Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:43][Mg]Br.Cl.C(OCC)(=O)C>C1COCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:43])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: C[Mg]Br
Reactant: Cc1cc(C(=O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(C)(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)(cyclohexyl)methanone (52 mg, 0.085 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. was added methylmagnesium bromide (3.0 M solution in THF, 25.6 mg, 0.114 mL, 0.342 mmol). The solution was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred for 1.5 hours. The solution was then poured into a mixture of 2 N hydrochloric acid (10 mL) and ethyl acetate (20 mL). The solution was stirred at room temperature for 10 minutes then the layers were separated and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organics layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 1-50% ethyl acetate in heptane) to yield the title compound (97.2%). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H) 7.68 (s, 2H) 7.33 (s, 1H) 7.17 (s, 1H) 5.39 (d, J=16.17 Hz, 1H) 4.82 (d, J=15.76 Hz, 1H) 4.77(s, 2H) 4.15(s, 3H) 2.39 (s, 3H) 1.62 (m, 6H) 1.24 (s, 3H) 1.04 (m, 5H). LC-MS calc. 623.5, found 624.6 (M+H)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:36]3[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
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: [Na+]
Product: COc1ccc(C(F)(F)F)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O

Procedure:
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Example 66, 100 mg; 0.171 mmol) was treated with [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid (Step B, 113 mg; 0.514 mmol), tetrakis(triphenylphosphine)palladium (0) (24 mg; 0.0206 mmol), and sodium carbonate (148 mg) as described in Example 291 to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass. LCMS=612.1 (M−19)+. 1H NMR (benzene-d6, 500 MHz, mixture of atropisomers): δ 7.61 (s, 1H), 7.40-7.36 (m, 1H), 7.31 (s, 1H), 7.27-7.23 (m, 4H), 6.74-6.72 (m, 1H), 6.35 (d, J=8.7 Hz, 1H), 4.42-4.32 (m, 2H), 3.70 (d, J=15.8 Hz, 1H), 3.14 (s, 3H), 2.28 (t, J=8.7 Hz, 1H), 1.98 (t, J=8.2 Hz, 1H).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH:1]=[CH2:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=C[Mg]Cl
Reactant: O=Cc1ccccc1Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1Cc1ccccc1

Procedure:
30 ml of a 1.6 molar solution of vinyl-magnesium chloride in tetrahydrofuran are introduced into 100 ml of absolute tetrahydrofuran at 0° C. 9.8 g (0.05 mole) of 2-benzylbenzaldehyde in 100 ml of absolute tetrahydrofuran are added dropwise whilst stirring and excluding moisture. The reaction mixture is stirred for 3 hours at 25° C. and is then cautiously decomposed by adding a cold saturated ammonium chloride solution and a few milliliters of 10% strength hydrochloric acid until the precipitate dissolves. The mixture is then extracted by shaking three times with ether and the combined ether phases are washed with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. 9.4 g of a yellowish oil, which is sufficiently pure for the further reactions, are obtained; nD21 =1.5855.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]I>CN(C=O)C>[CH3:28][O:26][C:25]([C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[C:11]2[CH:10]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Reactant: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The solution of 0.2 g (0.54 mmol) 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester in 2 ml DMF was cooled down to 0° C. and 26 mg (0.54 mmol; 55% dispersion in mineral oil) were added. After 15 min., 38 μl (85 mg, 0.6 mmol) methyl iodide were added and the cooling bath was removed. After 5 hours the reaction mixture was poured on water and was extracted five times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered and evaporated to give 0.19 g (93%) the compound as a light yellow oil which was pure enough for the preceding steps without further purification.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:12]([O:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11]1[C:7]([CH:8]=[N:9][NH:10]1)=[CH:6][CH:5]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]#[N:31]>CN(C=O)C>[I:1][C:2]1[C:3](=[O:21])[C:4]2[C:12]([O:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11]1[C:7]([CH:8]=[N:9][N:10]1[CH2:29][C:30]#[N:31])=[CH:6][CH:5]=2
Reactant: N#CCBr
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.1 %

Procedure:
To a solution of 7-iodo-8-phenylpyrano[3,2-g]indazol-6(1H)-one (350 mg, 0.903 mmol) in DMF (10 mL) was added potassium carbonate (415 mg, 3 mmol) and the reaction stirred at RT. After 5 minutes, bromoacetonitrile (162 mg, 1.353 mmol) was added and the reaction stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and water. The resulting biphasic mixture was separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 70% EtOAc in cyclohexane) to afford the title compound (116 mg, 30%), 1H NMR (500 MHz, CDCl3): δ 8.18 (br s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.90-7.88 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.64-7.60 (m, 3H), 5.52 (s, 2H). LCMS (Method J) RT=1.29 min, [M+H]+=428.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4](N)[CH:3]=1.C(ON=O)(C)(C)C.[Br:29]CBr>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[Br:29][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=1
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Reactant: BrCBr
Agent: CC(C)(C)ON=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of Example A2 (0.2 g, 0.71 mmol) in dibromomethane (5 mL) was treated with tetrabutylammonium bromide (0.92 g, 2.84 mmol) and t-butylnitrite (0.7 g, 7.11 mmol) and stirred at RT for 4 h. The mixture was diluted with EtOAc, washed successively with satd. NaHCO3, water, and brine, dried over Na2SO4 and concentrated to dryness to afford 2-bromo-4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine as off-white solid (0.21 g, 86%). MS (ESI) m/z: 345.1 (M+H+).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1)=[O:7])C>O.O1CCOCC1.[OH-].[Na+]>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][C:11]=2[CH:13]=1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2o1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (78 mg, 3.7 mmol) in water (6 ml) was added to a solution of 5-(trifluoromethyl)benzofuran-2-carboxylic acid ethyl ester (705 mg, 2.73 mmol) in 1,4-dioxane (6 ml). 1,4-Dioxane was added until a clear solution was obtained. The reaction mixture was stirred for 16 h at room temperature. It was diluted with an 1 N aqueous solution of sodium hydroxide and washed with tert-butyl methyl ether (2×30 ml). The aqueous solution was acidified with a 10% aqueous solution of sodium hydrogen sulphate until pH 3 was obtained. It was extracted with ethyl acetate (3×40 ml). The combined ethyl acetate layers were dried over magnesium sulphate. The solvent was removed in vacuo to give crude 5-(trifluoromethyl)benzofuran-2-carboxylic acid which was used in the next step without further purification.
Reaction SMILES: CO.C([O:5][CH:6]1[CH:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9][CH:8]([CH3:15])[CH2:7]1)=C>CC(O)C>[CH:8]1([CH3:15])[CH2:9][CH2:10][CH:11]([CH:12]([CH3:13])[CH3:14])[CH:6]([OH:5])[CH2:7]1
Reactant: C=COC1CC(C)CCC1C(C)C
Solvent: CO
Solvent: CC(C)O
Product: CC1CCC(C(C)C)C(O)C1
Reaction time: 1 h
Yield: 73 %

Procedure:
The reaction was conducted in the same manner as in Example 10 except that methanol was used in stead of the solvent 2-propanol, the reaction temperature was altered to 20° C. and the reaction time was altered to 1 hour. The obtained reaction solution was analyzed by GC, to find that 27% of the menthyl vinyl ether was left with an optical purity of 58% ee. Further, the reaction solution was purified by silica gel column chromatography to obtain the reaction product menthol in a yield of 73%. Also, the kre1 value showing the selectivity of reactions at this time was 2.5.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.O.[CH3:30][N:31](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.[C-]#N.[C-]#N.[Zn+2]>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:30]#[N:31])[C:10]=2[N:9]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of 4-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole (prepared following the same procedure as for Example 19, 300 mg, 0.69 mmol), Pd(PPh3)4 (80 mg, 0.069 mmol) and Zn(CN)2 (162 mg, 1.38 mmol) in DMF (30 mL) was stirred at 80° C. under N2 for 18 h. After cooling to rt, the mixture was poured into water and filtered. The filter cake was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the product (180 mg, 68%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 2.44 (s, 3H), 3.07 (t, 4H, J=4.5 Hz), 3.68 (t, 4H, J=4.5 Hz), 6.04 (s, 2H), 6.32 (d, 1H, J=7.2 Hz), 7.31-7.40 (m, 3H), 7.60-7.71 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.2 Hz), 8.22 (d, 1H, J=8.4 Hz); LC-MS: m/e=383 [M+1]−
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:26])=[S:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35](=O)[CH3:36].C([O-])(=O)C.[Na+].O>C(O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:34]=[C:35]([CH3:36])[N:26]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Reactant: CC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)cs3)cc12
Yield: 72 %

Procedure:
A suspension of tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.46 g, 1 mmol), bromoacetone (0.20 g, 1.5 mmol) and sodium acetate (0.12 g, 1.5 mmol) in ethanol (10 ml) was refluxed under heating for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 73.5%) as an amorphous.
Reaction SMILES: [CH2:1]([N:4]([CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:27]C)[CH2:18]1)[CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)[CH2:2][CH3:3].Cl.N1C=CC=CC=1.[NH4+].[OH-]>O>[CH2:1]([N:4]([C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[OH:27])[CH2:18]1)[CH2:5][CH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC1OC(=O)c2ccccc21)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCN(CC[C@@H]1OC(=O)c2ccccc21)[C@@H]1CCc2c(O)cccc2C1

Procedure:
The product of Example 35 and excess pyridine hydrochloride were heated in an oil bath at 200° C. for 1 hr. The reaction was cooled, diluted with H2O, basified with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silica: 6:4 pet ether/EtOAc) and the product [upper isomer by TLC (Silica: 1:1 pet ether/EtOAc) showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.9-6.6(m, 7H), 5.7(dd, 1H), 0.9(t, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH:12]([OH:30])[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[S:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[N:24]=2)[CH:14]=1)[C:3]([O:5]CC[Si](C)(C)C)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]([CH3:31])([CH:12]([OH:30])[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[S:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[N:24]=2)[CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C(=O)OCC[Si](C)(C)C)C(O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)C(O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reaction time: 2 h
Yield: 51.4 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-hydroxy-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate (0.11 g, 0.24 mmol) was dissolved in tetrahydrofuran (2 ml), and 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (0.58 ml, 0.58 mmol) was added thereto. The reaction mixture was stirred for 2 hrs and concentrated under reduced pressure. Trifluoroacetic acid (1.5 ml) was added to the residue, and the mixture was stirred at room temperature for 13 hrs. Diisopropyl ether was added to the mixture. The precipitated solid was collected by filtration and recrystallized from ethanol-hexane to give the titled compound (0.044 g, 51%) as white crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:37])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[C:7]=1[C:8]([F:11])([F:10])[F:9].[F:26][C:27]1[CH:32]=[C:31]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)[CH:30]=[CH:29][C:28]=1[OH:38]>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:6]3[C:7]([C:8]([F:9])([F:10])[F:11])=[C:3]([CH2:2][O:38][C:28]4[CH:29]=[CH:30][C:31]([N:33]5[CH:37]=[N:36][N:35]=[N:34]5)=[CH:32][C:27]=4[F:26])[CH:4]=[N:5]3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: Oc1ccc(-n2cnnn2)cc1F
Reactant: CCc1cnc(N2CCC(n3ncc(CCl)c3C(F)(F)F)CC2)nc1
Product: CCc1cnc(N2CCC(n3ncc(COc4ccc(-n5cnnn5)cc4F)c3C(F)(F)F)CC2)nc1

Procedure:
The title compound was synthesized using 2-(4-(4-(chloromethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-ethylpyrimidine and 2-fluoro-4-(1H-tetrazol-1-yl)phenol in manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.95 (1H, s), 8.18 (2H, s), 7.64 (1H, s), 7.52 (1H, m), 7.43 (1H, m), 7.19 (1H, m), 5.16 (2H, s), 4.92 (2H, m), 4.50 (1H, m), 3.02 (2H, m), 2.47 (2H, q), 2.22 (2H, m), 2.01 (2H, m), 1.19 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A suspension of N-(2-methyl-4-nitrophenyl)benzamide (0.256 g, 1.0 mmol) and tin (II) chloride dihydrate (0.89 g, 3.96 mmol) in ethyl acetate (6 mL) was heated at 70° C. for 19 hr. The reaction mixture was then chilled, poured onto 50 mL ice, basified with 5% NaHCO3 (20 mL), extracted into EtOAc, washed with brine, dried and concentrated in vacuo to give N-(4-amino-2-methylphenyl)-benzamide (0.22 g, 97%). ES-MS (M+H)+=227, (M+Na)+=249.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](Cl)(Cl)=[O:11].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]2[NH:1][C:10](=[O:11])[S:9][C:3]2=[N:4][CH:5]=1
Reactant: Nc1cc(Cl)cnc1S
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)cnc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
3-Amino-5-chloro-2-mercaptopyridine (18.8 g) was added to an ice-cooled solution of phosgene (30 g) in toluene (350 ml). 10% Aqueous solution of sodium hydroxide (300 ml) was added dropwise to the stirred mixtured for a period of 1 hour below 20° C. The final mixture was stirred for 1.5 hous at ambient temperature and then stirred for an additional 1 hour at 50° C. After cooling, the aqueous layer was adjusted to pH 4.0 with 4N hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give white powder of 6-chloro-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (15.08 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23]I)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:37]=[N+:38]=[N-:39].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:37]([CH2:23][C@@H:19]1[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:25]\[O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH:11]=2)[C:21](=[O:22])[NH:20]1)=[N+:38]=[N-:39]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CI)cs1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN=[N+]=[N-])cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(iodomethyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (24.0 g, 37.6 mmol) in THF (200 mL) at 0° C. was added TEA (10.5 mL, 75.2 mmol) followed by tetrabutylammonium azide (13.9 g, 48.9 mmol). The mixture was allowed to warm to rt and stirred for an additional 16 h, whereupon it was poured into ice-water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography, affording the title compound (17.0 g, 82%) as a pale yellow solid. LCMS: m/z=551.0 (M−1). 1H NMR data was an identical match to that described in WO2012073138(A1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 75.4 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (176 mg, 0.9 mmol) was treated with 60% NaH in oil (108 mg, 2.7 mmol) and tert-butyl bromoacetate (199.7 uL, 1.35 mmol) as above to yield 210 mg of a yellow solid. ES-MS calcd for C14H19N3O5 (m/e) 309.32, obsd 310.2 (M+H).