Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:13][CH:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC1CCN(c2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-ylamine (0.50 g, 2.84 mmol) (from Example 123) and 4-cyanobenzaldehyde (0.74 g, 5.64 mmol) were dissolved in anhydrous methanol (10 mL) and acetic acid (0.97 mL, 17 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium cyanoborohydride (0.267 g, 4.25 mmol) was added, then the reaction mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure and the residue was partitioned between sat. NaHCO3 (aq) (50 mL) and dichloromethane (25 mL), and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane--30% ethyl acetate to give the product as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[OH:17])([CH3:7])[CH3:6].C(OCC)(=O)C>C(O)(=O)C>[CH:14]([C:10]1[CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=[C:8]([CH:5]([CH3:7])[CH3:6])[C:9]=1[OH:17])([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
78.3 mmol (4.93 g) of fuming nitric acid are added dropwise to a solution, cooled to 0° C., of 53.9 mmol (9.62 g) of 2,6-diisopropylphenol in 350 ml of acetic acid. The reaction mixture is stirred at 0° C. for 1 hour 30 minutes and is then poured into a mixture of ethyl acetate and ice. The organic phase is isolated and then washed with water. After drying and evaporating off the solvent, an oily residue is recovered which is purified by chromatography on silica gel using a petroleum ether: ethyl acetate mixture 9:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[C:3]=1[F:15].CO[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([N:19]1[CH2:20][CH2:10][C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[F:15])([C:11]([F:14])([F:13])[F:12])[CH2:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1F)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(Cl)cc1C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
1,5-dichloro-2-fluoro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.2 g) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.7 g) were dissolved in dichloromethane (100 ml) and slowly added dropwise with a dichloromethane solution (8 ml) of anhydrous trifluoroacetic acid (0.15 ml) under ice cooling. Upon the completion of the dropwise addition, the reaction temperature was raised to the room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1-benzyl-3-(3,5-dichloro-2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (3.7 g).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Br:6])#[N:2].[CH:11]1[CH:16]=[CH:15][C:14]([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>CC#N>[Br-:6].[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1)#[N:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccccc1CBr
Solvent: CC#N
Product: N#Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 72 h

Procedure:
A mixture of 2-cyanobenzyl bromide (Aldrich; 2.0 g) and Ph3P (3.2 g) in 30 mL CH3CN were stirred for 3 days under nitrogen. The solution was concentrated to 15 mL, Et2O added, and the precipitate collected to provide 2-cyanobenzyltriphenylphosphonium bromide as a white solid.
Reaction SMILES: BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]3[CH:38]=[N:39][C:40]([C:41]([NH2:43])=O)=[C:30]3[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[C:41]([C:40]1[N:39]=[CH:38][N:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[N:29][C:30]=12)#[N:43]
Reactant: NC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ncn2c1nc(N1CCOCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bromine (0.15 ml) was added dropwise to a solution of triphenylphosphine (0.8 g) in 15 ml of methylene chloride at 5° C. 5-morpholino-imidazo[1,5-a]quinazoline-3carboxamide (0.5 g) and triethylamine (0.83 ml) were added to the solution. The resulting reaction mixture was stirred at room temperature for 3 hours and evaporated in vacuo. Ethyl acetate (10 ml) was added to the residue and crude crystals of the title compound were isolated by filtration. The dried crystals were dissolved in acetone (30 ml) and an excess of hydrogen chloride in diethyl ether was added separating the hydrochloride of the title compound as beige crystals. M.p. 225°-228° C. Yield 0.3 g.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42])([O-:37])=[O:36]>ClCCl.CN(C=O)C>[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH:42][C:14]([C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])=[O:16])([O-:37])=[O:36]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
A stirring slurry of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (1.0 g, 4.06 mmol) in dichloromethane (8.2 mL, 0.5 M) was treated with oxalyl chloride (1.1 mL, 12.2 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1–2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (8.2 mL, 0.5 M). To the stirring mixture at 0° C. was added diisopropylethyl amine (1.8 mL, 10.2 mmol) followed by 3-nitrobenzylamine hydrochloride salt (1.2 g, 6.1 mmol). Stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (1.0 g, 65%) as a yellow solid: Rf 0.33 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (bd t, J=6.2 Hz, 1 H), 8.10 (dd, J1=7.2 Hz, J2=2.4 Hz, 1 H), 7.84 (d, J=9.3 Hz, 1 H), 7.79 (d, J=7.5 Hz, 1 H), 7.63 (t, J=8.0 Hz, 1H), 7.52–7.43 (m, 5 H), 7.40–7.34 (m, 1H), 7.20 (d, J=12.9 Hz, 1H), 4.61 (d, J=6.0 Hz, 2 H), 3.96 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](=O)[NH:20][N:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][C:21]([Cl:28])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3ccc(=O)[nH]n3)cc2)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCC(c2ccc(-c3ccc(Cl)nn3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 50 Ml flask was charged with {4-[4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (0.76 g, 2.2 mmol, 1.0 equiv) in 20 Ml toluene followed by phosphorous oxychloride (0.62 Ml, 6.7 mmol, 3.0 equiv). The suspension was heated to 100° C., at which point a homogeneous solution ensued. The reaction was stirred overnight at 100° C., then cooled to room temperature. Removal of volatiles in vacuo afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.17 (m, 2 H) 1.20 (t, J=7.07 Hz, 3 H) 1.43-1.53 (m, 2 H) 1.78-1.90 (m, 5 H) 2.18 (d, J=6.57 Hz, 2 H) 2.44-2.52 (m, 1 H) 4.08 (q,J=7.07 Hz, 2 H) 7.29 (d, J=8.34 Hz, 2 H) 7.46 (d, J=9.09 Hz, 1 H) 7.72 (d, J=9.09 Hz, 1 H) 7.90 (d, J=8.59 Hz, 2 H); (M+H)+ 359.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5]([CH2:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
NaH (13.8 g, 0.6 mole) was washed twice with hexane (2×50 ml) and suspended in 250 ml of freshly distilled THF. Next ethyl acetoacetate (75 ml, excess) was added dropwise carefully while the receiving flask was cooled at -10° C. After the addition was complete, it was stirred at -10° C. for 2 hours and at room temperature for 30 min. Benzylbromide (51.0 g, 0.3 mole) in THF was added dropwise at room temperature to the above solution. The reaction mixture was stirred overnight at room temperature. The reaction was terminated the next day by pouring into ice cold water, brought to neutral pH, and extracted with ether/ethylacetate. The combined ether/ethylacetate extracts were rinsed over brine and dried over Na2SO4. Removal of the solvent followed by careful vacuum distillation gave ethyl-benzylacetoacetate, bp 276° C. IR: (neat), cm-1 : 2900-3050, 1690-1760 (broad), 1655. NMR (CDCl3):δ:1.25 (t1 3H, CH2CH3); 2.25 (s, 3H, COCH3); 3.20 (d, 2H, benzylic CH2); 3.8 (t, 1H, COCHCO); 4.20 (q, 2H, OCH2CH3); 7.15-7.35 (m, 5H, Ar-H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:40])([F:39])[S:34]([O:37]C)(=[O:36])=[O:35]>ClCCl>[F:32][C:33]([F:40])([F:39])[S:34]([O-:37])(=[O:36])=[O:35].[CH3:33][N+:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])=[CH:22][CH:23]=2)=[O:16])=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[CH:1]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OC(=O)c2c3ccccc3nc3ccccc23)cc1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1c2ccccc2c(C(=O)Oc2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Into a 50 mL round bottom flask equipped with magnetic stirrer under argon atmosphere charged a solution of 1.6 parts of 4-(tert-butyldimethylsilyloxy)phenyl acridin-9-carboxylate in 25 mL of dichloromethane. 3.2 Parts of methyl trifluoromethanesulfonate was added to the solution and stirred for 40 hrs at room temperature. Bright yellow solid was collected by filtration, washed with 2×1 mL of dichloromethane and air dried for 4 hr to yield 1.44 parts of 4-(tert-butyldimethylsilyloxy)phenyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate having the following structure confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][NH:27][C:28]([NH2:30])=[S:29]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NNC(N)=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
3-Fluoro-4-nitrobenzenecarboxylic acid (8.4 g, 45 mmol) and 1,1′-carbonyldiimidazole (10 g, 64 mmol) were mixed in 100 mL DMF. The mixture was stirred at 20° C. for 1 hour. A clear yellow solution formed. To this mixture was added thiosemicarbazide (8.3 g, 91 mmol). The resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was concentrated under vacuum to remove almost all the DMF. The remaining residue was treated with 2 N HCl with stirring until the solution reached pH 4. Upon standing, a yellow solid formed. The pure product was obtained as a yellow solid after filtering, washing with water, and drying (8.02 g, 68% yield). LCMS (API-ES) m/z (%): 259.1 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (s, 1H) 7.90 (d, J=8.41 Hz, 1H) 7.99 (s, 1H) 8.04 (d, J=11.93 Hz, 1H) 8.28 (t, J=8.02 Hz, 1H) 9.47 (s, 1H) 10.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:14]([CH3:16])[CH3:15])([CH2:20][CH2:21][CH2:22][Cl:23])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCCCBr
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 15 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile (6a) in toluene is slowly added to sodium amide (1.5 eq) in toluene, and the resulting mixture warmed to 80°-90° C. for one hour. The mixture was then cooled to 15° C. and 1-bromo-3-chloropropane (2 eq) slowly added and stirred for two hours at room temperature. The mixture is then carefully poured into ice water, extracted with CH2Cl2, and vacuum distilled to yield 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (21, b.p. 160°-165°/0.05 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][NH:19][CH2:20][CH3:21]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:18][NH:19][CH2:20][CH3:21]
Reactant: CCNC
Reactant: Fc1cc(Br)c(CCl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCNCCc1cc(F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 146 μl of methylethylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][NH:29][CH3:30])[CH:9]=1
Reactant: CNC(=O)COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OCC(=O)NC)cc2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4f (100 mg, 0.19 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of 1 mL of trifluoracetic acid and then the reaction solution was stirred for 1 h. 10 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product 2-(4-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide 4 (15 mg, a colorless oil), and the yield of the three steps was 16%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42]([O:50][CH2:51][CH3:52])[N:41]=1.Cl>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:31])([CH3:30])[CH3:32])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([O:50][CH2:51][CH3:52])[N:41]=2)[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ccccc2c(Cl)n1
Reactant: CCC1CC1(NC(=O)C1CC(O)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc2ccccc2c(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C2)n1
Yield: 42 %

Procedure:
1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (See Example 33), 0.21 g, 0.46 mmol) was diluted in DMSO (4 mL) and treated with potassium tert-butoxide (0.26 g, 2.3 mmol) at rt for 30 min. 1-Chloro-3-ethoxyisoquinoline (0.100 g, 0.48 mmol) was added and the solution allowed to age overnight. Icewater was added, followed by 1M HCl until the solution reaches pH 3. Extraction with EtOAc was followed by washing of the combined organics with brine and drying over anhydrous Na2SO4 prior to concentration in vacuo. The resulting residue was purified by preparatory HPLC to produce 0.127 g (42%) of 1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(3-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid as a white solid. LCMS found 626.90 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH3:20])[CH:3]=[CH:4][C:5]=1[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])#[N:8]
Reactant: COC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1C#N
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
To 15C (450 mg, 2 mmol) in pyridine (10 mL) at 0° C. was added methyl chloroformate (0.8 mL, 10 mmol). The reaction was stirred at 0° C. for 20 min, then warmed to rt for 2 h. The reaction was concentrated, then diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-60% ethyl acetate/hexanes) to provide 15D (490 mg, 88%). LC-MS: 283.35 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.N1C=CC=CC=1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:35][O:36][CH2:37][C:38]([O:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:18]3[CH2:22][CH:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:17])=[O:39]
Reactant: COCC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)OCC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
The (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (263 mg, 0.67 mmol) was slurried in dry CH2Cl2 (10 mL) and cooled to 0° C. in an ice bath. The soluton became homogeneous after the addition of the pyridine (0.216 mL, 2.67 mmol). Next, the methoxyacetyl chloride (0.064 mL, 0.69 mmol) was added drop wise. The reaction was stirred at 0° C. for 30 minutes and then the ice bath was removed. After one hour, the reaction was found to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with CH2Cl2 (100 mL) and then washed with 1N HCl/brine (50 mL each), saturated NaHCO3 /brine (50 mL each), and brine (100 mL). Each aqueous portion was back-extracted with more CH2Cl2 (2×25 mL). The organic layers were combined, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to give an orange solid. This solid was chromatographed on silica gel (35 g,) eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give an orange solid. The latter solid was recrystallized by dissolving it in a minimal amount of CH2Cl2 /MeOH and then triturating with ether to yield 158 mg (51%) of the title compound as an off-white solid with a melting point of 147°-148° C. Aqueous solubility (pH 7, phosphate buffer) was 6.4 mg/ml.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>CN(C)C=O.ClCCl.CO>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[N:7][CH:6]=2)=[O:9])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Reactant: CCCCN=C=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCCCNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
(6-Aminopyridin-3-yl)(4-benzylpiperazin-1-yl)methanone (90 mg, 0.304 mmol) and n-butyl isocyanate (103 μl, 91 mg, 0.914 mmol) were combined in dimethylformamide (3 mL) and the mixture was heated to 100° C. for 6 hours. After this time the mixture was taken up in dichloromethane/methanol and loaded on to a strong cation exchange column (2 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave a residue that was further purified by silica chromatography (eluting with 5% methanol/dichloromethane) to give the title compound (58 mg).