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH:29]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[C:22]3[CH2:23][CH:24]([CH2:26]O)[O:25][C:21]=3[CH:20]=2)=[O:18])=[N:12]1.CCN(S(F)(F)[F:47])CC>C(Cl)Cl>[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH:29]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[C:22]3[CH2:23][CH:24]([CH2:26][F:47])[O:25][C:21]=3[CH:20]=2)=[O:18])=[N:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(CO)C3)n1
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(CF)C3)n1
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A solution of 2,4,6-collidine (0.0311 mL, 0.235 mmol) and 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (200) (50 mg, 0.11 mmol) in CH2Cl2 (3 mL) was cooled to −15° C. DAST (0.0307 mL, 0.235 mmol) was added drop wise. The mixture was stirred at −15° C. to room temperature overnight, then quenched with MeOH at 0° C., concentrated, and purified by column chromatography eluting with 25-75% EtOAc in hexanes to give a white solid (9 mg, 18% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H) 7.78-8.03 (m, 2 H) 7.20-7.34 (m, 2 H) 7.02-7.20 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 5.01-5.19 (m, 1 H) 4.42-4.78 (m, 2 H) 3.79 (s, 3H) 3.25 (dd, J=16.55, 9.73 Hz, 1 H) 3.08 (s, 3 H) 2.99-3.06 (m, 1 H); LCMS for C21H20FN3O5S m/z 446.00 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:5]([O:17][CH2:18][CH3:19])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](B(CC)CC)[CH3:27]>CN(C=O)C.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>[CH:12]1([C:10](=[O:11])[CH2:9][CH2:8][C:6]2[C:5]([O:17][CH2:18][CH3:19])=[CH:4][N:3]=[C:2]([CH2:26][CH3:27])[CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCB(CC)CC
Reactant: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(CC)cc1CCC(=O)C1CCCC1
Temperature: 150 °C
Yield: 67.6 %

Procedure:
A solution of 3-(2-chloro-5-ethoxy-pyridin-4-yl)-1-cyclopentyl-propan-1-one (1.2 g, 4.3 mmol) dissolved in DMF (10 mL) was treated with potassium carbonate (0.88 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol), and triethylborane (4.5 mL, 4.5 mmol). The reaction was heated to 150° C. for 2 hours. The reaction was quenched with 1 N HCl and then made basic with 2 N NaOH. The mixture was extracted with ether and the organic layers were dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the product (0.8 g, 68%). 1H NMR (300 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3 H), 1.42 (t, J=6.9 Hz, 3 H), 1.55–1.87 (m, 8 H), 2.73 (m, 4 H), 2.86 (m, 3 H), 4.11 (q, J=6.9 Hz, 2 H), 6.93 (s, 1 H), 8.06 (s, 1 H).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C1(O)C=CC=CC=1.[H-].[Na+].F[C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[C:20]=1[C:21]#[N:22]>O1CCCC1.CS(C)=O>[O:1]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=2[F:34])[C:20]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1Nc1c(F)cccc1F
Reactant: [O-]c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: N#Cc1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Temperature: 110 °C

Procedure:
Sodium phenoxide was generated by dissolving phenol (0.25 g, 2.7 mmol) in dry tetrahydrofuran (5 mL), and adding sodium hydride (0.065 g, 2.7 mmol). After gas evolution ceased, the solvent was evaporated and 2-fluoro-6-(2,6-difluorophenylamino)benzonitrile (0.335 g, 1.35 mmol) dissolved in dimethyl sulfoxide (5 mL) was added. The mixture was heated to 110° C. while stirring under argon. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine(1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–40% CH2Cl2 in hexane to give the title compound as a white amorphous solid. mp 150–153° C.
Reaction SMILES: C[C@H]1O[C@H]2O[C@H]3[C@H](O[C@@]2(O)C(=[O:5])C1)[C@@H](NC)[C@@H](O)[C@@H](NC)[C@@H]3O.[CH:24]1[C:30]([F:31])=[C:29](N)[NH:28][C:26](=[O:27])[N:25]=1>>[CH:29]1[NH:28][C:26](=[O:27])[NH:25][C:24](=[O:5])[C:30]=1[F:31]
Reactant: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Reactant: Nc1[nH]c(=O)ncc1F
Product: O=c1[nH]cc(F)c(=O)[nH]1
Reaction time: 72 h

Procedure:
Bifidobacterium longum/pAV001-HU-eCD obtained in Reference Example 1 was inoculated into 5 mL of MRS medium containing the antibiotic spectinomycin and 50 μg/mL of 5-FC, followed by anaerobic culture at 37° C. for 72 hours. Then, 1 mL of the culture medium was similarly inoculated into 9 mL of MRS medium containing the antibiotic spectinomycin and 50 μg/mL of 5-FC, and cultured for 24 hours under the same culture conditions. This inoculation step was repeated three rounds to produce the 5-FU-resistant Bifidobacterium longum/pAV001-HU-eCD. Next, the 5-FU-resistant growth of the produced 5-FU-resistant Bifidobacterium longum/pAV001-HU-eCD was confirmed by inoculating into MRS medium containing 20 μg/mL of 5-FU and the antibiotic spectinomycin and culturing for 24 hours under the same culture conditions as above. Then, the bacteria were suspended with glycerol and stored at −80° C. as glycerol stocks. The stored bacteria sample and wild-type Bifidobacterium longum were inoculated respectively into MRS media containing 250 μg/mL of 5-FU and the antibiotic spectinomycin and growths thereof were compared. The growth of bacteria from the stored sample was observed on the following day, indicating the maintenance of 5-FU resistance, while the wild type did not grow. Viable cell counts of the post-culture bacterial culture were determined by plate count method. The viable cell count was 2 to 3×109 CFU/mL for the bacterial culture of the stored sample, while that of the wild type was below the limit of detection (below 103 CFU/mL).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[C:9](Cl)(=[O:11])[CH3:10].[N:13]1C=CC=CC=1>>[NH2:13][C:4]1[C:5]([CH3:8])=[N:6][S:7][C:3]=1[NH:2][C:9](=[O:11])[CH3:10]
Reactant: Cc1cc(N)sn1
Reactant: c1ccncc1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)Nc1snc(C)c1N

Procedure:
Compounds 179 and 189 were synthesized as shown Scheme 7. Reaction of 5-amino-3-methylisothiazole hydrochloride with acetic chloride in pyridine followed by nitration and reduction gave an intermediate of 4-amino-5-acetamido-3-methylisothiazole. Reaction of the intermediate (1.2 eq ) with DBD under N2 afforded Compound179. Refluxing 4-nitro-5-acetamido-3-methylisothiazole in 4N HCl aq. and further reacting with DBD under N2 with refluxing yielded Compound 189.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][C@H:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:19]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(C(C)(C)C)ccc1C2
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-tert-butyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate toluene 1:1). 1.9 g (70%) of (R)-1-(7-tert-butyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].O=[C:6]([CH3:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C>[Br:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[NH:4][C:2](=[O:3])[NH:1]1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1=C(C)NC(=O)NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
A mixture of urea (2.90 g, 48 mmol), ethyl 3-oxobutanoate (5.22 g, 40 mmol), 2-bromo-4-fluorobenzaldehyde (8.12 g, 40 mmol), chlorotrimethylsilane (3.75 g, 35 mmol) and sodium iodide (4.85 g, 35 mmol) in anhydrous acetonitrile (50 mL) was stirred at 25° C. for 12 hours in the dark. The mixture was filtered and the filter cake was washed with a little acetonitrile to give the title compound as a white solid (5.72 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(Br)C1C=CC=CC=1.C(Br)CC1C=CC=CC=1.C(Br)C=CC1C=CC=CC=1.[C:28]([CH2:32][C:33]1[CH:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:36]=[C:35]([CH2:47][C:48]([O:50]C)=[O:49])[CH:34]=1)([O:30]C)=[O:29].[C:52]([CH2:56][C:57]1[CH:62]=[C:61]([O:63][CH2:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:60]=[C:59]([CH2:72][C:73]([O:75]C)=[O:74])[CH:58]=1)([O:54]C)=[O:53]>>[C:48]([CH2:47][C:35]1[CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:38]=[C:33]([CH2:32][C:28]([OH:30])=[O:29])[CH:34]=1)([OH:50])=[O:49].[C:73]([CH2:72][C:59]1[CH:60]=[C:61]([O:63][CH2:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:62]=[C:57]([CH2:56][C:52]([OH:54])=[O:53])[CH:58]=1)([OH:75])=[O:74]
Reactant: COC(=O)Cc1cc(CC(=O)OC)cc(OCCc2ccccc2)c1
Reactant: COC(=O)Cc1cc(CC(=O)OC)cc(OCc2ccccc2)c1
Agent: BrCC=Cc1ccccc1
Agent: BrCCc1ccccc1
Agent: BrCc1ccccc1
Product: O=C(O)Cc1cc(CC(=O)O)cc(OCCc2ccccc2)c1
Product: O=C(O)Cc1cc(CC(=O)O)cc(OCc2ccccc2)c1

Procedure:
When the procedure of Example 1 is followed and benzyl bromide or phenethyl bromide are used in place of cinnamylbromide in Step G, then the products prepared are 1,3-di-(carbomethoxymethyl)-5-benzyloxybenzene and 1,3-di-(carbomethoxymethyl)-5-phenethyloxybenzene. These compounds are hydrolyzed in the same manner as Example 1, Step H to obtain 1,3-di-(carboxymethyl)-5-benzyloxybenzene and 1,3-di-(carboxymethyl)-5-phenethyloxybenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:3]4[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=4[Cl:1])=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: COc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 160 °C
Yield: 34.2 %

Procedure:
A mixture of 2-chloro-4-methoxy-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 29 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(2-chloro-4-methoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (28 mg, 34%) as a white solid. Mass spectrum MH+=460.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH:23]4[CH2:27][CH2:26][O:25][CH2:24]4)=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1.CO.C(OCC)(=O)C.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(OC3CCOC3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(OC3CCOC3)ccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
A mixture of benzyl 2-methyl-3-(2-nitro-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)phenylcarbamate (0.720 g, 1.397 mmol), ammonium chloride (1.121 g, 20.95 mmol), and zinc dust (1.370 g, 20.95 mmol) in tetrahydrofuran (35 mL) and methanol (35 mL) was stirred at room temperature for 4.5 hr. The mixture was diluted with ethyl acetate (40 mL) and filtered through CELITE®. The filtrate was concentrated under vacuum, and the residue was diluted with water (40 mL), basified with saturated NaHCO3 solution, and extracted with ethyl acetate (4×40 mL). The combined extract was washed with brine (40 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.678 g, 1.396 mmol, 100% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[O:20]1[CH:24]=[C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:22]=[N:21]1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cnoc2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), 4-isooxazolylboronic acid pinacol ester (119 mg, 0.609 mmol), tripotassium phosphate (194 mg, 0.914 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (24.9 mg, 0.0305 mmol) in dioxane (2 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 62.2%) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH3:33]>CCN(C(C)C)C(C)C.O>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([N:32]([CH2:31][CH2:30][O:29][CH3:28])[CH3:33])[C:7]=3[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CNCCOC
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1cc(C(=O)O)nc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc12

Procedure:
A mixture of Example 9 (0.1 g, 0.25 mmol) and N-(2-methoxyethyl)methyl amine (34 mg, 0.38 mmol) in DIEA (1 mL) and water (0.5 mL) was stirred at 170° C. for 2 hours. The two phases were separated and the aqueous layer concentrated in vacuo. Purification by column chromatography (increasing amount of MeOH in DCM) followed by washing with Et2O afforded the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][Si](C)(C)C)=[CH:15][CH:14]=1.C(#N)C>CN(C)P(=O)(N(C)C)N(C)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C[Si](C)(C)Sc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc(CSc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
1.50 g (7.0 mmoles) of 4-nitrobenzyl bromide was added to a mixture of 1.36 g (6.3 mmoles) of 4-chlorophenylthio(trimethyl)silane, 20 ml of acetonitrile and 2.3 ml of hexamethylphosphoric triamide and the conversion was complete after stirring for 5 minutes at room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed sequentially with water (twice 10 ml), 10 ml of a 1N KOH solution and water (twice 10 ml), dried and evaporated to dryness. The solid residue was washed with heptane on a sintered glass filter and the crystals obtained were vacuum dried at room temperature to obtain 1.67 g (95% yield) of 4-chlorophenyl 4-nitrobenzyl sulfide melting at 66°-68° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]([CH:10]=[O:11])=[C:8]([CH2:12][CH3:13])[N:7]=[C:6]1[CH2:14][CH2:15][CH3:16].[CH3:22][Mg]Br>C1COCC1.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]([C:10](=[O:11])[CH3:22])=[C:8]([CH2:12][CH3:13])[N:7]=[C:6]1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1nc(CC)c(C=O)n1Cc1ccc(I)cc1F
Reactant: C[Mg]Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(C)=O)n1Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a solution of 1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (16.52 g, 41.3 mmol) in THF (100 mL) was added methylmagnesium bromide (44.0 mL of 1.4/M in toluene/THF, 61.6 mmol) over 30 minutes. The reaction mixture was stirred at room temperature for 1.5 h. It was then quenched with 100 mL of 1N aqueous HCl. The mixture was extracted with CH2Cl2, the organic solution was washed with H2O and brine, dried over MgSO4, and concentrated to a yellow oil (16.87 g). The yellow oil was dissolved in 400 mL of CH2Cl2, and Manganese(IV) oxide (70.50 g, 811 mmol) was added. The mixture was refluxed under N2 overnight. The mixture was cooled. It was then filtered through celite and washed with CH2Cl2. The CH2Cl2 solution was concentrated and chromatographed on silica gel with 50% EtOAc/hexane and 10% MeOH/CH2Cl2 to give 4.70 g of the desired product and 6.87 g of the alcohol. MS m/e 415.0, [M+H]+ ; 1H NMR (300 MHz, CDCl3): δ 0.98 (t, 3H, CH3), 1.35 (t, 3H, CH3), 1.68 (m, 2H, CH2), 2.42 (s, 3H, CH3) 2.58 (m, 2H, CH2), 2.92 (q, 2H, CH2), 5.45 (s, 2H, CH2Ar), 6.28 (t, 1H, ArH), 7.35 (d, 1H, ArH), 7.42 (d, 1H, ArH). ##STR63##
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([O-:22])=[O:21])O)=[CH:11][CH:10]=1.[Li+]>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C([O-])CC1(O)CCc2ccc(F)cc21
Agent: [Li+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a stirred, chilled (ice-methanol bath) suspension of lithium 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (0.5 g, 2.3 mmol) in dichloromethane (13.5 mL). After 15 min, the mixture was concentrated in vacuo and the resulting white solid was recrystallized from aqueous acetone to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as white crystals (0.32 g, 73%) identical to compound of Example 1i by mixed m.p., (203-205° C.) and NMR;