Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[O:16])[NH:9]3)[CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:54](=[NH:67])([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.O>[C:54](=[N:67][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[O:16])[NH:9]3)[CH:7]=1)([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C1COCC2CC2(c2cc(Br)ccc2F)N1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1COCC2CC2(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)N1
Temperature: 105 °C
Yield: 85.2 %

Procedure:
Under argon in a sealed tube was added to a solution of (1SR,7RS)-1-(5-bromo-2-fluoro-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octan-3-one (intermediate B10A) (405 mg, 1.349 mmol) in toluene (9 ml), sodium tert-butoxide (NaOBut) (389 mg, 4.05 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu X-phos) (57 mg, 10 mol %) and tris(dibenzylideneacetone)dipalladium chloroform complex (Pd2(dba)3.CHCl3)(42 mg, 3 mol %) followed by benzophenone imine (453 uL, 2.7 mmol). The tube was sealed under argon and the mixture was stirred at 105° C. for 18 h to 2.5 days. The mixture was cooled to 23° C., poured into water, extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound as a yellow foam (460 mg, 85%). MS (ISP): m/z=401.3 [(M+H)+].
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:47][CH2:46][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:31][C:32]5[CH:44]=[CH:43][CH:42]=[CH:41][C:33]=5[C:34]([O:36]C(C)(C)C)=[O:35])[C:20]4=[O:45])[CH2:18][CH2:17]3)[C:5]2=[O:48])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:47][CH2:46][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:31][C:32]5[CH:44]=[CH:43][CH:42]=[CH:41][C:33]=5[C:34]([OH:36])=[O:35])[C:20]4=[O:45])[CH2:18][CH2:17]3)[C:5]2=[O:48])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCn3c(=O)n(C4CC4)c4ccccc43)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCn3c(=O)n(C4CC4)c4ccccc43)CC2)C1=O
Yield: 32.8 %

Procedure:
A solution of tert-butyl 2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (240 mg, 0.367 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane to afford the title compound as a white powder (72 mg, 33%); 1H NMR (400 MHz, DMSO-d6): δ 0.84-0.88 (m, 2H); 0.99-1.04 (m, 2H); 1.76 (d, 2H, J=13.6 Hz); 1.87 (bs, 2H); 2.41 (bs, 2H); 2.84-2.88 (m, 1H); 3.85 (t, 2H, J=6.8 Hz); 4.60 (s, 2H); 4.89 (s, 2H); 6.92-6.95 (m, 2H); 7.01-7.11 (m, 4H); 7.18-7.22 (m, 2H); 7.28 (d, 1H, J=7.6 Hz); 7.40 (t, 1H, J=7.6 Hz); 7.57 (t, 1H, J=8 and 7.2 Hz); 7.90 (d, 1H, J=6.8 Hz); 12.9 (bs, 1H); MS for C34H36FN5O4 m/z 598.4 (M+H)+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C>CN(C)C=O.[Cu]I>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CN(C)CCN
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCN(C)C)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
Methyl 4-iodobenzoate (1.19 g, 4.54 mmol, 1.0 eq) was dissolved in dry dimethylformamide (10 ml). N,N-dimethylethane-1,2-diamine (400 mg, 4.54 mmol, 1.0 eq), caesium carbonate (2.69 g, 9.08 mmol, 2.0 eq), 2-acetylcyclohexanone (120 μl, 0.908 mmol, 0.20 eq [20 mol %]) and copper (I) iodide (44 mg, 0.227 mmol, 0.05 eq [5 mol %]) were added and the mixture was stirred under nitrogen at 90° C. for 18 h. The reaction mixture was concentrated, dissolved in methanol and absorbed onto a SCX-2 cation exchange resin column. The column was washed with methanol and the product was eluted with 2M ammonia in methanol. Fractions were evaporated to give methyl 4-(2-[dimethylamino]ethylamino)benzoate (1.00 g, 99%) as a brown gum.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([NH:20][C:21]([C:23]4[N:27]5[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34][N:35]6[CH2:48][C:37]7([CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]7)[CH2:36]6)=[CH:31][C:26]5=[N:25][CH:24]=4)=[O:22])[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:49])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[ClH:50].O1CCOCC1>C(Cl)Cl.CO>[ClH:50].[ClH:50].[ClH:50].[CH2:48]1[C:37]2([CH2:38][NH:39][CH2:40]2)[CH2:36][N:35]1[CH2:34][CH2:33][O:32][C:30]1[CH:29]=[CH:28][N:27]2[C:23]([C:21]([NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[C:13]([CH3:49])=[N:12][N:11]4[CH2:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:9]=3)=[O:22])=[CH:24][N:25]=[C:26]2[CH:31]=1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CC6(C5)CN(C(=O)OC(C)(C)C)C6)ccn34)c12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CC6(CNC6)C5)ccn34)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
tert-Butyl 6-(2-(3-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.075 g, 0.113 mmol) was dissolved in 2 mL of 1:1 DCM/MeOH and 4M HCl/dioxane (0.282 mL, 1.13 mmol) was added. The mixture was stirred at ambient temperature for 4 hours, then concentrated under reduced pressure. The resulting residue was triturated with DCM and the solids were collected by filtration to give 57 mgs (75%) of the title compound. MS (APCI), positive scan, m/z=567.1 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]2[O:4][C:3](=[O:5])[C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[O:1]2)=[CH:13][CH:12]=1
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H]1OC(c2ccc(Br)cc2)OC1=O
Reaction time: 1 h

Procedure:
(2S)-2-hydroxy-4-methylpentanoic acid (46.4 g, 351 mmol) and 4-bromobenzaldehyde (50 g, 270.2 mmol) were dissolved in 400 ml toluene and pyridinium 4-methylbenzenesulfonate (340 mg, 1.35 mmol) was added. The mixture was refluxed in a Dean-Stark for 24 hours. The mixture was cooled, poured into 500 ml NaHCO3(sat) and 500 ether, the phases were separated and the organic phase washed with 500 ml NaHCO3(sat.) and brine. The organic phase was dried with Na2SO4 and the solvent striped. 400 ml Hexane was added to the resulting solid and the mixture was stirred 1 hour in salt ice bath. The solution was filtered thru Celite, and the solvent removed. (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture of cis/trans) was obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[N:6]=1.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>C1COCC1.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:5]1[N:6]=[CH:2][S:3][C:4]=1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1nc(C2OCCO2)cs1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scnc1C1OCCO1
Yield: 98.1 %

Procedure:
2-Bromo-4-(1,3-dioxolan-2-yl) thiazole (6.4 g 27.14 mmol) was stirred at −78° C. in dry THF (38 ml). 1.6M n butyl lithium in hexane (18.6 ml, 29.78 mmol) was added dropwise under nitrogen. After 30 min at this temperature, tributyl tin chloride (7.35 ml, 27.14 mmol) was added dropwise. The reaction was allowed to warm to 0° and water (20 ml) was added. The product was extracted into ether (3×100 ml). The combined organic extracts were dried (MgSO4 ) and evaporated. The residue was triturated with isohexane (3×100 ml) and the mother liquors were decanted, combined and concentrated to give a brown oil (11.88 g); m/z 444–450.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NC5C=CC(C6C=CC(CCCC=O)=CC=6)=CC=5)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH:70][C:71]([C:73]3[CH:74]=[C:75]([S:79]([C:82]4[CH:83]=[C:84]5[C:89](=[C:90]([CH3:92])[CH:91]=4)[N:88]=[CH:87][C:86]([C:93]([NH2:95])=[O:94])=[C:85]5[NH:96][C:97]4[CH:102]=[CH:101][CH:100]=[C:99]([O:103][CH3:104])[CH:98]=4)(=[O:81])=[O:80])[CH:76]=[CH:77][CH:78]=3)=[O:72])[CH:65]=2)=[CH:60][CH:59]=1>>[CH3:104][O:103][C:99]1[CH:98]=[C:97]([NH:96][C:85]2[C:84]3[C:89](=[C:90]([CH3:92])[CH:91]=[C:82]([S:79]([C:75]4[CH:76]=[CH:77][CH:78]=[C:73]([C:71](=[O:72])[NH:70][C:66]5[CH:65]=[C:64]([C:61]6[CH:60]=[CH:59][C:58]([CH2:57][CH2:56][CH2:55][CH:54]=[O:53])=[CH:63][CH:62]=6)[CH:69]=[CH:68][CH:67]=5)[CH:74]=4)(=[O:81])=[O:80])[CH:83]=3)[N:88]=[CH:87][C:86]=2[C:93]([NH2:95])=[O:94])[CH:102]=[CH:101][CH:100]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(-c6ccc(CCCCO)cc6)c5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(-c6ccc(CCCC=O)cc6)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 124, using Intermediate 91 as a substrate. ES/MS calcd. for C41H37N4O6S+ 713.2. Found m/z=713.4 (M−H)+.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)[CH:23]=2)=[N:20][C:19]([C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[NH2:47][CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH:44]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([C:19]2[N:20]=[C:21]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH2:33][NH:47][CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)=[CH:31][CH:32]=4)[CH:23]=3)[C:16]([NH2:8])=[N:17][CH:18]=2)=[CH:36][CH:37]=1)(=[O:43])=[O:42])([CH3:45])[CH3:46]
Reactant: NC1CCOCC1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CCl)cc4)no3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc(CNC5CCOCC5)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 9 (4.1 g, 6.127 mmol), 4-aminotetrahydro-2H-pyran (2.479 g, 24.51 mmol), KI (1.017 g, 324.9 μL, 6.127 mmol) and DIPEA (791.9 mg, 1.067 mL, 6.127 mmol) in DMF (51 mL) was stirred at 40° C. for 3 h then stirred overnight at rt. The mixture was slowly poured onto a stirred ice/water mixture (400 ml) and stirred at rt overnight. The mixture was filtered and washed with water to give a wet paste which was dissolved in warm EtAc (500 ml), washed with water then brine, dried over MgSO4 and concentrated under reduced pressure to give a yellow foam. The above material was dissolved into DCM (40 mL) and treated at RT with TFA (8 mL, 103.8 mmol). The mixture was stirred for 1 h at RT, then concentrated under reduced pressure. The residue was azeotroped three times with a DCM/MeOH yielding a yellow solid that was stirred in a mixture of ethanol (50 mL) and water (50 mL). Excess potassium carbonate (20 mL of 0.5 M, 10 mmol) was added and the mixture was stirred for 45 min at RT. The solid was filtered off, washed with water and dried under high vacuum at 77° C. to give 5-(4-isopropylsulfonylphenyl)-3-[3-[4-[(tetrahydropyran-4-ylamino)methyl]phenyl]isoxazol-5-yl]pyrazin-2-amine (2.857 g, 5.354 mmol) as a free base.
Reaction SMILES: [Na].[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]([O:16][CH3:17])=[O:15].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([N:6]1[C:7]2[C:12](=[N:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]1=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the sodium salt of methyl 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (2.0 g, 7.57 mmol) in water (50 mL) was added a solution of benzyl bromide (3.89 g, 22.72 mmol) in methylene chloride (50 mL). To the biphasic solution was then added tetrabutylammonium bromide (1.2 g, 3.79 mmol) and the reaction was sealed and heated to 50° C. After stirring overnight the reactions was cooled and the two layers were separated. The aqueous layer was extracted one time with methylene chloride and the combined organics were dried over sodium sulfate, filtered and concentrated. The crude mixture was separated by normal phase chromatography using an Isco 120 gram silica gel cartridge with a 50 minute gradient running at 40 mL/min. of 10% to 60% EtOAc/hexanes. The tubes containing the desired product were concentrated and taken on to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[NH2:36][C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[OH:50])[CH:40]=[CH:39][CH:38]=1>CS(C)=O.C(OCC)(=O)C.O>[NH2:36][C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[O:50][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=3[O:2][CH3:1])[C:19]3[S:23][N:22]=[CH:21][N:20]=3)(=[O:8])=[O:9])=[C:11]([F:18])[CH:12]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cccc(-c2cc(Cl)ccc2O)n1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3cccc(N)n3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a stirred mixture of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.41 g, 0.93 mmol) (prepared according to PCT Published Patent Application No. WO 2010/079443) and potassium carbonate (0.38 g, 2.8 mmol) in dimethylsulfoxide (4 mL) at ambient temperature was added 2-(6-aminopyridin-2-yl)-4-chlorophenol (0.19 g, 0.93 mmol). The mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 20-50% gradient of ethyl acetate in hexanes to afford 4-(2-(6-aminopyridin-2-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide in 83% yield (0.49 g): 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 7.84 (d, J=2.7 Hz, 1H), 7.51-7.34 (m, 3H), 7.14 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.42-6.26 (m, 3H), 6.17 (d, J=2.4 Hz, 1H), 5.25 (s, 2H), 4.39 (s, 2H), 3.75 (s, 3H), 3.63 (s, 3H); MS (ES+) m/z 645.6 (M+1), 647.6 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH2:14]1[CH:19]2[CH2:20][C:21]3([CH:24]=O)[CH2:23][CH:17]([CH2:18]2)[CH2:16][CH:15]1[CH2:22]3>>[C:21]12([CH:24]3[NH:1][C:2]4[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=4[S:10](=[O:12])(=[O:11])[NH:13]3)[CH2:20][CH:19]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:23]1)[CH2:22]2
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Product: O=S1(=O)NC(C23CC4CC(CC(C4)C2)C3)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using 1-adamantylcarboxaldehyde). M.p. 270–273° C.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([N:12]1[CH:16]=[C:15]([CH:17]=O)[N:14]=[C:13]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:11])=[O:10].CO.[CH3:28][NH2:29].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[C:1]1([CH3:25])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([N:12]1[CH:16]=[C:15]([CH2:17][NH:29][CH3:28])[N:14]=[C:13]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:11])=[O:10]
Reactant: CN
Reactant: Cc1cc(C)c(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2c(C)cc(C)cc2C)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
1-(Mesitylsulfonyl)-2-phenyl-1H-imidazole-4-carbaldehyde (2.20 g) was dissolved in methanol (30 mL), 40% methylamine methanol solution (1.45 g) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (353 mg) was added at 5-10° C., and the mixture was stirred for 30 min. 1 mol/L Hydrochloric acid (15 mL) was added at the same temperature, and the mixture was further stirred for 30 min. The reaction mixture was alkalified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→0:1) to give a free salt of the title compound as a colorless oil (yield 1.47 g). The obtained free salt (0.85 g) was dissolved in ethyl acetate (30 mL), and crystallized by adding a solution of anhydrous oxalic acid (208 mg) in ethyl acetate (30 mL) to give the title compound as colorless crystals (yield 932 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:50])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:9]([NH:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:13][C:14]([O:16]CC)=[O:15])=[O:10])[C:4](=[O:29])[N:3]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH3:47])=[O:39])=[C:33]([O:48][CH3:49])[CH:32]=1.Cl>>[CH3:1][C:2]1([CH3:50])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:9]([NH:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:4](=[O:29])[N:3]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH3:47])=[O:39])=[C:33]([O:48][CH3:49])[CH:32]=1
Reactant: CCOC(=O)CC(NC(=O)[C@H](CC1CC1)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)C(C)(C)C1=O)c1ccccn1
Agent: Cl
Product: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)NC(CC(=O)O)c3ccccn3)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C

Procedure:
The compound was prepared analogously to Example 10 from 170 mg (0.248 mmol) of the compound of Example 15, but was not converted into the hydrochloride by addition of hydrochloric acid. Yield: 160 mg (98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:23]=[CH:22][C:21]=1[OH:35]
Reactant: Cc1ccc([C@@H](C)Nc2cncc(Cl)n2)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N[C@H](C)c3ccc(C)cc3)n2)ccc1O
Yield: 6.5 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1R)-1-(4-methylphenyl)ethyl]pyrazin-2-amine (56.8 mg, 0.229 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 63 mg, 0.25 mmol) furnished the product (5 mg, 6%).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:30])[NH:15][C@H:16]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:52]2[C@H:53]([CH3:76])[C@H:54]3[C@@H:71]([C@H:72]([OH:74])[CH3:73])[C:70](=[O:75])[N:55]3[C:56]=2[C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[Si:23]([O:22][CH2:21][C@@H:16]([NH:15][C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:52]3[C@H:53]([CH3:76])[C@@H:54]4[C@@H:71]([C@H:72]([OH:74])[CH3:73])[C:70](=[O:75])[N:55]4[C:56]=3[C:57]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=3)=[O:58])[CH2:8]2)[S:10][CH:11]=1)=[O:30])[C@@H:17]([CH3:20])[CH2:18][CH3:19])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 3-acetylthio-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (910 mg, 1.93 mmol) (obtained as described in Reference Example 38) in dimethylformamide (46 ml) was added hydrazine acetate (213 mg, 2.31 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.15 g, 1.93 mmol) in acetonitrile (58 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.34 ml, 7.72 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: n-hexane: ethyl acetate (1:1→1:4)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (765 mg, yield 51%) as a pale yellow solid.