Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:26][CH:25]3[O:27][CH:22]([CH:23]([CH2:28][OH:29])[O:24]3)[CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[OH:29][CH2:28][C@H:23]1[C@H:22]2[O:27][C@H:25]([CH2:26][N:20]([S:17]([C:4]3[S:3][CH:2]=[C:6]([C:7]4[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=4[CH3:16])[CH:5]=3)(=[O:18])=[O:19])[CH2:21]2)[O:24]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC4OC(CO)C(C3)O4)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3C[C@@H]4O[C@@H](CO)[C@H](C3)O4)c2)s1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
N-{5-[2-Bromo-5-(7-hydroxymethyl-6,8-dioxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (450 mg; 0.86 mmol; 1 eq), is dissolved in anhydrous THF (45 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (3.4 ml; 1.6 M; 6.86 mmol; 8 eq) is added dropwise. The reaction is stirred 1 hour and it is quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (37) as a white-off solid (74.1 mg; 15%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH2:24][CH2:25][OH:26])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([S:22][CH3:23])[CH:20]=2)[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH2:24][CH:25]=[O:26])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([S:22][CH3:23])[CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CSc1ccc2c(c1)C(C)(CCO)CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSc1ccc2c(c1)C(C)(CC=O)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a chilled (−60° C.) solution of 0.31 mL (3.5 mmol) of oxalyl chloride in 5 μL of methylene chloride was added a solution of 0.5 mL (7 mmol) of DMSO in 2.5 mL of dichloromethane. After 10 minutes, a solution of 0.42 g (1.76 mmol) of 2-(4-methyl-6-methylsulfanylchroman-4-yl)ethanol in 2.5 mL of dichloromethane was added. The mixture stirred for 15 minutes and then 1.5 mL (10.6 mmol) of triethylamine was added. The reaction was warmed at room temperature for 30 minutes and then concentrated in vacuo. The residue was diluted with water and extracted with diethyl ether. The combined organic fractions were washed with four portions of water, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.4 g (94%) of (4-methyl-6-methylsulfanylchroman-4-yl)acetaldehyde as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=1)[CH2:28][CH:29]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=[O:37].C(OCC)(=O)C>C1COCC1.O>[OH:37][C:30]1([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:29]1[CH2:28][C:27]1[CH:38]=[CH:39][CH:40]=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1cccc(CC2CCCCCCC2=O)c1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CC2CCCCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 4,5-diphenyloxazole (2.1 g) in THF (30 ml) at −78° C. under N2 was added butyllithium (1.6M in hexane, 6.7 ml). After 30 minutes, a solution of 2-(3-methoxybenzyl)cyclooctanone (2.4 g) in THF (10 ml) was added thereto and stirred for 1 hour at the same temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(hydroxy)-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclooctane (3.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH2:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=1)=[O:9])([O-:3])=[O:2]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2ccccc2[nH]1)c1cccc([N+](=O)[O-])c1
Reaction time: 6 h
Yield: 83.2 %

Procedure:
A 200 mL flask was charged with 2.25 g 3-nitrobenzoic acid (13.46 mmol, 1.0 equiv), 3.59 g 2-aminobenzimidazole (26.92 mmol, 2.0 equiv), 5.63 g O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 14.81 mmol, 1.10 equiv), and 1-hydroxybenzotriazole hydrate (HOBT, 14.13 mmol, 1.05 equiv). The flask was then charged with 40 mL DMF, stirring was initiated (magnetic stirrer) and 1.71 mL N-methylmorpholine (NMM, 15.48 mmol, 1.15 equiv) was added in one portion to the suspension. After 6 h, the suspension was diluted with 200 mL of a 10% citric acid solution. After stirring an additional 30 min, the suspension was filtered and the resulting solid was washed (2×H2O, then 2×sat. NaHCO3). The solid was then triturated with EtOAc (30 mL), filtered, and dried under reduced pressure to give 3.16 g of the product as a tan solid (11.2 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 12.60 (broad s, 2H), 8.96 (t, J=2.1 Hz, 1H), 8.55 (d, J=7.8 Hz, 1H), 8.38 (m, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.43 (dd, J=3.2, 5.9 Hz, 2H), 7.18 (dd, J=3.2, 5.9 Hz, 2H); MS: ESI(−) m/z 281.1 (M−H).
Reaction SMILES: CO.C(O[CH2:7]/[CH:8]=[CH:9]/[CH2:10][O:11][CH:12]([CH3:14])[CH3:13])(C)C.[CH3:15][CH:16]([OH:18])[CH3:17]>>[CH:12]([O:11][CH2:10][CH2:9][C:8]([O:18][CH:16]([CH3:17])[CH3:15])=[CH2:7])([CH3:13])[CH3:14]
Reactant: CC(C)O
Reactant: CC(C)OC/C=C/COC(C)C
Solvent: CO
Product: C=C(CCOC(C)C)OC(C)C

Procedure:
A reaction was carried out using the catalyst and according to the procedure described in example 6, except that the methanol was replaced with an equivalent amount of 2-propanol (30 ml). 1.8 mmol of 1,3-diisopropoxy-3-butene and 9.7 mmol of cis + trans 1,4-diisopropoxy-2-butene were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(C#N)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-hydroxy-benzonitrile and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 342(MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][C:22]1([O:25][CH2:24]1)[CH3:23]>CN(C=O)C>[CH3:21][C:22]([OH:25])([CH3:24])[CH2:23][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a 20 mL pressure vial was charged pyrazole-4-boronic acid pinacol ester (5.15 mmol, 1.00 g), DMF (10 mL), and Cs2CO3 (5.67 mmol, 1.85 g). To this suspension was added isobutylene oxide (15.45 mmol, 1.38 mL). The vial was flushed with argon and sealed. The reaction was stirred 18 hours at 80° C. After 18 hours, the reaction was filtered through celite and the solvent removed in vacuo. This residue was pumped dry under high vacuum and then purified via flash chromatography to yield the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[CH:3]=1.C(N(CC)CC)C.[CH:17]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.P([O-])([O-])([O-])=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.CN1CCCC1=O>[CH:17]1([S:22][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(I)cc(I)c1
Reactant: SC1CCCC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc(I)cc(SC2CCCC2)c1
Reaction time: 1 h

Procedure:
A mixture of 1,3-diiodo-5-methylbenzene (2.00 g), tris(dibenzylideneacetone)dipalladium (0) (20 mg), bis(diphenylphosphino)ferrocene (22 mg), triethylamine (1.5 ml) and 1-methyl-2-pyrrolidinone (3 ml) were stirred at to 20° under nitrogen for 1 h. Cyclopentanethiol (0.15 ml) was added and the mixture was heated to 60° for 18 h. The mixtue was cooled to 20° and was treated with phosphate buffer solution (pH 6.5) and water. The mixture was extracted with EtOAc and the extract dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by Flashmaster™ chromatography (silica, 70 g). Elution with cyclohexane gave the title compound (444 mg). LCMS RT=4.21 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][C:16](=[O:21])[CH2:15][CH2:14][C:13]=4[CH:12]=3)[S:10][C:6]=2[C:5]([C:22]([NH2:24])=[O:23])=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH:16]([OH:21])[CH2:15][CH2:14][C:13]=4[CH:12]=3)[S:10][C:6]=2[C:5]([C:22]([NH2:24])=[O:23])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2cc(-c3ccc4c(c3)CCC(=O)C4)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cnc(N)c2cc(-c3ccc4c(c3)CCC(O)C4)sc12
Reaction time: 1.25 h

Procedure:
To a suspension of 4-amino-2-(6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-thieno[3,2-c]pyridine-7-carboxylic acid amide 89 (24.5 mg, 0.07 mmol) in absolute ethanol (4 mL) was added sodium borohydride (11.5 mg, 0.30 mmol). After 1.25 h at room temperature, the reaction mixture was concentrated, partially dissolved in a mixture of DMSO and MeOH, and filtered. The filtrate was purified by reverse phase preparative HPLC to give 90. 1H NMR (400 MHz, d6-DMSO) δ: 1.63–1.74 (m, 1H), 1.87–1.96 (m, 1H), 2.57–2.68 (m, 1H), 2.73–2.81 (m, 1H), 2.90–3.02 (m, 2H), 3.93–4.01 (m, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.44–7.48 (m, 2H), 7.70–7.83 (br s, 1H), 8.26 (s, 2H), 8.41 (s, 1H), 8.63–8.83 (br s, 2H). MS (EI) m/z (M+H+) 340, (2M+H+) 679.
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:36][C:37](=[O:45])[C@:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([C:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:36][C:37](=[O:45])[C@:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH2:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1Br)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)ccc1NC(=O)[C@@](C)(O)C(F)(F)F
Reaction time: 7 h

Procedure:
Tributylvinyltin (0.28 ml) was added to a deoxygenated suspension of (R)-N-[2-bromo-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 140) (0.50 g) and tris(dibenzylideneacetone)dipalladium(0) (0.05 g) in anhydrous toluene (10 ml). The mixture was heated under reflux with stirring. After 14 hours a further portion of tris(dibenzylideneacetone)dipalladium(0) (0.05 g) and tributylvinyltin (0.28 ml) was added and heating was continued for a further 7 hours. The reaction mixture was allowed to cool and volatile materials were removed by evaporation. The residue was purified on a silica gel Mega Bond Elut column eluting with 5-50% ethyl acetate/hexane to give the title compound (0.146 g) as a solid. NMR (CDCl3) 1.74 (s, 3H), 3.06 (s, 3H), 5.65-5.82 (dd, 2H), 6.67-6.77 (dd, 1H), 7.86-7.89 (dd, 1H), 7.95 (s, 1H), 8.06-8.16 (m, 4H), 8.35 (d, 1H), 8.79 (s, 1H); MS (ESP−): 477.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[I:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:28]([C:25]3[CH:26]=[CH:27][C:22]([I:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(I)cc1

Procedure:
Starting with (R)-(5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (example 1-2, method B, 1st step) and 4-iodobenzenesulfonyl chloride, using the method analogous to the one used for example 1-1, method A, 4th step, (R)-[5-(4-iodo-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was obtained. MS cald. for C22H26INO5S 543, obsd. 544 [(M+H)+].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7][C@@H:6]1[OH:28].[CH2:29](O)[CH2:30][OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16]2([O:31][CH2:30][CH2:29][O:18]2)[CH3:17])[CH2:7][C@@H:6]1[OH:28]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1

Procedure:
2β-(2'-Chloroethoxy)-3α-hydroxy-5α-pregnane-11,20-dione (600 mg.) was dissolved in benzene (50 ml.), ethylene glycol (5 ml.) and toluene-p-sulphonic acid (2 mg.) added, and the vigorously stirred mixture refluxed under a Dean and Stark head for 20 hours. The cooled mixture was washed with sodium bicarbonate solution (5 ml.), water (2 × 100 ml.) and dried over anhydrous sodium sulphate. The dried solution was evaporated in vacuo to give the title compound (605 mg.) as a pale yellow foam, [α]D + 47.2° (c 1.11).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccccc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccccc2F)cc1
Yield: 95.9 %

Procedure:
A mixture of 4-[[2-(2-fiuorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in methanol (20 mL) and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.55 g of colorless 4-[[2-(2-fluorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(C)(C)C)[CH:5]=[CH:4][C:3]=1[F:13]>ClCCCl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:13]
Reactant: CC(C)(C)Nc1ccc(F)c(Br)n1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)c(Br)n1
Yield: 68.9 %

Procedure:
A solution of (6-bromo-5-fluoropyridin-2-yl)-tert-butylamine (46 mg, 0.19 mmol) in DCE (2 mL) and TFA (2 mL) was heated at 120° C. for 10 min in a microwave reactor, and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH to give 6-Bromo-5-fluoropyridin-2-ylamine as an off-white solid (25 mg, 71%). 1H NMR (400 MHz, CHCl3-d): δ 7.21 (dd, J=8.7, 7.2 Hz, 1 H); 6.39 (dd, J=8.7, 2.7 Hz, 1 H); 4.89-3.75 (s, 2 H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.II.[I:21]([O-])(=O)=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>C(O)(=O)C>[I:21][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:7][CH:6]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Ic1ccc(Cc2ccncc2)cc1

Procedure:
5.0 g (30 mmol) of 4-benzylpyridine was dissolved in 30 ml of acetic acid. 3.53 ml (65 mmol) of concentrated sulfuric acid, 2.99 g (11.8 mmol) of iodine and 1.17 g (5.9 mmol) of sodium iodate were added to the solution, and the resultant mixture was stirred at 70° C. for 20 hours. After cooling, 0.15 g of sodium metaperiodate was added to the reaction mixture. After the distillation under reduced pressure, water was added to the residue, which was washed with dichloromethane. After the addition of 1 N aqueous sodium hydroxide solution followed by the extraction with dichloromethane twice, the solvent was evaporated. The residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>CN(C=O)C>[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:13][CH:12]=[CH:11][N:10]=2)[S:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(O)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)OC(C)(C)C)c2)n1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenol (prepared according to Example 22; 900 mg, 2.87 mmol), potassium carbonate (992 mg, 7.18 mmol), and tert-butyl 2-bromoacetate (0.424 mL, 2.87 mmol) were added to a 100 mL round bottom flask and dissolved in DMF (10 mL). The reaction mixture was stirred for 3 hours, then water (90 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The resultant solids were filtered and purified over silica gel (20% ethyl acetate in hexanes) to afford tert-butyl 2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetate (680 mg, 55.4% yield) as a white foam. 1H NMR (CDCl3) δ 8.60 (bs, 1H), 7.94 (dd, 1H), 7.32 (t, 1H), 7.07 (dd, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.89 (dd, 1H), 6.80 (dd, 1H), 6.39 (q, 1H), 5.08 (s, 2H), 4.53 (s, 2H), 2.33 (s, 3H), 1.48 (s, 9H). Mass spectrum (apci) m/z=372 (100), 428 (20).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C1COCC1>[C:38]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:41])[CH2:39][CH3:40]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)ONC(=O)CCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (2.8 g) in THF (40 ml) was added triethylamine (1.4 ml) followed by addition of propionyl chloride (669 mg) at 0° C. The reaction mixture was stirred for 1 hour and partitioned between water and ethyl acetate. The organic layer was dried and concentrated. The residue was purified with silica gel chromathography using hexane-ethyl acetate as an eluent to give the titled compound (2.1 g).
Reaction SMILES: [NH2:1][C:2]1([CH2:18][OH:19])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C1COCC1.[C:25](#[N:28])[CH:26]=[CH2:27].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:1][C:2]1([CH2:18][O:19][CH2:27][CH2:26][C:25]#[N:28])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2
Reactant: C=CC#N
Reactant: NC1(CO)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCCOCC1(N)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reaction time: 4 h

Procedure:
A 200-mL RBF was charged with (5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (5.416 g, 15.86 mmol), tetrabutylammonium hydrogen sulfate (0.269 g, 0.793 mmol), THF (79 mL), and acrylonitrile (5.22 mL, 79 mmol) to give a clear, brown solution. NaOH (2N aq.) (19.82 mL, 39.6 mmol) was added, and the resulting biphasic mixture was stirred for 4 h. The mixture was diluted with water (110 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (100 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc/Hexane) to afford 3-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)propanenitrile. 1H NMR (400 MHz, DMSO-d6) δ=8.28 (d, J=0.4 Hz, 7 H), 7.98 (s, 7 H), 7.88 (d, J=0.4 Hz, 7 H), 7.50 (dd, J=2.5, 8.7 Hz, 8 H), 7.13 (d, J=8.7 Hz, 7 H), 3.61-3.48 (m, 2 H), 3.34 (t, J=6.0 Hz, 2 H), 2.95 (s, 2 H); MS m/z=394.0. Calc'd for C16H14BrClN3O2: 394.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.F[C:22]1C=C(C(O)(C)C)C=C(F)C=1>>[F:17][C:6]1[CH:5]=[C:4]([C:18]([OH:20])([CH3:22])[CH3:19])[CH:3]=[C:2]([F:1])[C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]1
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 2-(3,5-difluorophenyl)propan-2-ol (see US2012/225062) provided the title compound.