Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:27])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 60 °C

Procedure:
4-Dodecylsulfonylbenzoic acid (25.45 g, 71.8 mMole) was added to thionyl chloride (100 mL) together with 2 drops of dirnethylformarnide. The resulting mixture was heated to 60° C. for 3 hours. The solution was then cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (2×50 mL). The residual solid, assuming a quantitative yield, was taken on to the next step.
Reaction SMILES: COC1C=CC(C[N:8]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([NH2:25])=[O:24])[CH2:19][CH2:18][O:17][C:16]=3[CH:30]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23]([NH2:25])=[O:24])[CH2:19][CH2:18][O:17][C:16]=2[CH:30]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To a solution of 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzamide (800 mg, 1.48 mmol) in DCM (15 mL) was added TFA (1.6 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by prep purification to obtain 2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzamide (21 mg, 3.38%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.54 (s, 1H), 7.68 (s, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.37 (dt, J=15.2, 7.7 Hz, 3H), 7.21 (d, J=4.6 Hz, 1H), 7.09 (d, J=1.9 Hz, 1H), 7.04 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.26 (d, J=8.5 Hz, 1H), 4.29-4.27 (s, 2H), 3.71-3.68 (m, 2H). LCMS (ESI) m/z; 417.5 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]=[CH:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:24]1([C:30]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:38][C:32]=3[O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:43]1([C:30]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39]([N:12]4[CH2:11][CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=5)[CH2:14][CH2:13]4)(=[O:40])=[O:41])=[CH:38][C:32]=3[O:31]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Fc1ccc(C2C=CNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (2.56 g, 12 mmol) was suspended in methylene chloride (150 ml). Ethyldiisopropylamine (4.2 ml, 25 mmol) was added and the solution was stirred for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.72 g, 10 mmol) was added and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silical gel (100 g, dichloromethane eluant). The product was stirred with n-hexane, filtered and dried to yield the sulfonamide as white crystals (3.86 g, 75%).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH:15]([N-]C(C)C)(C)C.[Li+].CI.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC.CCCCCCC>[C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12]([CH3:13])[CH3:14])=[N:5][C:6]([CH2:9][CH3:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccc(C#N)c(N=CN(C)C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of the product from Example 10B (0.942 g, 5.0 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to −78° C. under a nitrogen atmosphere. To this solution was added slowly dropwise a solution of lithium diisopropylamide (3.0 mL of a 2.0 M solution in toluene/hexane/heptane, 6.0 mmol, 1.2 eq). After the addition was complete the reaction mixture was stirred at −78° C. for 1 h, and then methyl iodide (1.42 g, 10.0 mmol, 2.0 eq) was added dropwise. The reaction mixture was stirred for an additional 1.5 h at −78° C., during which time all solids dissolved. The reaction flask was then removed from the cooling bath and saturated aqueous ammonium chloride (25 mL) and water (25 mL) was added. The reaction mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with a 3/2 hexane:ethyl acetate to provide the title compound (0.87 g, 86% yield).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1]
Reactant: BrCc1ccccc1I
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Br)c(OCc2ccccc2I)c1
Yield: 102.5 %

Procedure:
Stir a mixture of 2-iodobenzyl bromide (0.29 mol, 90 g), 2-bromo-5-fluorophenol (0.29 mol, 57.9 g), and potassium carbonate (0.46 mol, 63 g) in N,N-dimethylformamide (750 mL) at room temperature for 16 h. Add water (1 L), stir the resulting mixture for one hour, filter off solids, rinse with water and dry in a vacuum oven (20 mm Hg/60° C.) to obtain the title compound (121 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 5.11 (s, 2H), 6.81 (t, 1H), 7.13 (t, 1H), 7.19 (dd, 1H), 7.46 (t, 1H), 7.59 (d, 1H), 7.62 (t, 1H), 7.93 (d, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40].CO.C(Cl)Cl>C(Cl)Cl>[CH:38]([S:39]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:41])=[O:40])=[CH2:37]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reaction time: 1.25 h

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 370 mg 0.98 mmol) was stirred in DCM (10 ml) at room temperature. Triethylamine (150 mg 1.49 mmol) was added followed by dropwise addition of 2-chloro-1-ethanesulphonyl chloride (196 mg 1.2 mmol) in DCM (1 ml). After stirring for 1.25 hours, the reaction was evaporated under reduced pressure and triturated with ether. The resulting solid was treated with water (15 ml), the basified with saturated sodium hydrogen carbonate solution and extracted into DCM (2×20 ml). The organics were washed with brine (10 ml), dried and evaporated to give a gum. After chromatography on silica gel using MeOH:DCM (3:97 to 5:95), the title compound was obtained as a yellow solid (140 mg 30.4%). NMR 1.39 (d, 6H), 2.46 (s, 3H), 3.16 (s, 8H), 5.68 (septuplet, 1H), 6.20 (d, 1H), 6.85 (dd, 1H), 6.91 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.47 (d, 2H), 8.30 (d, 1H), 9.16 (s, 1H); m/z 468.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=1[CH:36]([CH3:38])[CH3:37]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[CH:36]([CH3:38])[CH3:37])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CC(C)c1c(N)ncnc1Cl
Product: CC(C)c1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “4” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridine and 6-chloro-5-isopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=515, obsd.=515). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.16-8.01 (m, 6H), 7.97 (d, J=5.2 Hz, 2H), 6.11 (s, 4H), 3.94 (t, J=6.2 Hz, 4H), 3.46-3.25 (m, 4H), 3.12 (t, J=7.0 Hz, 8H), 2.92 (qd, J=12.0, 4.3 Hz, 7H), 2.72 (t, J=6.1 Hz, 4H), 2.03-1.84 (m, 13H), 1.30 (d, J=7.2 Hz, 13H).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:3][CH:4]=3)[S:9][C:10]=2[CH:16]=1
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: C1CCNC1
Solvent: O
Product: COc1ccc2nc(-c3ccc(N4CCCC4)nc3)sc2c1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.29 mmol), water (2.5 mL) and pyrrolidine (0.50 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and methanol and dried in a desicator over P2O5 to give the title compound (76 mg) as a white solid. 1H NMR (CHLOROFORM-d) δ 8.77 (d, 1 H) 8.13 (dd, 1 H) 7.87 (d, 1 H) 7.33 (d, 1 H) 7.05 (dd, 1 H) 6.44 (d, 1 H) 3.89 (s, 3 H) 3.63-3.46 (m, 4 H) 2.11-1.98 is (m, 4 H); MS m/z (M+H) 312.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[NH2:14][C:15]1[C:20]([NH2:21])=[C:19]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])[C:18]([Br:33])=[CH:17][N:16]=1.C([O-])(=O)C.[NH4+]>>[Br:33][C:18]1[C:19]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:20]2[N:21]=[C:7]([C:6]3[S:5][C:4]([N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[N:3][C:2]=3[Cl:1])[NH:14][C:15]2=[N:16][CH:17]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCCC2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4sc(N5CCCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5.2 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-pyrrolidin-1-yl-thiazole-5-carbaldehyde (204.9 mg, 0.9456 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (290 mg, 0.85 mmol), and Ammonium acetate (131.2 mg, 1.702 mmol) were reacted to produce 23.46 mg (5%) of the title compound. (300 MHz, DMSO-d6) 2.68 (s, 1H), 8.00 (s, 1H), 7.74 (m, 2H), 7.23 (s, 1H), 7.13 (m, 1H), 6.38-6.31 (m, 2H), 5.05 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 m, 4H), 2.87 (s, 1H), 2.73 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.21 (d, J=8 Hz, 1H), 2.01 (m, 5H). MS=535 (M+H), HPLC: 2.54 min. (G Method)
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:34](=[O:35])[N:14]2[C:15]([C:31]([OH:33])=[O:32])=[C:16]([CH2:19]OC(=O)C(C3C=CC=CC=3)O)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[SH:36][C:37]1[N:41]([CH3:42])[N:40]=[N:39][N:38]=1.C(=O)([O-])O.[Na+:47]>O>[Na+:47].[C:1]([NH:11][C@@H:12]1[C:34](=[O:35])[N:14]2[C:15]([C:31]([O-:33])=[O:32])=[C:16]([CH2:19][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)C1=C(COC(=O)C(O)c2ccccc2)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
In water (5 ml) was dissolved 7β-(D-mandelamido)-3-mandelyloxymethyl-3-cephem-4-carboxylic acid (0.50 g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.17 g). The solution was stirred at 60° C. for 30 minutes. After cooling in the air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2, elution being carried out with water and a solvent mixture of water and methanol. The fractions containing the desired product were pooled, concentrated and lyophilized. The procedure provided 7β-(D-mandelamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (0.34 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH3:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[N:26]=[N:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33]([C:31]2[CH:30]=[CH:29][C:28]3[N:24]([CH3:23])[N:25]=[N:26][C:27]=3[CH:32]=2)=[O:34])[CH2:7][CH2:6]1
Reactant: Cn1nnc2cc(C(=O)O)ccc21
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cn1nnc2cc(C(=O)NC3CCN(CCn4c(=O)ccc5c(F)cc(F)cc54)CC3)ccc21
Yield: 44.5 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 1-methyl-1H-1,2,3-benzotriazole-5-carboxylic acid (70 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mol) to give title compound (67.6 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=1)[CH2:8][CH:9]1[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20])([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=1)[CH2:8][CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Yield: 99.2 %

Procedure:
Dimethyl 2-(3,5-di-tert-butylbenzyl)piperidine-1,4-dicarboxylate (3.886 g, 9.63 mmol) was dissolved in acetonitrile (40 mL) and water (0.8 mL), then lithium bromide (6.69 g, 77.04 mmol) and triethylamine (5.34 mL, 38.52 mmol) were added and the resulting yellow suspension was heated at reflux. After 5 h water (100 mL) and MTBE (250 mL) were added. The organic phase was extracted with water (×2). The pooled aqueous layer was acidified to pH 1 with 3.8 M HCl and then extracted with MTBE (×3). The combined organic layer was washed with water, dried Na2SO4, filtered and evaporated to yield 2-(3,5-di-tert-butylbenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.723 g, 99%) as a yellow gum. MS m/z 390 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(C(CC)=O)C>[CH3:19][O:10][C:9](=[O:11])[C:8]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:7]=1[O:6][C:5]1[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(Oc2ccc(F)cc2)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: COC(=O)c1c(C)cccc1Oc1ccc(F)cc1
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A mixture of 2-(4-fluoro-phenoxy)-6-methyl-benzoic acid (21.6 mmol, 5.32 g), dimethylsulfate (43.2 mmol, 4.2 mL), K2CO3 (43.2 mmol, 6 g), and diethyl ketone (80 mL) was refluxed with stirring for 18 h before it was concentrated in vacuo. To the residue was added water (50 mL) and the mixture was extracted with ethyl acetate (1×100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan oil (5.5 g); 1H NMR (CDCl3, 200 MHz): δ=7.20 (t, 1H), 6.92 to 7.04 (m, 5H), 6.66 (d, 1H), 3.84 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CCO.O>[Fe].CC(O)=O>[NH2:1][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a refluxing solution of 59A (1.7 g, 5.9 mmol), EtOH (60 mL), water (15 mL) and AcOH (4 mL) was added portion-wise Fe powder (1.6 g, 29.5 mmol) over 30 min. Mixture was heated for 45 min. before cooling to ambient temperature and filtering through celite. Filtration and concentration in vacuo afforded 59B (1.5 g, 94%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (d, J=6.59 Hz, 3 H) 5.00-5.17 (m, 2 H) 5.40 (d, J=7.47 Hz, 1 H) 6.53-6.60 (m, 2 H) 6.69 (d, J=7.47 Hz, 1 H) 7.11 (t, J=7.69 Hz, 1 H) 7.29-7.39 (m, 5 H).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>>[Cl:13][CH2:9][C:2]1[O:3][CH:4]=[C:5]([OH:8])[C:6](=[O:7])[CH:1]=1
Reactant: O=c1cc(CO)occ1O
Reactant: O=S(Cl)Cl
Product: O=c1cc(CCl)occ1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To Kojic acid (FLUKA, 1 g) was added thionyl chloride (ALDRICH, 1.027 mL). The yellow mixture was stirred at room temperature for 2 h. The precipitate was filtered, then washed with hexane and vacuum dried to afford 1.08 g of the title compound as a pale yellow solid.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1.[CH3:41][NH:42][CH3:43]>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:41][N:42]([CH3:43])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN(C)C)C(=O)c1cc2c(cc1-3)OCO2
Yield: 48.2 %

Procedure:
Sodium iodide (0.061 g, 0.408 mmol) and compound 19 (0.020 g, 0.034 mmol) were diluted with dioxane (10 mL), and dimethylamine (0.023 mL, 0.408 mmol) was added dropwise. The mixture was stirred at reflux for 52 h. The mixture was diluted to a volume of 250 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (SiO2, ˜40 g), eluting first with a gradient of 0.5% MeOH in CHCl3, and then with 1% MeOH in CHCl3, to yield the product 23 as a solid (0.009 g, 47%): mp 176-178° C. (dec). IR (film) 2922, 1698, 1650, 1483, 1306, 1032, 786 cm−1: 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.09 (s, 2H), 4.54-4.48 (t, 8.4 Hz, 2H), 4.29-4.25 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 3.78-3.74 (t, J=4.8 Hz, 2H), 2.57-2.53 (m, 14H), 2.27 (s, 2H), 2.03-2.02 (m, 2H); ESIMS m/550 (MH+); HRESIMS m/z 550.2558 (MH+), calcd for C30H36N3O7 550.2553; HPLC purity: 97.57% (C-18 reverse phase. MeOH—H2O, 85:15).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=[O:32])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:33][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]([OH:32])[CH3:33])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (700 mg) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1M tetrahydrofuran solution) (3.27 mL) and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (301 mg, yield 42%) as a colorless amorphous solid. MS: 488 (MH+).