Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
In a round-bottomed flask, 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (81 mg, 0.13 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.41 ml, 5.32 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.54 ml, 8.00 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered and washed with hot water and ethyl acetate and dried under high vacuum to provide 38 mg (60%) of 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white powder. MS: (M+Na)+=502; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.81 (br. s., 1H), 9.04 (s, 1H), 8.49 (dd, J=8.8, 5.3 Hz, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.62 (dd, J=10.0, 2.1 Hz, 1H), 7.16 (td, J=9.1, 2.3 Hz, 1H), 5.60 (s, 2H), 3.69-3.77 (m, 2H), 3.57-3.67 (m, 4H), 3.42-3.50 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (50 mg, 0.11 mmol) were added methanesulfonyl chloride (18 μL, 0.23 mmol) and DIPEA (59 μL, 0.34 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 15 min and diluted with CH2Cl2. The organic phase was then washed with 1M Na2CO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 28 mg (47%) of the title compound, m/z 517.7 [M−1]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH:13]=[CH:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.F[B-](F)(F)F.[C:26]1([N+]#N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.O.O.C([O-])(=O)C.[Na+]>C(#N)C.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]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C=CC(c2cc(F)ccc2F)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 16 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (59 mg, 064 mmol, 0.020 equiv) was added to a deoxygenated mixture of tert-butyl 3-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (2-2, 900 mg, 3.20 mmol, 1 equiv), benzenediazonium tetrafluoroborate (1-3, prepared by the method described above for 1-1, 614 mg, 3.20 mmol, 1.00 equiv), and sodium acetate trihydrate (1.32 g, 9.60 mmol, 3.00 equiv) in acetonitrile (70 mL) at 23° C. The reaction mixture was stirred for 16 h, then partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×70 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% hexanes in EtOAc) to provide tert-butyl 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (2-3) as an orange oil. LRMS m/z (M+H—CH3) 343.0 found, 343.1 required.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1>>[ClH:1].[ClH:14].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[N:27]3[CH2:28][CH2:29][N:30]([C:2]4[C:3]5[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:31][C:26]3=[N:25][N:24]=2)[NH2:22])=[CH:17][CH:16]=1
Reactant: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: Cl
Product: C[C@@H]1CCc2ncnc(N3CCn4c(nnc4C(N)c4ccc(Cl)cc4)C3)c21
Yield: 64 %

Procedure:
Using the procedure from Example 8, Step 5, using (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (100 mg, 0.30 mmol) to afford (4-chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (75 mg, 0.19 mmol, 64%): LCMS APCI+ (M+H+): 396 (60%), 398 (20%), rt 2.48 min. HPLC purity at 254 nm>99%, rt=1.68 min. 1H NMR (400 MHz, d6-DMSO) □ 9.51 (s, 3H), 8.85 (d, J=9.4 Hz, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 6.08 (br d, J=9.0 Hz, 1H), 5.42 (dd, J=26 Hz, 16 Hz, 1H), 5.19 (dd, J=21 Hz, 18 Hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 3.79 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.32 (m, 1H), 1.82 (m, 1H), 1.15 (t, J=6.8 Hz, 2H), 1.04 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]=[C:12]=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(OC1C=C(C=CC=1)C(O)=O)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[N:33]([CH3:39])[C:32]([CH2:40][OH:41])=[C:31]2[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:13])[O:41][CH2:40][C:32]2[N:33]([CH3:39])[C:34](=[O:38])[C:35]3[C:30]([C:31]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:29][C:28]([Cl:27])=[CH:37][CH:36]=3)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cn1c(CO)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: CC(C)Oc1cccc(N=C=O)c1
Agent: CC(C)Oc1cccc(C(=O)O)c1
Solvent: c1ccccc1
Product: CC(C)Oc1cccc(NC(=O)OCc2c(-c3ccccc3)c3cc(Cl)ccc3c(=O)n2C)c1

Procedure:
To a solution of 3-isopropoxyphenylisocyanate in benzene (25 ml) [prepared from 3-isopropoxybenzoic acid (405 mg) in substantially the same manner as described in Method A of Example 1] was added 6-chloro-1,2-dihydro-3-hydroxymethyl-2-methyl-1-oxo-4-phenylisoquinoline (Reference Example 3) (300 mg), and the mixture was heated for 1.5 hours under reflux. The solvent was distilled off. To the residue was added ethyl acetate. This mixture was washed with water, dilute hydrochloric acid, water, an aqueous solution of sodium carbonate and water, successively, followed by drying (Na2SO4). The solvent was distilled off to leave the title compound as colorless crystals (435 mg).
Reaction SMILES: N1CCCCC1.C1C2C(COC([NH:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]4[CH:47]=[CH:46][CH:45]=[C:44]5[C:40]=4[CH:41]=[CH:42][NH:43]5)=[O:36])=[CH:31][C:30]=3[Cl:48])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[NH2:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[CH:42][NH:43]3)=[O:36])=[CH:31][C:30]=1[Cl:48]
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Piperidine (88 μL, 0.89 mmol) was added to a solution of 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 30 min and then the solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give 3-amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester as an off-white solid (59 mg, 81%). N,N-Dimethylformamide (5 mL) was added, followed by HOAT (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), and thiophene-2-carboxylic acid (18 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40–80% ethyl acetate/hexanes) to give 3-[(thiophene-2-carbonyl)amino]-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (58 mg, 78%). A solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in tetrahydrofuran/methanol/water (3:1:1) was added, and the solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified by HPLC to give 3-(thiophene-2-carbonyl)amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (45 mg, 80% from ester, 48% for three steps) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)nc2)CCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: NCC1(c2ccc(Cl)nc2)CCCCC1
Temperature: 25 °C

Procedure:
A soln. of 1-(6-chloropyridin-3-yl)cyclohexanecarbonitrile (20.1 mmol) in THF (88 mL) was added dropwised to a solution BH3 in THF (60.2 mmol, 1 M). After heating to reflux for 1 h, the reaction mixture was cooled in an ice bath before aq. 2 M HCl (120 mL) was slowly added. The mixture was then heated to reflux for another 20 min. After cooling to RT, the mixture was washed with DCM, then, it was basified with aq. 1 M NaOH and extracted with DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1[O:24]C1C.C1OC1.C(C1C=CC=CC=1O)CCCCCCCC.C1OC1>>[CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([C:14]1([OH:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCc1ccccc1O
Agent: CC1CO1
Solvent: C1CO1
Product: CCCCCCCCCC1(O)CCCCC1

Procedure:
The reaction, filtration, dehydration and solvent removal were carried out by the same procedures as Example 12 except that nonylphenol propylene oxide adduct having a propylene oxide addition mole number of 5.0 was used in place of nonylphenol ethylene oxide adduct having an ethylene oxide addition mole number of 5.0. Nonylcyclohexanol propylene oxide adduct was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 63.8 %

Procedure:
Reaction of 4,5-diphenyl-1H-imidazole (300 mg, 1.36 mmol), NaH (60%, 55 mg, 1.36 mmol), and SEMCl (289 uL, 1.63 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (304 mg, 64%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.88 (t, 2H, J=7.5 Hz), 3.46 (t, 2H, J=9.0 Hz), 5.12 (s, 2H), 7.27–7.38 (m, 3H), 7.40–1.52 (m, 7H), 7.75 (s, 1H).
Reaction SMILES: F[C:2](F)(F)[C:3]([CH3:5])=[O:4].CC1[CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12]C=1.OOS([O-])=O.[K+].C(=O)(O)[O-].[Na+]>C(#N)C.C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.O.O.[Na+].[Na+]>[CH3:2][C:3]12[O:4][CH:5]1[CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:12]2
Reactant: CC1=CCN(C(=O)OCc2ccccc2)C1
Reactant: CC(=O)C(F)(F)F
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])OO
Solvent: O
Solvent: CC#N
Product: CC12CN(C(=O)OCc3ccccc3)CC1O2
Temperature: 0 °C
Yield: 75.6 %

Procedure:
A 0.004 M aqueous solution of EDTA disodium salt dihydrate (354 mL, 0.142 mmol) and 1,1,1-trifluoroacetone (49.6 mL, 567 mmol) was added sequentially to a solution of benzyl 3-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (15.4 g, 70.9 mmol) in acetonitrile (700 mL) at 0° C. A mixture of oxone (153 g, 248 mmol) and sodium bicarbonate (35.7 g, 425 mmol) was added in 5 portions over 1 h. After additions were complete, the mixture was stirred for another hour at 0° C. and filtered. The filtrate was extracted with dichloromethane (3×300 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-40% ethyl acetate in hexanes, gave benzyl 1-methyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (12.5 g, 76% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.73-7.30 (m, 5H), 5.21-4.94 (m, 2H), 4.33-4.05 (m, 1H), 3.93-3.70 (m, 2H), 3.56-3.13 (m, 2H), 1.58-1.44 (m, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([S:19][CH2:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)C([O-])=O.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36](/[CH:44]=[C:45]1/[C:46](=[O:68])[N:47]([CH2:50][C:51]3[CH:56]=[CH:55][N+:54]([CH2:57][C:58](=[O:67])[NH:59][C:60]4[CH:65]=[CH:64][C:63]([OH:66])=[CH:62][CH:61]=4)=[CH:53][CH:52]=3)[CH2:48][CH2:49]/1)=[C:37]2[C:41]([OH:43])=[O:42].Cl>CN(C)C(=O)C.O.C(#N)C>[OH:66][C:63]1[CH:62]=[CH:61][C:60]([NH:59][C:58]([CH2:57][N+:54]2[CH:55]=[CH:56][C:51]([CH2:50][N:47]3[CH2:48][CH2:49]/[C:45](=[CH:44]\[C:36]4[CH2:35][S:34][C@H:33]5[N:38]([C:39](=[O:40])[C@H:32]5[NH:31][C:21](=[O:23])[CH2:20][S:19][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:37]=4[C:41]([O-:43])=[O:42])/[C:46]3=[O:68])=[CH:52][CH:53]=2)=[O:67])=[CH:65][CH:64]=1
Reactant: O=C(O)CSc1ccccc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CC#N
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccccc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)cc1

Procedure:
With 70.0 mg (0.43 mmol) 1,1′-carbonyldiimidazole, 71.0 mg (0.43 mmol) 2-(phenylthio)acetic acid and 188.4 mg (0.29 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml ml N,N-dimethylacetamide. The resulting solid was suspended in 6 ml water:acetonitrile (1:1) and HCl was added until all compound dissolved. After column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitril (1:0, 4:1, 3:1, 2:1, 1:1) the organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C.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>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (271 g, 0.81 mol) (from multiple batches), tetrakis(triphenylphosphine)palladium (0) (37.4 g, 0.032 mol), 2 M sodium carbonate solution (1.3 L) and 4-hydroxyphenyl boronic acid (134 g, 0.97 mol) in ethylene glycol dimethyl ether (1.5 L) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 L) and water (2 L). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to a dark semisolid residue. The crude material was purified by crystallization from dichloromethane-heptane to give 199 g of the product as a tan solid. 1H NMR (DMSO-d6): 9.64 (s, 1H), 8.76 (d, J=9 Hz, 1H), 8.21 (m, 2H), 8.07 (d, J=7 Hz, 1H), 7.93 (m, 1H), 7.66 (d, J=9 Hz, 2H), 7.58 (t, J=8 Hz, 1H), 6.89 (d, J=9 Hz, 2H), 3.93 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].[ClH:28]>C1COCC1.CO>[ClH:28].[F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
24.06 g (70.1 mmol) of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 120A were initially charged in 1.5 l of THF/methanol (5:1), 350.4 ml (350.4 mmol) of 1 N aqueous lithium hydroxide solution were added and the reaction mixture was stirred at 40° C. for 2.5 h. After cooling, the pH was adjusted to about 4 using 1 N aqueous hydrochloric acid and the solution was freed from THF/methanol under reduced pressure. The residue was cooled and the precipitated solid was filtered off and dried under reduced pressure. This gave 22.27 g (100% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)[C:17]([O:19]C)=[O:18].[OH-].[K+].[CH:39]([NH:42][CH:43]([CH3:45])[CH3:44])([CH3:41])[CH3:40]>C1C=CC=CC=1.CCOCC.CCCCCC.C(O)C.O.CO>[CH:39]([NH:42][CH:43]([CH3:45])[CH3:44])([CH3:41])[CH3:40].[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:25][CH:26]=2)[C:17]([OH:19])=[O:18])[CH:4]=1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(OCOc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4.05 g of m-trifluoromethylphenol, 40 ml of methanol and 1.19 g of sodium methoxide is added 7.71 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 10 ml of benzene. The mixture is refluxed for 21 hours and the solvent removed under reduced pressure. The residue is triturated with dichloromethane, filtered and the filtrate chromatographed on a column of silica gel (eluent methylene chloride). The main fraction is collected and the solvent removed under reduced pressure to give an oil. The above oil is combined with 4.0 g of potassium hydroxide, 75 ml of ethanol:water (9:1) and the mixture is refluxed for 4 hours. The mixture is concentrated under reduced pressure, diluted with water and acidified with concentrated HCl. The mixture is extracted with dichloromethane, the extract is dried (MgSO4) and the solvent removed under reduced pressure to give an oil. The above oil is dissolved in ether, diisopropylamine is added and the solution is diluted with hexane. Chilling and filtering gives 6.75 g of product as off-white crystals, mp 95°-100° C.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[C:29]([F:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=1[F:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:31][C:27]1[CH:28]=[C:29]([F:30])[C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([F:32])[CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3c(F)cc(Cl)cc3F)c[nH]c12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.30 g (4.57 mmol) of potassium cyanide was added to 1.05 g (2.28 mmol) of the compound from Example 111A in 21 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.74 g (83% of theory) of the target compound was obtained.