Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C@H:17]([NH:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:16]2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]1[C:7]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([NH:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH2:16]3)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1
Reactant: OB(O)c1ccc(F)nc1F
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Br)cc2C1
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+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(F)nc3F)cc2C1

Procedure:
To a solution of (2,6-difluoro-3-pyridinyl)boronic acid (2 g, 12.56 mmol) in dry 1,4 dioxane (30 ml), polymer supported Pd(PPh3)4 (126 mg, 0.5 mmol/g, 0.063 mmol) was added along with N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (2 g, 6.28 mmol) and 7.3 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCl and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 798 mg of title compound were recovered as whitish solid (36%) Due to the use of the chiral Intermediate 6, the title compound is believed to be N-[(2S)-5-(2,6-difluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)=[O:4].[C:15]([O:19][C:20](=[O:39])[C@@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26])[CH2:22][NH2:23])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12](=[O:14])[NH:23][CH2:22][C@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]23[CH2:36][CH:35]4[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]4)[CH2:30]2)[CH2:38]3)=[O:26])[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:39])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C=Cc1ccc(C(=O)O)s1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Yield: 32.4 %

Procedure:
The title compound was synthesized analogously to example 3, step a) from 360 mg (1.84 mmol) of 5-(2-methoxycarbonyl-vinyl)-thiophene-2-carboxylic acid and 650 mg (1.84 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-amino-propionic acid tert-butyl ester. After chromatography (silica gel; ethyl acetate/n-heptane (1/1, v/v)) 326 mg of the title compound were obtained as colourless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
4-Nitrophenol (13.9 g, 100 mmol) was dissolved in N,N-dimethylformamide (20 ml), and t-butyl bromoacetate (29.3 g, 150 mmol) and potassium carbonate (27.6 g, 200 mmol) were added, which was followed by stirring at 70° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the previously-obtained organic layer were combined. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 21.8 g of t-butyl 4-nitrophenoxyacetate as pale-yellow crystals (86%).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(OC3CCCCC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OC3CCCCC3)ccc2CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
To methyl 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (412 mg, 1.37 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4.0 ml), and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.0 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (388 mg, 1.35 mmol, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.Cl>O>[O:20]1[CH2:19][CH:18]1[CH2:16][NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: BrCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
p-Nitrobenzene sulphonamide (6.06 g, 30 mmol) was added portionwise to a solution of sodium hydroxide (1.32 g, 33 mmol) in water (60 ml) at room temperature. Epibromohydrin (4.5 g, 33 mmol) was added quickly dropwise and the solution stirred at room temperature for 24 hours. The mixture was acidified to pH 1 with 2M hydrochloric acid and extracted with DCM (2×30 ml). The combined organic extracts were dried with sodium sulphate, filtered and the volatiles removed by evaporation. The resulting yellow oil was purified by chromatography on silica eluting with DCM/methanol (100:0) increasing in polarity to (99:1) to give the title compound as a pale yellow solid (2.5 g, 32%); NMR (CDCl3) 2.65 (m, 1H), 2.80 (t, 1H), 3.10 (m, 2H), 3.50 (m, 1H), 5.08 (brs, 1H), 8.08 (d, 2H), 8.38 (d, 2H); m/z: 257.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: Nc1nnn[nH]1
Product: Cc1cc(F)ccc1-c1nc(Nc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.33 mmol) and 5-amino-1H-tetrazole (143 mg, 1.68 mmol) were reacted to give the crude material, which was purified preparative hplc to afford the title compound, 17 mg (9%). LC-MS: 451.0 (MH+, m/z), 2.04 (Rt, min).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O.C1COCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:21])[C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A suspension of cis4-hydroxy-D-proline (10.0 g) in THF-water (1:1, 100 mL) was added 1N NaOH solution (50 mL) at 5° C. To the mixture was added a solution of benzyloxycarbonyl chloride (12.5 mL) in THF (10 mL) keeping pH to 8.5-10 by the addition of 2N NaOH solution at 5-10° C. After stirring at the same temperature for 1 h, the reaction mixture was washed with EtOAc (50 mL), adjusted to pH 2 by the addition of 4N HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated in vacuo to give cis4-hydroxy-N-benzyloxycarbonyl-D-proline (18.74 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:17]2[CH:21]=[C:20]([C:22](O)=[O:23])[C:19]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:18]2)([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:33][N:34](C(C)C)C(C)C.CN.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:15]([CH2:14][C:11]1([N:17]2[CH:21]=[C:20]([C:22](=[O:23])[NH:34][CH3:33])[C:19]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:18]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(=O)O)c(Nc3ccccc3)n2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxylic acid (25 mg, 0.059 mmol) in DCM (0.6 mL) was added DIPEA (0.030 mL, 0.18 mmol), methylamine (0.040 mL, 0.082 mmol, 2.0 M in THF), HOBT (13 mg, 0.082 mmol), and EDC (16 mg, 0.082 mmol). The resulting mixture was maintained at ambient temperature for 18 hours, then purified directly by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:29]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:14][CH2:13][CH2:12][C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:11]=3)[CH2:27][CH2:28]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)cc1
Yield: 57.1 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(diphenylmethyl)piperazine (13 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0.15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2.75 hr and followed the same processes as in Example 1 to obtain 12.5 mg (57.1%) of the target compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][CH:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CON(C)C(=O)C(CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21a) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.90 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.40 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22a as an oil which crystallized to a white solid upon standing. Rf=0.54 (50% EtOAc/hexanes); mp=71-72° C.; IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[OH:25][CH2:26][CH:27](CO)[OH:28].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH:26]([CH2:27][OH:28])[OH:25])=[O:6]
Reactant: OCC(O)CO
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCC(=O)OCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
1.0 g (3.0 mmol) of methyl 4,8,12,16-tetramethylheptadec-3-enoate was slowly added dropwise to a solution of 0.68 g (7.4 mmol) of glycerol and 0.61 g (4.4 mmol) of potassium carbonate in dry N,N-dimethylformamide (3.5 mL) at 100° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The reaction solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 347 mg of the title compound (29% yield) as a yellow viscous product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])[CH3:16])(=[O:12])=[O:11].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:16])[CH3:17])(=[O:11])=[O:12])(=[O:37])[CH3:36]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A solution of benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (451 mg, 1.08 mmol) in dichloromethane (5 ml) was cooled to 0° C. Pyridine (200 μl, 2.48 mmol), then acetic anhydride (150 μl, 1.59 mmol) were added. The solution was stirred for 3 hours, and another portion of pyridine (200 μl, 2.48 mmol) then acetic anhydride (150 μl, 1.59 mmol) were added. The solution was stirred for an additional 20 hours, concentrated in vacuo, and the residue purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (440.2 mg, 0.959 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 6H), 2.04 (s, 3H), 2.15-2.20 (m, 2H), 3.09-3.16 (m, 4H), 3.54-3.61 (m, 6H), 3.85 (t, J=5.6 Hz, 2H), 4.16 (m, 2H), 5.02 (s, 3H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 460 [M+H]+, 482 [M+Na]+.
Reaction SMILES: ClC([N:6](C)C)=C(C)C.[NH2:9][C:10]1[C:11]([Cl:20])=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13](O)=[O:14].N>C1COCC1>[NH2:9][C:10]1[C:11]([Cl:20])=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([NH2:6])=[O:14]
Reactant: Nc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: CC(C)=C(Cl)N(C)C
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethyl-amine (16.1 mL, 116 mmol) was added to 3-amino-2,4-dichloro-benzoic acid (20.0 g, 97.1 mmol) in THF (320 mL). After 4 h at rt the mixture was added dropwise to conc. NH3 (320 mL) and stirred at rt overnight. The reaction mixture was concentrated, cooled and filtered. The filtercake was dried to give the sub-title compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1>[NH4+].CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:17]=1.[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:17]=1
Reactant: CCOC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Product: COC(=O)CCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Yield: 19 %
Yield: 54 %

Procedure:
A solution of ethyl 3-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)propanoate (50 mg, 0.1 mmol) in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 6 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give ethyl 3-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)propanoate as a white solid (22 mg, yield 54%) and methyl 3-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)propanoate as a white solid (7.3 mg, 19%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[C:30]1([N:40]=[C:41]=[O:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH2:25]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:14]=2)[C:3]([CH2:2][NH:1][C:41]([NH:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:42])=[C:4]([Cl:29])[N:5]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CNC(=O)Nc2cccc3ccccc23)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 55.2 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.00 g, 2.4 mmol, 1 eq) and 1-naphthyl isocyanate (0.35 mL, 2.4 mmol, 1 eq), were mixed and stirred in chloroform at room temperature for 3 days. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel in 1:1 hexane/ethyl acetate to yield 770 mg of a white glass. NMR (200 MHz, CDCl3) δ 7.83 (d, 3H, J=6Hz); 7.67 (d, 1H, J=6Hz); 7.56-7.18 (m, 9H); 6.97 (d, 2H, J=7Hz); 6.74 (s, 1H); 5.27 (s, 2H); 4.74 (s, 1H); 4.39 (d, 2H, J=7Hz); 3.58 (s, 3H); 2.60 (t, 2H, J=7Hz); 1.43-1.21 (m, 4H); 0.85 (t, 3H, J=7Hz).
Reaction SMILES: [OH:1][C:2]1([CH2:9][CH3:10])[CH:7]=[CH:6][O:5][C:4](=O)C1.S([O:16][CH3:17])(OC)(=O)=O.[C:18](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:4][O:5][C:6]1[CH:7]=[C:2]([CH2:9][CH3:10])[O:1][C:17](=[O:16])[CH:18]=1
Reactant: CCC1(O)C=COC(=O)C1
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1cc(OC)cc(=O)o1
Reaction time: 7 h

Procedure:
A suspension of 4-hydroxy-4-ethyl-2-pyrone (360 mg, 0.00257 mol), dimethyl sulphate (0.3 ml) and potassium carbonate (1 gm) in 2-butanone was heated at reflux with stirring for 7 hours. The mixture was cooled, filtered and the filtrate was evaporated to give an oil. This oil was further purified by column chromatography (Whatman LPS-II silica gel, 30% ethyl acetate:pet. ether 30-60) to yield 4-methoxy-6-ethyl-2-pyrone (370 mg), m.p. 54°-55° C., IR (KBr): 1730, 1710, 1650, 1570 cm-1. Anal. calcd. for C8H10O3 : C, 62.33, H, 6.54. Found: C, 62.26, H, 6.55.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].O1CCCC1.[OH-].[Li+]>O.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:19])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCOC(=O)C(C)c1ccc(CS(C)(=O)=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a stirred solution of ethyl 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoate (950 mg, 3.295 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added lithium hydroxide (236 mg, 9.885 mmol). The reaction mixture was refluxed for overnight, then cooled to room temperature, diluted with water (25 mL) and diethyl ether (25 mL). After phase separation the aqueous layer was acidified by HCl to a pH=3 and extracted with DCM (3×50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent of the filtrate was removed in vacuo to give 2-(3-fluoro-4-(methylsulfonylmethyl)-phenyl)propanoic acid (846 mg, 99%).