Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH:30]([NH2:34])[CH2:31][CH2:32][CH3:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([NH:34][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH2:32][CH3:33])=[O:22])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCC(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.27 g of N-(tert-butoxycarbonyl)aspartic acid-4-benzyl ester (manufactured by PEPTIDE INSTITUTE, INC.) and 2.1 mL of 1-phenylbutyl amine were dissolved in 40 mL of DMF, and then 2.70 g of WSC hydrochloride and 1.93 g of HOBt were added thereto, and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried with magnesium sulfate, and then distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 3.94 g of Compound 1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34]C)=O)[CH:28]=[CH:29][CH:30]=1.[NH2:36][C:37]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:38]=1[C:39](OC)=[O:40]>C1COCC1.CO>[Cl:47][C:45]1[CH:46]=[C:37]2[C:38]([C:39]([OH:40])=[C:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH:26]=3)[C:32](=[O:34])[NH:36]2)=[CH:43][CH:44]=1
Reactant: COC(=O)Cc1cccc(Oc2ccccn2)c1
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1cccc(Oc2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
Potassium bis(trimethylsilyl)amide in toluene (0.5M, 10.8 ml, 5.4 mmol) was added dropwise to a solution of methyl [3-(2-pyridyloxy)phenyl]acetate (0.52 g, 2.14 mmol) and methyl 2-amino-4-chlorobenzoate (0.43 g, 2.32 mmol) in dry THF (30 ml). The reaction mixture was stirred at room temperature for 3 hours then methanol (10 ml) was added. The solution was concentrated in vacuo, the residue was dissolved in 0.5M sodium hydroxide (25 ml) and washed with diethyl ether (2×25 ml). The aqueous phase was acidified with 5M hydrochloric acid. The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a pale cream solid (0.463 g, 59%). A further recrystallisation from propan-2-ol gave analytically pure material; m.p. 269°-271° C. (from propan-2-ol) (Found: C, 65.92; H, 3.71; N, 7.59. C20H13ClN2O3 requires C, 65.85; H, 3.71; N, 7.68%); δH (360 MHz, DMSO-d6) 7.03-7.14 (4H, m, ArH), 7.23 (1H, dt, J 2, 8.5 Hz, ArH), 7.32 (1H, d, J 2 Hz, ArH), 7.43 (1H, t, J 8 Hz, 5'-H), 7.85 (1H, m, ArH), 7.94 (1H, d, J 8.7 Hz, 5-H), 8.18 (1H, dd, J 5, Hz, 6"-H), 10.46 (1H, br s, OH), 11.55 (1H, br s, NH); m/z 364 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C([Li])CCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:19][C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=[CH:11][N:12]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc(-n2cncn2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncnc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.3 %

Procedure:
Under an atmosphere of nitrogen a solution of 1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (15.7 g, 86.7 mmol) in THF (300 mL) at −78° C. was treated with n-butyllithium (38 mL, 2.5 M, 95.3 mmol) dropwise. After stirring for 1.5 h a solution of hexachloroethane (22.6 g, 95.3 mmol) in THF (30 mL) was added dropwise. The resultant reaction mixture was stirred for 1.5 h before allowing to warm to RT and quenching with water. The resultant mixture was diluted with water and extracted with ethyl acetate, the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give an oil which crystallised on standing. The solid was recrystallised from cyclohexane to give 5-Chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (12.4 g, 66%). 1H NMR δ (ppm) (CDCl3): 8.04 (1H, s), 7.51-7.43 (1H, m), 7.10-7.04 (2H, m).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH:8]=[CH:7][CH2:6][CH2:5][C@H:4]1[C:9]([OH:11])=[O:10].[CH3:12][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO.C1C=CC=CC=1>[ClH:1].[CH3:12][O:10][C:9]([CH:4]1[CH2:5][CH2:6][CH:7]=[CH:8][CH:3]1[NH2:2])=[O:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N[C@H]1C=CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C1CCC=CC1N
Temperature: 0 °C
Reaction time: 6 h

Procedure:
cis-2-Amino-cyclohex-3-enecarboxylic acid hydrochloride (0.5 g, 2.8 mmol) was dissolved in a mixture of methanol (12 mL) and benzene (12 mL) at 25° C., cooled to 0° C., a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (4.2 mL, 8.4 mmol) was added slowly, and, after removing the ice-bath, the reaction mixture was stirred at 25° C. for 6 h. The reaction mixture was concentrated in vacuo, to afford the desired crude product, 2-amino-cyclohex-3-enecarboxylic acid methyl ester hydrochloride, which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)[CH2:10][N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][S:36]([CH2:39][C:40]#[N:41])(=[O:38])=[O:37])=[O:34])=[C:29]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:28]=2)=[CH:23][CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-:56].[K+].[K+].OO.Cl>CS(C)=O>[NH2:41][C:40](=[O:56])[CH2:39][S:36]([NH:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][N:11]([CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:26][CH:25]=2)=[CH:28][C:29]=1[O:42][CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)=[O:34])(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CC#N)c(OC3CCCCC3)c2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CC(N)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of tert-butyl [(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl][2-[4′-[[[(cyanomethyl)sulfonyl]amino]carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl]carbamate (52.9 mg) in dimethyl sulfoxide (1.0 ml) was added potassium carbonate (28.3 mg), 30% aq. hydrogen peroxide solution (100 μl) at 0° C. After stirring for 16 hours at room temperature, 1N hydrochloric acid was added to the reaction mixture. The products were extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=95/5) to give tert-butyl [2-[4′-[[[(2-amino-2-oxoethyl)sulfonyl]amino]-carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]-carbamate (30.0 mg).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[C:10]([OH:12])=O)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.Cl.[C:34]([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)([CH3:37])([CH3:36])[CH3:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:34]([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:10](=[O:12])[CH:9]([CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]2[C:1]1=[O:32])[CH2:13][CH2:14][CH2:15][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C(CCCN1C(=O)c2ccccc2C1=O)CCCN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(CCCN1C(=O)c2ccccc2C1=O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 245 %

Procedure:
Bis(3-phthalimidopropyl)acetic acid (Step B) (2.5 g, 5.5 mmol), proline tert-butyl ester hydrochloride (0.42 g, 2.0 mmol), and N-methylmorpholine (1.19 g, 5.4 mmol) in 7 mL of DMF are cooled to 0° C. and treated with TBTU (0.64 g, 2.0 mmol). The mixture is then stirred at room temperature for 18 hours. The reaction mixture is poured into 70 mL of saturated sodium bicarbonate solution and extracted with two 50 mL portions of ethyl acetate. The combined organics are washed with 1 M KHSO4, saturated aqueous bicarbonate and brine, and dried over Na2SO4. The volatiles are removed under reduced pressure and the residue is chromatographed over silica gel (4:1 chloroform, ethyl acetate eluent) to give 2.88 g of 1-[Bis(3-phthalimidopropyl)acetyl]-proline tert-butyl ester.
Reaction SMILES: O[C@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[N:47]([C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=C(N2CCC3(CCN(C[C@@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To a suspension of 8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 7, 300 mg, 0.68 mmol) and diphenylphosphoryl azide (578 mg, 1.36 mmol) in a mixed solvent of toluene and dichloromethane (v:v, 10:1, 11 mL) was added DBU (310 mg, 1.36 mmol). The reaction mixture was stirred at 35° C. for 20 h. The solvent was removed by evaporation and the residue was purified by flash column chromatography (0-100% ethyl acetate in petroleum ether gradient) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 5.18 (s, 2H), 4.94 (dd, J=4.0 Hz, 9.2 Hz, 1H), 3.94 (t, J=6.8 Hz, 2H), 2.88-2.85 (m, 2H), 2.72-2.67 (m, 1H), 2.54-2.50 (m, 1H), 2.42-2.39 (m, 1H), 2.33-2.27 (m, 4H), 2.04 (t, J=6.8 Hz, 2H), 1.95 (s, 3H), 1.94-1.87 (m, 2H), 1.51-1.47 (m, 2H); MS-ESI (m/z): 466 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[CH:24])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].C(OCCNC(=O)OC(C)(C)C)C#C.Br[C:40]1[CH:41]=[N:42][CH:43]=[N:44][CH:45]=1.BrC1C=NC=CC=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:40]2[CH:41]=[N:42][CH:43]=[N:44][CH:45]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2]
Reactant: C#CCOCCn1c(COCC)nc2c1c(C)c(C)n1nnnc21
Reactant: Brc1cncnc1
Agent: C#CCOCCNC(=O)OC(C)(C)C
Solvent: Brc1cccnc1
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1cncnc1

Procedure:
The method described in Part B of Example 81 was followed. 8-Ethoxymethyl-5,6-dimethyl-7-(2-prop-2-ynyloxyethyl)-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine (5.5 g, 17 mmol) was used as the starting material in lieu of tert-butyl 2-(prop-2-ynyloxy)ethylcarbamate, and 5-bromopyrimidine was used in lieu of 3-bromopyridine. The crude product was purified by column chromatography on silica gel (620 g, eluting with 98:2 dichloromethane:methanol), and the resulting solid was mixed with 2-propanol (150 mL). Insoluble impurities were removed by filtration, and the solution was concentrated to a volume of 20 mL. The product crystallized and was isolated by filtration and washed with 2-propanol and diethyl ether to provide 6.10 g of 8-ethoxymethyl-5,6-dimethyl-7-[2-(3-pyrimidin-5-ylprop-2-ynyloxy)ethyl]-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine as white crystals.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-n2cncn2)c(F)c1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4cncn4)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.25 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: COCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: COCCOc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)ccc2F)c(F)c1
Yield: 50 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 189 as a white solid (19 mg, 50%). 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.26 (dd, J=8.6, 3.9 Hz, 1H), 8.19-8.09 (m, 1H), 7.95 (s, 1H), 7.03 (d, J=10.5 Hz, 2H), 4.95 (dd, J=8.3, 3.6 Hz, 1H), 4.69 (s, 1H), 4.57 (s, 1H), 4.24 (t, J=4.2 Hz, 2H), 3.98-3.78 (m, 2H), 3.73 (s, 3H), 3.70 (t, J=4.2 Hz, 2H), 3.30 (s, 3H), 3.15 (m, 1H), 2.20-2.11 (m, 1H), 1.89-1.72 (m, 2H), 1.72-1.62 (m, 1H), 1.59-1.50 (m, 1H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Si](C)(C)C)=[C:13]([F:21])[CH:12]=2)[N:8]=[C:7]([C:22]([O:24][CH3:25])=[O:23])[C:6]=1[Cl:26])(=[O:3])[CH3:2].[Br:27]Br.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:27])=[C:13]([F:21])[CH:12]=2)[N:8]=[C:7]([C:22]([O:24][CH3:25])=[O:23])[C:6]=1[Cl:26])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2)cc(NC(C)=O)c1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2)cc(NC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a 100-mL round bottom flask, equipped with a stir bar was added methyl 4-acetamido-3-chloro-6-(3-fluoro-4-(trimethylsilyl)phenyl)picolinate (433 mg, 1.11 mmol), dichloromethane (10 mL) and bromine (0.225 mL, 4.39 mmol). The reaction was allowed to stir at room temperature for 18 hrs. The reaction was then poured into 1 N Na2SO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in Hexanes) to afford the title compound as a light tan solid (0.440 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.71 (s, 1H), 7.98-7.81 (m, 2H), 7.74 (dd, J=8.4, 2.1 Hz, 1H), 3.94 (s, 3H), 2.23 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −107.44; ESIMS m/z 402 [(M+H)+].
Reaction SMILES: C[O-].[K+].C[O:5][C:6](=[O:20])[CH:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CO>[C:12]([O:11][C:9](=[O:10])[CH2:8][CH:7]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:6]([OH:20])=[O:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Potassium methoxide (0.15 g, 2.04 mmol) in methanol (3 mL) was added dropwise to a stirring solution of 2 (0.49 g, 2.04 mmol) in methanol (5 mL) at 0° C. After 10 minutes, the mixture was partitioned between ether (100 mL) and water (50 mL). The ether layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane/ether, 98:2) to give the nitro-alkene 3 (0.21 g, 57%) as a pale yellow oil; Rf (heptane/ethyl acetate, 8:2) 0.54; vmax(film)/cm−1 1643 (C═C), 1509 (NO2), 1342 (NO2); δH (400 MHz; CDCl3): 7.12 (1H, quint, J=2.0, CHNO2), 3.01 (1H, ddt, J=20.5, 8.0, 2.1), 2.90 (1H, ddt, J=20.5, 7.3, 2.1), 2.54 (1H, ddt, J=17.8, 7.1, 2.0), 2.43 (1H, ddt, J17.7, 5.6, 1.9), 2.21 (1H, m), 2.12 (1H, m), 1.60–1:24 (8H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:24][CH3:25])[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][C:14]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>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>[CH2:24]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=3)=[C:14]([CH3:26])[CH:15]=2)[O:23][CH2:22][CH2:21][O:20]1)[CH3:25]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCC1(c2ccc(Br)c(C)c2)OCCO1
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+]
Product: CCC1(c2ccc(-c3cccc(C=O)c3)c(C)c2)OCCO1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 6.6 g (44 mmol) of 3-formylbenzeneboronic acid and 10 g (37 mmol) of 2-(4-bromo-3-methylphenyl)-2-ethyl-[1,3]dioxolane with 45 mL of 2.0M potassium carbonate and 2.14 g of tetrakis(triphenylphosphine)palladium, the desired product is obtained in the form of a thick oil (m=9.1 g; Y=84%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Br[CH2:20][CH2:21][F:22].O>CN(C=O)C>[F:22][CH2:21][CH2:20][O:18][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccnc1-c1cccc(O)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1-c1cccc(OCCF)c1
Reaction time: 2 h
Yield: 45.3 %

Procedure:
Sodium hydride 60% (0.021 g, 0.925 mmol) was added to a solution containing 3-(3-nitropyridin-2-yl)phenol (0.2 g, 0.925 mmol) and 1-Bromo-2-fluoroethane (0.138 ml, 1.850 mmol) in DMF (Volume: 3.08 ml). The reaction was stirred for 2 hours. Diluted reaction with water and extracted with ethyl acetate. Combined organics, dried, filtered, and purified by ISCO column using 35% ethyl acetate in hexanes to afford 2-(3-(2-fluoroethoxy)phenyl)-3-nitropyridine (0.11 g, 0.419 mmol, 45.3% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[CH:5]2.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:22]([O:21][C:17]([CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[CH:5]2)=[O:20])[CH3:23]
Reactant: Brc1ccc2c(ccn2-c2cccnc2)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc2c(ccn2-c2cccnc2)c1

Procedure:
A solution of 0.75 g of 5-bromo-N-(3-pyridyl)indole and 0.5 g of ethyl acrylate in 20 ml of triethylamine is refluxed for 48 hours with 10.8 mg of palladium acetate and 30 mg of tri-o-tolylphosphine. The reaction mixture is cooled, evaporated and chromatographed on 20 g of silica gel with diethyl ether to yield 5-(2-ethoxycarbonylethenyl)-N-(3-pyridyl)indole. Saponification by refluxing for 15 hours in 30 ml of ethanol with 5 ml of 2N sodium hydroxide yields a solution which is evaporated to dryness. The residue is partitioned between 20 ml of ether and 10 ml of water. The aqueous phase is separated, brought to pH 5 and the resulting solid is filtered to yield 5-(2-carboxyethenyl)-N-(3-pyridyl)indole which melts with decomposition at 180°.
Reaction SMILES: [CH2:1]1[S:5](=O)[CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:8][CH2:9][CH3:10].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:41][C:42]([F:57])([S:53]([O-:56])(=[O:55])=[O:54])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46].[K+]>ClCCl.C(OCC)C.O>[F:57][C:42]([F:41])([S:53]([O-:56])(=[O:55])=[O:54])[C:43]([F:51])([F:52])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46].[CH2:7]([O:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[S+:5]1[CH2:4][CH2:3][CH2:2][CH2:1]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc2ccccc2c1
Reactant: O=S1CCCC1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCCCOc1ccc2ccccc2c1[S+]1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Next, 2.9 g (0.05 mol) of tetramethylene sulfoxide was added to 5.0 g (0.025 mol) of the 2-n-butoxynaphthalene and 15 g of Eaton's reagent (Aldrich), followed by 24 hours of stirring at room temperature. 200 g of water and 50 g of diethyl ether were added to the reaction mixture for separation into two layers. To the aqueous layer, 8.5 g (0.025 mol) of potassium perfluorobutanesulfonate and 100 g of dichloromethane were added, followed by one hour of stirring at room temperature. The organic layer separated was washed three times with 50 g of water, after which the solvent was evaporated off on a rotary evaporator. The oily matter was recrystallized from ethyl acetate, filtered and dried. There was obtained 13.8 g of the end compound, 2-n-butoxy-1-naphthyltetrahydrothiophenium perfluorobutanesulfonate (yield 94%).