Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:15]([N:6]1[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (8.0 g. 28.6 mmol) and sodium hydride (1.03 g, 43 mmol) in DMF (150 mL) was stirred at rt for 1 hour. n-Hexyl bromide (8.03 mL, 57.2 mmol) was added, and the mixture was stirred for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed, dried, filtered and evaporated. Chromatography of a portion of the residue over silica gel (20% petroleum ether/methylene chloride) gave 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)C1C=CC=CC=1.[CH2:25]([O:32][C:33]([O:35]N1C(=O)CCC1=O)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.CN(C=O)C.O.[OH-].[OH-].[Pd+2]>[CH2:25]([O:32][C:33]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:35])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(NCC1CN(Cc2ccccc2)CCO1)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CN(C(=O)OCc2ccccc2)CCO1)c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (Step 1 above) (320 mg) was dissolved in ethanol (20 mL) and hydrogenated at 1 atm over 20% Pd(OH)2/C (250 mg) for 18 h. The catalyst was removed by filtration, washed with ethanol, and the filtrate evaporated, to give a solid. A portion (21 mg) of this material was dissolved in DMF (0.5 mL) and N-(benzyloxycarbonyloxy)succinimide (27 mg) was added. The reaction mixture was stirred for 10 min, one drop of water was added and the solution was purified by preparative reverse phase HPLC to give the 2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine4-carboxylic acid benzyl ester compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Nc1cc[nH]n1
Product: Cc1ccc(Cl)cc1NC(=S)Nc1cc[nH]n1
Yield: 66 %

Procedure:
Prepared using Method A from 5.5 g (30.1 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (30.1 mmol) of 3-amino-1H-pyrazole to give 5.3 g of title compound as a white solid (66% yield, m.p. 221-222° C.).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][NH:7][C:8]([NH:10][CH3:11])=[S:9])=O.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+].Cl>>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]1[N:10]([CH3:11])[C:8](=[S:9])[NH:7][N:6]=1
Reactant: CNC(=S)NNC(=O)c1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2F)n[nH]c1=S
Yield: 48.1 %

Procedure:
1-(2-Fluorobenzoyl)-4-methylthiosemicarbazide (11.3 g, 4.97×10-2 mole) or the aforementioned mixture of the above and pyridine hydrochloride and 1 molar aqueous NaHCO3 (480 ml, 4.80×10-1 mole) were stirred and heated to reflux After refluxing overnight, the reaction was cooled in an ice bath before being acidified by the drop-wise addition of concentrated hydrochloric acid (40 ml, 4.8×10-1 mole). The resulting precipitate was collected by filtration, washed with a little H2O, and dried by suction. This afforded a colorless powder 5.0 g (48%). This material was of sufficient purity to go on to the next step. If desired this material could be crystallized from EtOAc/hexane affording colorless needles, mp 137°-139° C.
Reaction SMILES: N1CCCCC1.C([Li])CCC.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][CH:21]=1.[CH:26](=[O:28])[CH3:27]>C1COCC1>[CH3:12][O:13][CH2:14][O:15][C:16]1[C:17]([CH:26]([OH:28])[CH3:27])=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[N:20][CH:21]=1
Reactant: COCOc1ccc(C(F)(F)F)nc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COCOc1cnc(C(F)(F)F)cc1C(C)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of piperidine, 2,2,6,6-tetramethyl-(9.2 ml, 54 mmol) in THF (400 ml) at −78° C. was added butyllithium (˜2.5 m in toluene; 18 ml, 45 mmol) dropwise. The reaction was then stirred at 0° C. for 5 min at −78° C., and a solution of 5-(methoxymethoxy)-2-(trifluoromethyl)pyridine (7.5 g, 36 mmol) in THF (100 ml) was added dropwise. The mixture was stirred for an additional 10 min, then acetaldehyde (20 ml, 362 mmol) was added and stirring continued for 15 min. the reaction was slowly quenched with H2O, warmed to RT, extracted with EtOAc (3×), combine organic layers were dried over MgSO4, filtered, concentrated and the crude product was purified by ISCO (20% EtOAc/Hexanes) to give the title compound as a light yellow solid. MS (m+1): 252.2.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:23])[CH2:10][C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:7].[NH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>O.C(O)C>[CH2:6]([O:8][C:9]([C:10]1[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][NH:24][C:11]=1[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])[CH3:7]
Reactant: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Reactant: NCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
A stirred solution of anhydrous sodium acetate (2.66 g, 82 mmol) in 140 ml of water was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (4.20 g, 16.2 mmol) in 20 ml of absolute ethanol at room temperature. Upon completion of the addition, the mixture was stirred for 5 minutes, added with 2-amino-1-phenyl-ethanone (2.5 g, 14.6 mmol) and heated to reflux for 3 hours. The resulting mixture was added with water (300 ml), extracted with ethyl acetate (100 ml×3). The organic extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.0 g, 88.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21]Br)[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C1CC1
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1C1CC1
Temperature: 70 °C

Procedure:
To a solution of 4-(3-bromo-propoxy)-3-cyclopropyl-benzofuran-2-carboxylic acid ethyl ester (92 mg) in ethanol (4 ml) was added 3-aminomethylpyridine (500 μl) and heated at 70° C. overnight. The mixture was diluted with ethyl acetate (10 ml) and washed with saturated aqueous ammonium chloride solution (5 ml) and water (5 ml), then dried over anhydrous sodium sulfate, concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 3-cyclopropyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester as a pale yellow oil (108 mg). ESI-MS: m/z 395 (MH+); 1H-NMR (CDCl3): δ 0.95-1.08 (4H, m), 1.44 (3H, t, J=7.3 Hz), 2.10 (2H, quintet, J=6.3 Hz), 2.54-2.60 (1H, m), 2.89 (2H, t, J=6.3 Hz), 3.85 (2H, s), 4.17 (2H, t, J=6.3 Hz), 4.45 (2H, q, J=7.3 Hz), 6.63 (1H, d, J=7.9 Hz), 7.13 (1H, d, J=7.9 Hz), 7.21-7.34 (2H, m), 7.68 (1H, d, J=7.9 Hz), 8.48 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.56 (1H, d, J=1.7 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:43])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1COCC1>[C:37]1([O:36][C:35](=[O:43])[NH:3][C:4]2[CH:27]=[CH:26][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=4)=[CH:13][N:14]=3)=[CH:6][CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (700 mg, 1.57 mmol) in THF (20 mL) was added triethylamine (1.1 mL, 7.89 mmol). To the resulting solution was then added dropwise phenyl chlorocarbonate (0.39 mL, 3.14 mmol) under ice cooling. The resulting reaction solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, whereupon the residue solidified into a powder. The powder was filtered, and washed with diethyl ether, to thereby yield 470 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(NC(=O)OC(C)(C)C)C4)c3n2)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(N)C4)c3n2)c2ccc(Cl)cc21
Reaction time: 18 h

Procedure:
The more polar, diastereomer A of (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester (53 mg, 101 μmol) was dissolved in dichloromethane (5 mL) and treated with TFA (1.19 g, 803 μL, 10.4 mmol), the light yellow solution became a bright red-orange solution, stirring continued for 18 h at room temperature. Solvents were evaporated and the residue dissolved in dichloromethane/MeOH, adsorbed on silica gel and purified by chromatography (25 g column, 50 μm from Thomson, 0-10% MeOH containing 10% ammonium hydroxide in dichloromethane, 10 min gradient) to give an off white solid that was sonicated in MeOH and allowed to stand to promote complete solid formation. The solid was separated by decanting the mother liquor and dried under high vacuum to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide (diastereomer A) (27 mg, 63%) as an off-white solid. MS (M+H)+=424; 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.38-8.49 (m, 2H), 8.06 (d, J=7.9 Hz, 1H), 7.99 (s, 1H), 7.33 (d, J=10.2 Hz, 1H), 4.16 (s, 3H), 3.91 (d, J=4.2 Hz, 1H), 3.32 (br. s., 1H), 3.15 (s, 1H), 2.22 (d, J=11.0 Hz, 1H), 2.04 (d, J=11.7 Hz, 1H), 1.79 (br. s., 1H), 0.98-1.24 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[N:8][CH:7]=1)=[O:4].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21]([C:23]1([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:13]2.C(OCC)C>C(#N)C>[CH:21]([O-:22])=[O:20].[C:30]1([C:23]2([C:21]([O:20][C@@H:14]3[CH:15]4[CH2:18][CH2:19][N+:12]([CH2:2][C:3](=[O:4])[NH:5][C:6]5[CH:11]=[CH:10][N:9]=[N:8][CH:7]=5)([CH2:17][CH2:16]4)[CH2:13]3)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CCl)Nc1ccnnc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccnnc1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.5 %

Procedure:
2-Chloro-N-pyridazin-4-yl-acetamide (Example 27a) (58 mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (100 mg) in acetonitrile (2 mL). The reaction mixture was allowed to stir at room temperature for 24 h. Diethyl ether (2 mL) was added to the reaction mixture and stirred for 15 minutes. The solid was filtered off, washed with diethyl ether, and dried under vacuum at 40° C. overnight. The filtrate was evaporated, combined with the solid and purified by column chromatography, eluting with 0-15% MeOH/dichloromethane. Further purification by reverse-phase prep HPLC with gradient elution from 15% MeCN/H2O containing 0.1% formic acid increasing by 1% per minute gave the title compound (19 mg) as a colourless gum.
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])[CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[OH:8][NH:9][C:10]([C:12]1[CH:17]=[N:16][C:15]([N:18]2[CH2:19][CH:20]3[CH:22]([CH:21]3[N:24]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])[CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[CH2:23]2)=[N:14][CH:13]=1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2=O)S(=O)(=O)c2ccc3ccccc3c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(NO)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2=O)S(=O)(=O)c2ccc3ccccc3c2)nc1
Reaction time: 8 h
Yield: 11 %

Procedure:
To N-(1-isobutoxyethoxy) 2-(6-{(naphthalene-2-sulfonyl)-[2-(2-oxopyrrolidin-1-yl)ethyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide was added TFA:DCM:MeOH (3.5 ml, 1:2:2 mixture). The solution was stirred overnight, and then concentrated in vacuo. The product was purified by reverse phase HPLC to yield the title compound as a white solid (18 mg, 11%). LCMS Purity >98%, m/z 537 [M+H]+, 1H NMR (300 MHz, d6-DMSO) 1.83-1.95 (3H, m), 2.17 (2H, t, J=8.2 Hz), 2.22-2.26 (2H, m), 3.36-3.45 (6H, m), 3.52-3.59 (2H, m), 3.79 (2H, t, J=11.8 Hz), 7.66-7.76 (2H, m), 7.83 (1H, dd, J=1.8, 8.7 Hz), 8.04-8.09 (1H, m), 8.18 (1H, d, J=8.8 Hz), 8.22-8.27 (1H, m), 8.53-8.56 (1H, m), 8.63 (2H, s), 8.99 (1H, br s), 11.03 (1H, br s).
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:29].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][K:29])=[O:25])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [K+]
Reactant: CCCN(CCCC(=O)OC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN(CCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 163.2 %

Procedure:
A round bottom flask fitted with a heating mantle and an overhead stirrer was charged with C4F9SO2N(C3H7)CH2CH2CH2COOCH3 (63.0 g; 0.143 mole), KOH (11.0 g; 0.196 mole; pellets) isopropanol (22 mL) and deionized water (18 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)CH2CH2CH2COOK (108.6 g; 53.4% solids).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][O:14]2.[C@H:20]1([NH:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:40])[CH:36]=3)[N:31]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[C@H:20]1([NH:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:40][C:1]([N:17]4[CH2:18][C@@H:13]5[CH2:19][C@H:16]4[CH2:15][O:14]5)=[O:12])[CH:36]=3)[N:31]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1O[C@@H]2CN[C@H]1C2
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1C[C@@H]2C[C@H]1CO2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=401.6 (M+H+).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11](C=CC(O)=O)[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1.C1(C2C=CC(O)=CC=2)C=CC=CC=1.[H-].[Na+].[Br:41]C1C=C(C=CC=1)CBr>CN(C)C=O.O>[Br:41][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][O:7][C:4]1[CH:5]=[CH:6][C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:2][CH:3]=1
Reactant: BrCc1cccc(Br)c1
Reactant: O=C(O)C=Cc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Agent: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Yield: 95 %

Procedure:
3-(3-(Biphenyl-4-yloxymethyl)phenyl)acrylic acid ##STR3## To a solution of 4-phenylphenol (6.13 g, 36 mmol) in dry N,N-dimethyl-formamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (1.73 g, 43.2 mmol, 60% dispersion in mineral oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. 3-Bromobenzyl bromide (10.0 g, 39.61 mmol) was added in portions and the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture water (50 ml) was added. The precipitate was filtered off and washed with water (3×100 ml), 96% ethanol (2×30 ml), diethyl ether (2×80 ml), and dried in vacuo at 50° C. for 18 h affording 11.64 g (95 %) of 4-(3-bromo-benzyloxy)biphenyl as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].N1C=CC=CC=1.[S:17](Cl)([CH3:20])(=[O:19])=[O:18]>ClCCl>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 59.8 %

Procedure:
Ex-100A: A solution of 4-aminoacetophenone (5.0 g, 37.0 mmol) and pyridine (3.0 mL) in anhydrous dichloromethane (300 mL) was treated with mesyl chloride (2.86 mL, 37.0 mmol). The reaction was stirred for 84 hours at room temperature under nitrogen, and then quenched with saturated NH4Cl solution (100 mL). The organic phase was collected, washed with water (100 mL) and brine, dried over sodium sulfate, and concentrated over silica. The material was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give 4.72 g (60%) of N-(4-acetyl-phenyl)-methanesulfonamide as a yellowish oil. 1H-NMR (DMSO-d6) δ 10.28 (s, 1H), 7.90 (d, 1H), 7.24 (d, 1H), 3.06 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:11]=[CH2:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(C(C(C)C)=C[CH2:18][B:19]([O-])[O-:20])(C)C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[OH:20][B:19]1[CH2:18][CH:12]=[CH:11][CH:2]([CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])[O:1]1
Reactant: CC(C)C(=CCB([O-])[O-])C(C)C
Reactant: C=CC(O)CC(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1C=CCB(O)O1
Temperature: 65 °C
Yield: 92.7 %

Procedure:
To a solution of tert-butyl 3-hydroxypent-4-enoate, XLVI (674 mg, 3.92 mmol) in DCM (15 mL) was added diisopropylallylboronate XLV (2 g, 11.76 mmol) via syringe. To the mixture was then added Grubbs' first generation catalyst (260 mg, 0.31 mmol, 7.5 mol %) and the vessel was purged with argon. The reaction was heated at 65° C. under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified by flash column chromatography (100% hexane→30% EtOAc/hexane) to afford tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)acetate XLVII (770 mg, 3.63 mmol, 92.7% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[C@H:14]([CH3:37])[C@@H:15]2[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])=[O:5])[CH3:2].C(=O)([O-])[OH:41].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:38]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:13]1[C@H:14]([CH3:37])[C@@H:15]2[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19])=[O:41])=[O:5])[CH3:39]
Reactant: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
10 ml of a methylene cloride solution containing 554 mg (1.00 mmol) of 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 37) were cooled in an ice bath, and then 1.5 ml (1.5 mmol) of a 1M aqueous solution of sodium hydrogencarbonate and then 215 mg (1.00 mmol) of m-chloroperbenzoic acid (80% purity) were added, and the reaction solution was stirred for 90 minutes at the same temperature. At the end of this time, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was stirred for 10 minutes to complete the reaction. The reaction solution was then diluted with methylene chloride, ice-cooled, washed with an aqueous solution of sodium hydrogencarbonate and condensed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel. Elution with ethyl acetate afforded 145 mg (yield 25%) of an isomer of the title compound of lower polarity (the isomer is a result of the configuration of the S-oxide), followed by 96 mg (yield 17%) of a higher polarity isomer of the title compound, both as foam-like solids.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.[CH3:18][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-n2cnc(Br)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(4-bromo-1H-imidazol-1-yl)-3-methoxybenzoic acid (1.90 g) in toluene (20 mL) and methanol (5 mL) was added trimethylsilyldiazomethane (2M hexane solution, 3.84 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added trimethylsilyldiazomethane (2M hexane solution, 0.96 mL), the mixture was stirred for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (1.32 g).