Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][Si:13]([CH3:17])([CH3:16])[C:14]#[CH:15].C(Cl)Cl>C(#N)C.C1COCC1.[Cu]I.Cl[Pd]Cl>[CH3:12][Si:13]([C:14]#[C:15][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1

Procedure:
Under an argon atmosphere a solution of 32.5 g (138.0 mmol) ethyl 5-bromo-thiophene-2-carboxylate in 320 ml acetonitrile and 640 ml THF is combined with 1.3 g (7.0 mmol) copper-(I)-iodide and 39.0 g (276.0 mmol) trimethyl-silylacetylene with stirring, the mixture is stirred for 5 min and then 5.6 g (7.0 mmol) 1,1-bis-(diphenylphosphino)-ferrocene-dichloropalladium(II))-PdCl2 in a complex with CH2Cl2 1/1 and 57.4 ml (414.0 mmol) TEA are added. The reaction mixture is stirred overnight at room temperature, evaporated down i. vac., the residue is combined with ethyl acetate and washed with ammonia solution (5%) and water. The organic phase is dried on sodium sulphate and evaporated to dryness i. vac. The residue is combined with diethyl ether, the precipitate is suction filtered and dried.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C[Li].C([Li])CCC.CN(C)[CH:33]=[O:34]>O.C1COCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[C:2]([CH:33]=[O:34])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:4]=1
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Reactant: CN(C)C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=O)cn2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A flask was charged with 5-bromo-4-(2,6-difluorophenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 128; 1.0 g, 2.51 mmol) and THF (50 mL) and cooled to −78° C. Methyllithium (1.96 ml, 3.14 mmol) was added slowly and the reaction mixture was stirred for 5 minutes. Butyllithium (1.26 ml, 3.14 mmol) was added and the reaction mixture was stirred for 5 minutes. N,N-dimethylformamide (0.551 g, 7.53 mmol) was added and the reaction mixture was stirred for 5 minutes. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated. The residue was titurated with a mixture of hexanes, ether, and DCM and filtered to give the title compound (0.480 g, 51.2% yield) as yellow solid. 1H NMR (d6-DMSO) δ 11.48 (s, 1H), 10.23 (s, 1H), 8.73 (s, 1H), 7.48 (m, 3H), 6.68 (s, 1H), 6.53 (bs, 1H), 2.19 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:14]1([C:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a solution of indoline-5-sulfonamide (Intermediate 54A, 100 mg, 0.50 mmol) in MeCN (5.0 mL) was added cyclohexanecarbonyl chloride (0.14 mL, 1.00 mmol) and K2CO3 (174 mg, 1.26 mmol). The resulting reaction mixture was stirred at room temperature overnight and then diluted with EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with 1 N aq. NaOH solution, followed by 10% aq. LiCl solution. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with CH2Cl2 to give the title compound (31 mg, 20%) as a white solid. 1H NMR (DMSO-d6) δ 8.16 (d, J=6.8 Hz, 1H), 7.64-7.60 (m, 2H), 7.19 (m, 2H), 4.22 (t, J=8.5 Hz, 2H), 3.21-3.16 (m, 2H), 2.62-2.55 (m, 1H), 1.91-1.65 (m, 5H), 1.45-1.16 (m, 5H); MS(ESI+) m/z 309.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:20]>C(O)C.CO>[OH:19][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][C:12]=1[C:13]([NH2:20])=[O:14]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: N
Solvent: CO
Solvent: CCO
Product: NC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
A mixture of methyl 4-benzyloxy-2-hydroxybenzoate (20 g) and concentrated aqueous ammonia (30 mL) in ethanol (100 mL) is heated on the steam bath in a sealed pressure vessel overnight. The contents of the pressure vessel are dissolved in methanol and the solution is evaporated to dryness. The residue is subjected to flash chromatography, eluting first with dichloromethane to remove unreacted starting material, and then with a mixture of ethyl acetate and dichloromethane (3:7 v/v), to obtain 2-hydroxy-4-benzyloxybenzamide (4 g), in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[CH3:11][C:12]1([C:16](O)=[O:17])[CH2:15][O:14][CH2:13]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:16]([C:12]2([CH3:11])[CH2:15][O:14][CH2:13]2)=[O:17])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: CC1(C(=O)O)COC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C(=O)NCc2nccnc2Cl)COC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To a stirred suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 4.34 mmol, 0.81 g) in dichloromethane (150 ml) were added 3-methyl-3-oxetanecarboxylic acid (4.34 mmol, 0.504 g), triethylamine (9.56 mmol, 1.33 ml), 4-dimethylaminopyridine (0.434 mmol, 0.053 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.69 mmol, 1.67 g). After stirring for 16 hours at room temperature the suspension was filtered over decalite and the decalite was washed with dichloromethane. The combined filtrates were washed with 0.3 N hydrochloric acid (350 mL), 0.03 N hydrochloric acid (350 mL) and sodium hydrogencarbonate (aq). All aqueous layers were twice extracted with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give crude material. Solid sodium chloride was added to all aqueous layers and these were extracted five times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give a second crop of crude material. The combined crude products were purified using chromatography (silica gel, ethyl acetate) to yield N-((3-chloropyrazin-2-yl)methyl)-3-methyloxetane-3-carboxamide (0.58 g).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](Cl)(=[O:50])=[O:49])=[N:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])=[N:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Cl)ncc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)ncc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (0.048 g, 0.218 mmol) and THF (1.00 mL), and the vessel was cooled to −78° C. for 15 minutes. LHMDS (1.0 M in THF) (0.238 ml, 0.238 mmol) was then added drop wise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine-7-sulfonyl chloride (0.080 g, 0.199 mmol) in THF (1.00 mL) was added drop wise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were concentrated under reduced pressure and the resulting material was taken up in DCM (10 mL) and TFA (1 mL) was added. The reaction was stirred for 2 hours and then the solvent was removed under reduced pressure. The resulting material was taken up in DCM (30 mL) and washed with aqueous sodium bicarbonate (sat. solution). The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid was triturated with diethyl ether (20 mL) and filtered. The solid was dried under reduced pressure to provide 0.018 g of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1,6-naphthyridine-7-sulfonamide as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.86 (s, 3H) 6.94 (d, J=4.60 Hz, 1H) 7.34 (d, J=4.60 Hz, 1H) 7.56-7.62 (m, 2H) 7.69 (d, J=7.73 Hz, 1H) 7.81 (d, J=4.50 Hz, 1H) 8.47-8.51 (m, 1H) 8.98-9.02 (m, 1H) 9.36 (d, J=4.50 Hz, 1H) 12.99 (br. s., 1H). m/z (ESI) 467.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].O.[OH-].[Li+].C(OCC)C>O1CCCC1.CO.O.ClCCl>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:4]([CH:9]=1)[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of (2R, 5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester (4.12 g, 9.18 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and water (4 ml) was added lithium hydroxide monohydrate (1.93 g, 45.9 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction was then concentrated, diluted with 1N hydrochloric acid and extracted with dichloromethane (2×). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a white foam. Triteration in dichloromethane and diethyl ether gave the title compound (1.38 g, 35% yield).
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][I:10].[P:11](OCC)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>>[I:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(OCC)OCC
Reactant: ICCOCCOCCI
Product: CCOP(=O)(CCOCCOCCI)OCC
Temperature: 160 °C

Procedure:
1,2-bis(2-iodoethoxy)ethane (1.0 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH™ system using 85-100% EtOAc/Hex to give diethyl 2-(2-(2-iodoethoxy)ethoxy)ethylphosphonate as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=3)=[N:17][N:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl.O>[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[N:17][N:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COc1ccc(-c2nn3ncccc3c2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(O)cc3)nn3ncccc23)cc1
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
Boron tribromide (1M solution in CH2Cl2, 2.1 eq) was added to 3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine (3.58 g) in CH2Cl2 at −70°. The mixture was stirred for 10 min then warmed to 0° and stirred at 0° overnight. The reaction mixture was made alkaline with potassium carbonate then acidified with hydrochloric acid (2M), poured into water and extracted into CH2Cl2. The organic phase was dried, filtered and concentrated to give the title compound (1.87 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])=[O:15])[C:5]2[N:9]=[C:8]([CH2:10][O:11][CH3:12])[NH:7][C:6]=2[CH:13]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:58][C:59]1[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:60]=1[C:61](O)=[O:62].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:58][C:59]1[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:60]=1[C:61]([NH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])=[O:15])[C:5]2[N:9]=[C:8]([CH2:10][O:11][CH3:12])[NH:7][C:6]=2[CH:13]=1)=[O:62]
Reactant: O=C(O)c1c(F)cccc1Br
Reactant: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3c(F)cccc3Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
To a solution of 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (50 mg) in DMF (1.5 mL), were added HBTU (66 mg), N,N-diisopropylethylamine (30 μL) and 2-bromo-6-fluorobenzoic acid (38 mg) in turn, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-bromo-6-fluorophenyl) carbonyl]amino}-N-(3-chloro-2-m ethylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (46 mg). This was dissolved in ethyl acetate (2 mL), and treated with 4N hydrogen chloride/ethyl acetate (1.2 Eq). The precipitate was collected by filtration, and dried to obtain the titled compound (24 mg) as white powder.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C1C=CN=CC=1)C.ClCCl>[N:28]1([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[CH2:11]2)=[O:27])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 93 μl of cyclopentanecarbonyl chloride (0.762 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 133 mg (57% of theory)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl.[N:56]1[CH:61]=[CH:60][CH:59]=[C:58]([S:62](Cl)(=[O:64])=[O:63])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:58]2[CH:57]=[N:56][CH:61]=[CH:60][CH:59]=2)(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2cccnc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and pyridine-3-sulfonyl chloride hydrochloride as starting materials in 31% yield. LCMS for C29H30ClN8O3S (M+H)+: m/z=605.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][CH:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 200 mg of trifluoromethanesulfonate 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylester was dissolved in 3 ml of dimethylformamide. 54 mg of 60% sodium hydroxide and 1.0 ml of methyl iodide were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by preparative thin-layer chromatography (ethyl acetate/hexane=1/2) to obtain 42 mg of the above compound as a yellow oily matter.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.[BrH:11].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O.C(OCC)(=O)C>[Br:11][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c(C)c1C
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(Br)c(C)c1C
Temperature: -13.5 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
10.3 g (0.075 mol) of 2-amino-3,4,5-trimethylpyridine was added to 30 mL of 60% HBr. The mixture was cooled to −10 to −17° C. and pre-cooled 36.0 g (0.23 mol) bromine was added dropwise and the mixture was stirred for 20 mins. Pre-cooled (0° C.) NaNO2 solution of 13.5 g (0.19 mol) NaNO2 dissolved in 20 mL water was added dropwise into the reaction mixture at −10° C.˜−17° C. After addition, the reaction was stirred for one hour. Ice-cooled 25% NaOH solution was added slowly until the solution became basic. 200 mL of ethyl acetate was added to the mixture to extract the organic phase. The organic phase solvent was evaporated and the residue was distilled under vacuum. ˜13.1 g (87% yield) of the desired product was obtained which was confirmed by GC/MS.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5](=[O:29])[C@@H:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[C:9]1=[O:28])[CH3:7].N1C=CC=CC=1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].Cl>C(Cl)Cl>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([NH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C@@H:6]([CH3:7])[C:5]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:3][CH2:2][NH:1][S:39]([CH3:42])(=[O:41])=[O:40])=[O:29])[C:9]1=[O:28])(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(CCN)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N(CCNS(C)(=O)=O)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (0.04 g) was dissolved in DCM (3 ml) at 0° C. and was treated with pyridine (0.027 ml) and mesyl chloride (0.03 ml). The reaction mixture was allowed to reach room temperature and then stirred at room temperature for 3 h. Additional DCM (3 ml) followed by hydrochloric acid (5 ml) was added. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM, diethyl ether, ethyl acetate:10% aqueous NH3) to give the title compound (0.024 g) as gum.
Reaction SMILES: CN(N=O)C(N[C@H:6]1[CH:11]([OH:12])[O:10][C@H:9]([CH2:13][OH:14])[C@@H:8]([OH:15])[C@@H:7]1[OH:16])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>>[O:14]=[CH:13][C@@H:9]([C@H:8]([C@@H:7]([C@@H:6]([CH2:11][OH:12])[OH:22])[OH:16])[OH:15])[OH:10]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
SD/IGS rats at 7 weeks of age (male, Charles River Laboratories Japan Inc.) were fasted for about 16 hours and then injected with 50 mg/kg streptozotocin (STZ) via the caudal vein under ether anesthesia to prepare diabetic model rats. Similarly, another group of SD/IGS rats at 7 weeks of age was injected with 1.25 mmol/L citric acid in physiological saline (1 mL/kg) via the caudal vein under ether anesthesia to prepare normal control rats. At one week after injection of STZ or 1.25 mmol/L citric acid in physiological saline, the rats (8 weeks old) were provided for an oral glucose tolerance test.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2].[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].N1C=CC=CC=1>CCOC(C)=O>[C:23]([O:22][C:20]([NH:19][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])=[CH:13][C:12]([S:14][S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:11]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:10]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using (2-tert-butoxycarbonylamino-4-tert-butyl-5-mercapto-phenyl)-carbamic acid tert-butyl ester (prepared in Example TT-2; 16.9 g, 42.8 mmol), tosyl bromide (10.04 g, 42.76 mmol), pyridine (10 mL), and EtOAc (150 mL). The crude product was purified by flash chromatography (5%-60% EtOAc in hexanes as eluents). 1H-NMR (CDCl3): δ 1.19 (s, 9H), 1.53 (s, 18H), 2.42 (s, 3H), 6.42 (br s, 1H), 7.22 (d, 2H), 7.28 (s, 1H), 7.5 (m, 3H), 7.87 (br s, 1H).