Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[CH2:21]O)=[C:5]([CH2:23][OH:24])[CH:4]=1.O.C(OCC)(=O)C>C1COCC1.Cl>[CH3:12][O:11][C:7]1[C:6]2[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[CH2:21][O:24][CH2:23][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c(CO)cc(OC)c(OC)c2OC)c(CO)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)COCc1cc(OC)c(OC)c(OC)c1-2
Yield: 93 %

Procedure:
A solution of (4,4′,5,6-tetramethoxybiphenyl-2,2′-diyl)dimethanol (170 mg, 0.51 mmol) in THF (2 mL), 2M HCl (2 mL) and concentrated hydrochloric acid (1 mL) was stirred under reflux for 3 hours. Water (15 mL) and ethyl acetate (15 mL) were added to the reaction mixture, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography of the residue over silica gel (20 g), eluting with hexane-ethyl acetate (4:1), yielded the title compound as a white solid (150 mg, 93%); m.p. 151-153° C.; Elemental Analysis Found: C, 68.5; H, 6.5 (C18H20O5 requires C, 68.34; H, 6.37%); NMR Spectrum δH (300 MHz, CDCl3) 7.63 (1H, d, J 8.4 Hz, 11-H), 6.98 (1H, dd, J 2.6, 8.4 Hz, 10-H), 6.96 (1H, d, J 2.6 Hz, 8-H), 6.75 (1H, s, 4-H), 4.42 (2H, m), 4.08 (2H, m), 3.94 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.65 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 55.7, 56.4, 61.2, 61.5, 68.1, 109.1, 114.2, 114.8, 126.7, 129.7, 131.1, 131.4, 136.8, 143.1, 150.9, 153.1, 159.4; νmax/cm−1 (thin film) 2963, 2936, 2858, 2839, 1612, 1491, 1456, 1332, 1243, 1150, 1104, 1052, 1006; m/z (ES) 380 (MNa2H2O+, 100%), 287 (MH+—CH2O, 100); Rf (hexane-ethyl acetate 3:1) 0.39.
Reaction SMILES: [CH3:1][N:2]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].C(OO)(=[O:22])C>>[CH3:1][N:2]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1)[S:3]([C:6]1[N+:7]([O-:22])=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CN(c1ncc(Cl)cc1Cl)S(=O)(=O)c1ccccn1
Reactant: CC(=O)OO
Product: CN(c1ncc(Cl)cc1Cl)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
Following the procedures of Example 1, N-methyl-N-(3,5-dichloro-2-pyridyl)-2-pyridinesulfonamide is oxidized with 40% peracetic acid to give the title compound, MS m/e 334.00 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)c(O)c1
Yield: 70 %

Procedure:
3-Hydroxy-4-iodobenzoic acid (12.55 g, 47.5 mmol) is dissolved in MeOH (200 mL), treated slowly drop-wise with thionyl chloride (32.3 mL, 443 mmol) at RT, then heated to reflux for 20 h. The mixture is concentrated to dryness and partitioned between CH2Cl2 (100 mL) and saturated NaHCO3 (50 mL). Not all of the residue dissolves, so the mixture is filtered and the solid is washed with a small amount of CH2Cl2 in MeOH. The original filtrate and the organic washes are combined, concentrated to dryness, dissolved in 10% MeOH/CH2Cl2 (200 mL), diluted with water (50 mL) and the layers separated. The organics are washed with saturated NaHCO3 (2×50 mL), then water (50 mL), dried (Na2SO4) and concentrated to a tan solid. This solid is triturated with CH2Cl2 (50 mL) and filtered. The two solids are combined to afford 9.4 g (70%) of methyl 3-hydroxy-4-iodobenzoate as a beige solid. HRMS (FAB) calcd for C8H7IO3+H: 278.9520, found 278.9521 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C@H:13]([OH:31])[C@@H:14]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1.CN(C1C=CC=CN=1)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C@@H:6]2[C@H:5]([C@H:13]([O:31][C:41](=[O:43])[CH3:42])[C@@H:14]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1
Reactant: CCOC(=O)[C@H](NC(=O)OCc1ccccc1)[C@@H](O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Yield: 100 %

Procedure:
A solution of ethyl (2R,3R)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-{[(benzyloxy)carbonyl]amino}-3-hydroxypropanoate (3.1 g, 7.054 mmole, obtained from Reference Example 42) in acetic anhydride (25 ml) and dry pyridine (50 ml) in the presence of dimethylaminopyridine (500 mg) was stirred at room temperature under nitrogen for 15 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride:ether:methanol=97:2:1) to give ethyl (2R,3R)-3-[(3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-(acetyloxy)-2-{[(benzyloxy)carbonyl]amino}propanoate (3.4 g, 100%) as a white amorphous solid.
Reaction SMILES: I[C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH2:35]1C[O:38][CH2:37][CH2:36]1.CCN(CC)CC.C(O)C#C>CCOC(C)=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:38][CH2:37][C:36]#[C:35][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(I)c3c2C(=O)NC3)c1
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(C#CCO)c3c2C(=O)NC3)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To an oven dried glass pressure vessel was added tert-butyl (1S,2R)-2-(7-iodo-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (25 mg, 0.043 mmol), copper(I) iodide (12.37 mg, 0.065 mmol), bis(triphenylphosphine) palladium(II)chloride (9.12 mg, 0.013 mmol), butylated hydroxytoluene (one granule), THF (866 μL), and Et3N (121 μL, 0.866 mmol). The mixture was degassed 3 min with nitrogen. Propargyl alcohol (31 μL, 0.520 mmol) was added and the vessel was capped and heated at 80° C. with stirring for 2 h and then at RT for 12 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was collected, dried with Na2SO4, and concentrated to give the title compound as a brown residue, which was used without further purification (22 mg, 101%). [M+H] calc'd for C28H35N5O4, 506; found, 506.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:11]([N:21]2[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]2)=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13]([O:15][CH3:16])=[O:14].CON(C)[C:32](=[O:34])[CH3:33]>C1COCC1>[C:32]([C:18]1[C:19]([F:20])=[C:10]([Cl:9])[C:11]([N:21]2[CH2:22][C@H:23]([CH3:28])[O:24][C@H:25]([CH3:27])[CH2:26]2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:34])[CH3:33]
Reactant: COC(=O)c1ccc(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Reactant: CON(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of LDA (3.1 eq) at −50° C. in THF was added methyl 3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoate (Intermediate 47, 1.5 g, 4.96 mmol) in anhydrous THF (10 mL) dropwise and the solution was stirred for 1 h at −50° C. N-methoxy-N-methylacetamide (1.66 g, 14.9 mmol) in THF (5 mL) was added dropwise and stirring was continued for additional 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to obtain the title compound. Yield: 800 mg, (47%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][CH:32]([F:41])[O:33][C:34]1[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:40][C:37]3[CH:38]=[N:39][C:34]([O:33][CH:32]([F:41])[F:31])=[CH:35][CH:36]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(OC(F)F)nc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(OC(F)F)nc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 14.5 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 6-(difluoromethoxy)pyridin-3-amine (Intermediate-36, 0.065 g, 0.399 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.09 (s, 2H), 7.12 (d, J=8.7 Hz, 1H), 7.30-7.46 (m, 4H), 7.66 (s, 1H), 7.90 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.59 (s, 1H), 9.79 (s, 1H), 11.20 (s, 1H); MS [M+H]+: 518.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH3:38])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([N:37]([CH2:35][CH3:36])[CH3:38])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNC
Solvent: O
Solvent: C1CCOC1
Product: CCN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.019 ml (0.22 mmol) of N-ethylmethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 63 mg (99% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]3[CH2:14][CH:15]([OH:20])[CH:16]([N:17]=[N+:18]=[N-:19])[CH:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:21](=[O:24])([O-])O.[Na+]>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1C=CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]3[CH2:14][CH:15]([O:20][CH:7]4[CH2:6][CH2:5][CH2:3][CH2:21][O:24]4)[CH:16]([N:17]=[N+:18]=[N-:19])[CH:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc2c1OC1CC(O)C(N=[N+]=[N-])C21
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1OC1CC(OC3CCCCO3)C(N=[N+]=[N-])C21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1RS, 2RS, 3aSR, 8bRS)-1-azido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-carboxylic acid methyl ester (2) (2.5 g) was dissolved in anhydrous THF (40 ml) followed-by addition of a catalytic amount of p-toluenesulfonic acid and 2,3-dihydropyrane (1.64 ml) and stirring for 16 hours at room temperature. A saturated aqueous solution of sodium hydrogencarbonate (50 ml) was added to the reaction mixture followed by extraction with ethyl acetate (150 ml, 100 ml), combining of the organic layers, washing with water (50 ml) and saturated brine (50 ml) and concentration after drying with magnesium sulfate. The resulting residue was purified with column chromatography (silica gel: ethyl acetate/cyclohexane 1/10) to obtain the target confound (3.2 g, 98%).
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:4]3[O:3][C:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:6][CH:5]=3)[N:12]=2)[CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)n2)c1
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: O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccccc4)o3)n2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
A solution of [6-(2-iodo-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (46 mg, 0.121 mmol), phenylboronic acid (30 mg, 0.246 mmol), K2CO3 (37 mg, 0.268 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) in a mixture of THF (4 ml) and water (2 ml) was stirred at 90° C. for 18 h. The cooled reaction mixture was treated with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 eluting with 30% EtOAc in cyclohexane to afford the title compound as a pale orange solid (30 mg, 75%). 1H NMR (DMSO-d6, 300 MHz): δ=9.79 (s, 1H), 8.12 (m, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.78 (m, 2H), 7.58 (m, 2H), 7.40 (t, J=7.0 Hz, 1H), 7.33 (t, J=7.0 Hz, 1H), 6.78 (d, J=5.0 Hz, 1H), 2.37 (s, 3H). (ESI+) m/z 329 (M+H)+. Retention time=2.84 mins (method 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH2:6].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>Cl.C(OCC)C>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH:5]=[CH2:6]
Reactant: C1=COCCC1
Reactant: C=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCOCC
Product: C=Cc1ccc(OC2CCCCO2)c(OC2CCCCO2)c1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To 100 g (0.73 mol) of the 3,4-dihydroxystyrene prepared in a) are added 320 g (3.8 mol) of dihydropyran and a few drops of concentated hydrochloric acid. The reaction mixture is stirred for 12 h at 40° C. The solution is then diluted with diethyl ether and poured on to ice. The organic phase is washed twice at 0° C. with 1N NaOH, dried, and treated with activated carbon. After filtration and concentration of the filtrate there is obtained a colourless viscous liquid which is chromatographed over a column of silica gel with a 4:1 mixture of hexane/ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14]Cl)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1cn(-c2cccc(Br)c2)cn1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cccnc1)c1cn(-c2cccc(Br)c2)cn1
Yield: 24.6 %

Procedure:
1-[1-(3-Bromo-phenyl)-1H-imidazol-4-yl]-2-chloro-ethanone 4 (60 mg; 0.17 mmol) was dissolved in acetone (5 mL). 3-Hydroxypyridine (22 mg; 0.23 mmol) and K2CO3 (117 mg; 0.85 mmol) were added and heated to reflux for 16 h. The mixture was partitioned between EtOAc and water. The organic phase was then washed with 2N NaOH, saturated aqueous NaCl and was dried over Na2SO4. Concentration of the organic layer afforded 15 mg (25%) of 5. HRMS (ESI+): m/z=358.1938 [M+H]
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:25]#[N:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH:24]1[C:19]2[C:20](=[C:25]([NH2:26])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc2ccccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid. 1H NMR (acetone d-6): δ 9.04 (d, 1H), 8.91 (d, 1H), 8.45 (d, 1H), 7.86 (dd, 1H), 7.53-7.62 (m, 2H), 7.35 (t, 1H), 6.65 (br, 2H). LRMS [M+H]=196.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.N[C@H:23](C1C=NC=C(Br)C=1)[C@](C1C=C(F)C=CC=1F)(O)C>>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])([CH3:23])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Product: C[C@@]1(c2cc(F)ccc2F)OC(=O)N[C@@H]1c1cncc(Br)c1

Procedure:
Prepared according to the same procedure as ((4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2S)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.52-8.46 (m, 1H), 8.29 (s, 1H), 7.66 (s, 1H), 7.19 (ddd, J=9.2, 5.9, 3.2 Hz, 1H), 7.13-7.06 (m, 1H), 7.00 (ddd, J=10.6, 9.2, 4.6 Hz, 1H), 5.15 (d, J=1.8 Hz, 1H), 1.89 (s, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: O=Cc1ccc(F)cc1
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: OC(c1ccc(F)cc1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and 4-fluorobenzaldehyde (1.64 mL, 15 mmol) using the procedure described for compound (96) (4.27 g, 100%).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][NH:11][C:10](=[O:13])[N:9]1[CH3:14])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:14][N:9]1[C@@H:8]([C:6]([OH:7])=[O:5])[CH2:12][NH:11][C:10]1=[O:13]
Reactant: CN1C(=O)NC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN1C(=O)NC[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester (94 mg) in chloroform (2 ml) was added trifluoroacetic acid (1 ml) at room temperature, and the mixture was stirred for 3 hours. This reaction solution was concentrated under reduced pressure, additional toluene (3 ml) was added thereto, and the mixture was again concentrated. To the resulting residue was added diethyl ether (0.5 ml) at room temperature, and the mixture was stirred. Next, n-hexane (2 ml) was added thereto, and the mixture was further stirred. The insoluble substance was collected by filtration, and dried under reduced pressure to give the titled compound (52 mg).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11](=[O:12])[CH:10]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:9][C:8]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:21][C:7]=2[CH2:6]1)([OH:3])=[O:2].N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1>O>[C:1]([CH2:4][N:5]1[C:11](=[O:12])[CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:8]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:21][C:7]=2[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(=O)O)C1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Solvent: O
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(=O)O)C1=O
Yield: 56 %

Procedure:
According to the procedure of Example 1(c) except substituting methyl (±)-2-(carboxymethyl)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound (0.30 g, 56%) was prepared: MS (ES) m/e 428.4 (M+H)+. Anal. Calcd for C22H25N3O6.2 H2O: C, 57.01; H, 6.31; N, 9.07; Found: C, 57.27; H, 6.24; N, 8.86.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:13]=[N:12][C:11]=2[O:25][CH2:26][CH3:27])[CH:7]=[CH:8][CH:9]=1.[OH-:29].[Na+].OO>CO>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([NH2:24])=[O:29])=[N:21][CH:22]=3)[CH:13]=[N:12][C:11]=2[O:25][CH2:26][CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CCOc1ncc(Cc2cnc(C#N)nc2)nc1-c1cccc(OC(F)F)c1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CCOc1ncc(Cc2cnc(C(N)=O)nc2)nc1-c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 5-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine-2-carbonitrile (Example 1, 100.00 mg, 0.26 mmol) in MeOH (1.3 mL) was added aq. NaOH (0.78 mL, 0.78 mmol), followed by hydrogen peroxide (0.78 mL, 0.79 mmol) The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated, and the precipitate filtered and washed with water to obtain the title compound as a white solid (70 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.91-7.84 (m, 1H), 7.81 (t, J=1.8 Hz, 1H), 7.72 (br s, 1H), 7.52 (s, 1H), 7.44-7.02 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=402.26.