Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[N+:11]([C:10]1[C:2]([O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:3][CH:4]=[C:5]2[C:9]=1[C:8](=[O:14])[CH2:7][CH2:6]2)([O-:13])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2ccc(O)c([N+](=O)[O-])c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1[N+](=O)[O-])C(=O)CC2
Temperature: 0 °C
Yield: 94.3 %

Procedure:
To a solution of 6-hydroxy-7-nitro-1indanone (8.0 g, 41 mmol.) in N,N-dimethylformamide (50 mL) was added potassium carbonate (11.7 g, 82 mmol.). The mixture was stirred under ice-cooling, to which was added dropwise ethyl bromoacetate (5.5 mL, 50 mmol.). The reaction mixture was then stirred for one hour at room temperature, which was poured into ice-water, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crystalline precipitate was collected by filtration and washed with hexane to afford the title compound (yield 10.8 g, 94%).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]3[CH:17]=[C:18]([C:21](=[O:31])[NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=4)[CH:19]=[CH:20][C:14]=3[N:13]=2)=[C:8]([Cl:32])[CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:32][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[C:12]1[NH:16][C:15]2[CH:17]=[C:18]([C:21](=[O:31])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=3)[CH:19]=[CH:20][C:14]=2[N:13]=1)[O:5][CH2:4][C:3]([OH:33])=[O:2]
Reactant: COC(=O)COc1ccc(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4ccc(OCC(=O)O)cc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {3-chloro-4-[6-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester (100 mg, 0.21 mmol) in MeOH (3 mL) was added 1N NaOH (3 mL) and the solution was stirred at ambient temperature for 3 h. The solution was carefully acidified to pH 3-4 with 1N HCl and the suspension was filtered, washed with water, and the white solid was dried in vacuum oven to give the title compound. 1H NMR (Methanol-d4, 400 MHz): δ 8.26 (s, 1H), 7.92 (dd, 1H), 7.84 (d, 2H), 7.74 (d, 1H), 7.48 (dd, 1H), 7.44 (dd, 1H), 7.23 (dd, 1H), 7.14 (m, 2H), 4.80 (s, 2H), 2.30 (s, 3H), 2.27 (s, 3H). MS (m/z) 450.2 (M+1) Retention time: 1.19 min (Method 10).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[O:11]([C:7]1[N:6]=[C:5]([C:3](=[O:4])[C:2]([F:19])([F:1])[F:18])[CH:10]=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(Oc2ccccc2)n1)C(F)(F)F

Procedure:
9.38 g (0.035 mol) of 2,2,2-trifluoro-1-(6-phenoxy-2-pyridyl)ethanol and 0.58 g (0.0017 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 200 ml of methylene chloride at room temperature. 22 ml (0.042 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 15 minutes with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 30° C. The reaction mixture is added to 200 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.4 mbar, 180° C. bath temperature), 4.75 g (50.6% of theory) of 6-phenoxy-2-trifluoroacetylpyridine are obtained. nD20 : 1.5298.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16].CI.[C:21](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][O:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=NO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CON=Cc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Yield: 24.8 %

Procedure:
A mixture of 0.8 g (3.25 mmol) of methyl 3-(hydroxyiminomethyl)-4,7-dimethylindole-2-carboxylate, 0.60 g (4.23 mmol) of methyl iodide, 0.59 g (4.23 mmol) of potassium carbonate and 20 ml of acetonitrile was refluxed for 19 hours. After potassium carbonate was removed by filtration, acetonitrile was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water three times and dried over anhydrous magnesium sulfate. The crude crystals were purified by silica gel column chromatography to provide 210 mg of light yellow crystals. Yield: 25%
Reaction SMILES: CC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[C:32]1[C:36]([CH3:37])=[CH:35][S:34][CH:33]=1)[C:25]([O:27]C)=[O:26]>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[C:32]1[C:36]([CH3:37])=[CH:35][S:34][CH:33]=1)[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1ccc(-c2cscc2C)c(C)c1
Agent: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: Cc1cc(C(=O)O)ccc1-c1cscc1C

Procedure:
The title compound was prepared following procedure described for Intermediate 5, step 2, but starting from methyl 3-methyl-4-(4-methyl-3-thienyl)benzoate (2.0 g; 8.12 mmol; 1 eq.), affording Intermediate 6 as a beige solid. 1H NMR: (DMSO-d6, 300 MHz) δ 12.97 (s, 1H), 7.91 (s, 1H), 7.84-7.81 (dd, J=8.12 Hz, J=1.87 Hz; 1H), 7.41 (d, J=3.20 Hz, 1H), 7.35-7.34 (m, 1H), 7.28-7.26 (d, J=7.80 Hz, 1H), 2.18 (s, 3H), 2 (s, 3H). LC/MS (Method A): 232.9 (M+H)+; 231.0 (M−H)−. HPLC (max plot) Rt 4.26 min (Purity: 99.6%).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>C(O)(C)(C)C.ClCCl>[Cl:16][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(Cl)nc1NCC1CC1
Temperature: 170 °C
Yield: 107.1 %

Procedure:
In a sealable tube, 3 g (42 mmol) of cyclopropylmethylamine is added to 3 g (14 mmol) of 2,6-dichloronicotinic acid in solution in tert-butanol (14 ml), the tube is sealed and heated at 170° C. for 30 minutes in a Biotage Initiator microwave. The reaction mixture is cooled to room temperature, diluted in dichloromethane (100 ml) and washed with a 10% aqueous solution of acetic acid (12 ml). The organic phase is dried over Na2SO4, filtered, concentrated and dried under vacuum. 3.4 g of product is obtained in the form of an orange oil.
Reaction SMILES: [Mg].[H-].C([Al+]CC(C)C)C(C)C.Br[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:22][CH3:23])[O:20][CH3:21])=[CH:15][CH:14]=1.COC(OC)C1C=CC([Mg]Br)=CC=1.Cl[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[N:45]=[N:46][N:47]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:48]=1.ClC1C=CC=CC=1C1N(C2CCCCO2)N=NN=1.CO.C(OC(C)C)(=O)C.[Cl-].[NH4+]>O1CCCC1.O.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:16]1[CH:17]=[CH:18][C:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]2[N:45]=[N:46][N:47]([CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[N:48]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccccc1-c1nnn(C2CCCCO2)n1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(OC)c1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Solvent: CO
Product: COC(OC)c1ccc(-c2ccccc2-c2nnn(C3CCCCO3)n2)cc1
Temperature: 14 °C
Reaction time: 0.33 h

Procedure:
A suspension of magnesium turnings (2.35 g) in anhydrous tetrahydrofuran (66 mL) is cooled to 14° C., treated with a 1 M solution of diisobutylaluminium hydride in tetrahydrofuran (1.8 mL; 1.8 mmol) and stirred for 20 min. At 14° C., 1-bromo-4-dimethoxymethyl-benzene (1.02 g; 4.4 mmol) is added under vigorous stirring. After the reaction starts, more 1-bromo-4-dimethoxymethyl-benzene (19.32 g; 83.6 mmol) is added over 50 minutes. The resulting mixture is further stirred at about 25° C. for 2.5 hours. The concentration of 4-(dimethoxymethyl)phenylmagnesium bromide in the solution above the excess of magnesium turnings is about 0.96 M. In another flask, a mixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (94% content; 4.22 g; 15.0 mmol) is dissolved in anhydrous tetrahydrofuran (2.8 mL) under an inert atmosphere and dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) (80.8 mg; 0.15 mmol) is added. The vigorously stirred resulting suspension is cooled to about 15° C. and the above 0.96 M 4-(dimethoxymethyl)phenylmagnesium bromide solution (18 mL; 17.3 mmol) is added over one hour while keeping the temperature below 25° C. by external cooling. The dark brown reaction mixture is agitated at room temperature for 22.5 hours. After that, about 94% of the starting material are converted. Methanol (1.2 mL; 30 mmol) is added to the mixture followed by isopropyl acetate (35 mL), a solution of ammonium chloride (0.4 g) in water (10 mL) and water (10 mL). The layers are separated. The organic layer is washed with water (10 mL), three times with a solution of sodium hydrogencarbonate (1.0 g) in water (12 mL) and twice with water (10 mL) before it is evaporated in vacuo. The resulting brown oil is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% of triethylamine) to afford the main isomer (N2-isomer) 5-(4′-dimethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)2H-tetrazole as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C:30]1([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)C>CN(C)C=O.CCCCCC>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:41])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH2:26]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)c(F)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (30 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (0.901 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which were added diethyl ether (1.5 ml) and hexane (3 ml) to suspend. The solid was filtered off and dried under aeration to provide the titled compound (14.0 mg) as white powder.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].CCOC(C)=O>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3cccnc3n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(n2)NCCC3)CC1
Reaction time: 20 h

Procedure:
A mixture of 4-3 (2.6 g, 8.4 mmol), 10% Pd/C (0.52 g), and EtOAc (100 mL) stirred under a hydrogen atmosphere (1 atm) for 20 hrs. The reaction mixture was then filtered through a celite pad and the filtrate concentrated. Flash chromatography (silica, 70% hexanes/EtOAc to EtOAc) gave 4-4 as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]2[S:20][N:19]=[CH:18][N:17]=2)(=[O:14])=[O:13])=[CH:7]3)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: COc1cc(C#N)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C#N)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
A vial was charged with 5-bromo-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (INTERMEDIATE D, 82.49 mg, 0.168 mmol), (4-cyano-2-methoxyphenyl)boronic acid (59.5 mg, 0.336 mmol), Pd(AmPhos)2Cl2 (5.96 mg, 8.41 μmol), potassium phosphate (107 mg, 0.505 mmol), 1,4-dioxane (631 μl), and water (210 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 30 min h at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 40 min, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give a light-yellow solid. The material was concentrated from DCM, and then taken up in DCM. The solvent was mostly removed via pipette, then the solid was again concentrated from DCM to give 5-(4-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (35.5 mg, 0.084 mmol, 50.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.54 (d, J=1.9 Hz, 1H), 8.46 (s, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.78-7.67 (m, 3H), 7.61-7.50 (m, 3H), 7.46 (d, J=7.6 Hz, 1H), 3.71 (s, 3H). m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([CH3:17])[CH3:9])=[CH:4][CH:3]=1
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccc(Cl)nn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(NS(=O)C(C)(C)C)c1ccc(Cl)nn1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
Crude 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-eth-(E)-ylidene]-amide (56 mg, 0.22 mmol) was dissolved in dry THF (2.2 mL) and cooled to −20° C. under an atmosphere of inert gas. Methylmagnesium bromide (1.0 M in MePh/THF, 0.26 mL, 0.26 mmol) was added in one portion via syringe and the reaction was stirred −20° C. for 1.5 h. To the reaction mixture was added saturated aqueous NH4Cl (4 mL) and EtOAc (7 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, concentrated and then purified by flash chromatography (silica, 0→4% MeOH/CH2Cl2). 15 mg of impure 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-1-methyl-ethyl]-amide was isolated as a light brown solid. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]([C:11]1[C:26]2[O:25][CH2:24][C:18]3([CH2:23][O:22][CH2:21][O:20][CH2:19]3)[CH2:17][O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].[OH:30]O>C(Cl)Cl.C[Re](=O)(=O)=O>[Cl:29][C:6]1[CH:5]=[N+:4]([O-:30])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[C:26]2[O:25][CH2:24][C:18]3([CH2:23][O:22][CH2:21][O:20][CH2:19]3)[CH2:17][O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: OO
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(COCOC1)CO2
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)c2c1OCC1(COCOC1)CO2
Reaction time: 18 h

Procedure:
To a solution of 2-(3,5-Dichloropyridin-4-yl)-1-{9-methoxy-spiro[2H-1,5-benzodioxepin-3(4H),5′-[1,3]dioxane]-6-yl}ethanone [130] (100 mg) in CH2Cl2 (2 mL) was added 30% H2O2 (120 pt) and methyltrioxorhenium(VII) (5 mg). The mixture was stirred for 18 h and subsequently washed with water. The organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 85 mg of the product.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][C:7]([F:11])([F:10])[C@H:6]1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:13]([NH:12][C@@H:6]1[C:7]([F:10])([F:11])[CH2:8][CH2:9][C@H:5]1[OH:4])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)O[C@@H]1CCC(F)(F)[C@H]1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O[C@@H]1CCC(F)(F)[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-2-(benzylamino)-3,3-difluorocyclopentyl acetate (100 mg, 0.37 mmol) in CH3OH (2 mL), K2CO3 (52 mg, 0.37 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford trans-2-(benzylamino)-3,3-difluorocyclopentanol. MS ESI calc'd. for C12H15F2NO [M+H]+ 228. found 228.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].[Br:21][C:22]1[C:23]([F:33])=[C:24]([F:32])[C:25](F)=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]>C1COCC1>[Br:21][C:22]1[C:23]([F:33])=[C:24]([F:32])[C:25]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of i-Pr2NH (25.0 mL, 178 mmol) in THF (200 mL) at 0° C. was added n-BuLi (71.0 mL, 178 mmol, 2.5 M solution in hexanes). After stirring for 15 minutes, this solution was cooled to −78° C. 2-Chloroaniline (12.7 mL, 118 mmol) was added. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluorobenzoic acid (14.95 g, 58.63 mmol) in THF (30 mL) was added. The dry-ice bath was removed, and the reaction mixture was stirred for 2 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (120 mL), extracted with EtOAc, dried over MgSO4, filtered, and concentrated to give the crude solid which was triturated with boiling CH2Cl2 (125 mL). The yellow solids were filtered, and dried in vacuo to give the desired product (17.4 g, 82%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([Sn](C)(C)C)[N:16]=3)=[C:9]([F:26])[CH:8]=1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:33]([CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[O:34])[N:16]=3)=[C:9]([F:26])[CH:8]=1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: O=C(Cl)C1CCOCC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Temperature: 80 °C

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)-thiazolo[5,4-b]pyridine (1.00 g, 2.087 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (0.434 mL, 2.92 mmol) in 15 mL toluene was sealed and heated to 80° C. After 4 h a precipitate formed. The reaction mixture was cooled and filtered, rinsing with Et2O, and the solid was dried in vacuo to give (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-thiazolo[5,4-b]pyridine-5-yl)(tetrahydro-2H-pyran-4-yl)methanone as a white solid. MS (ESI) m/z: Calculated: 428.1; Observed: 428.8 (M++1).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])=[O:5].Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>CC(N(C)C)=O>[CH2:20]([O:19][C:17]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])=[O:5])=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: C[C@H](N)C(=O)NC(=O)c1ccccc1S
Reactant: CC(C)COC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)COC(=O)Sc1ccccc1C(=O)NC(=O)[C@H](C)N
Reaction time: 8 h

Procedure:
To a solution of N-(2-mercaptobenzoyl)-L-alaninamide (0.22 g, 1.00 mmol) in DMA (5 ml) was added iso-butyl chloroformate (0.2 g, 1.50 mmol), and the mixture was stirred for 8 h. The solvent was evaporated to dryness, and the residue was triturated with ethyl ether (25 ml). The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield, 73%. The product was further purified by column chromatography on silica using chloroform-methanol (7:3 v/v) as eluent with 82% recovery. 1H NMR (DMSO-d6): 0.94 (d, 6H, 2CH3), 1.34 (d, 3H, CH3), 1.96 (m, 1H, CH), 4.06 (d, 2H, CH2), 4.44 (quintet, 1H, CH), 7.16 (brs, 1H, NH2), 7.38 (brs, 1H, NH2), 7.54-7.80 (m, 4H, Ar—H), 8.42 (d, 1H, NH).