Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(OC)=CC(CC(OC)=O)=CC=1OC)C.[H-].[Na+].C(OC)(=O)C(OC)=O.[CH2:28]([C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([CH:38]([C:43](=O)C(OC)=O)[C:39]([O:41][CH3:42])=[O:40])=[CH:32][C:31]=1[O:49][CH3:50])[CH3:29].C=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCCC1.O>[CH2:28]([C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([C:38](=[CH2:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:32][C:31]=1[O:49][CH3:50])[CH3:29]
Reactant: CCc1c(OC)cc(C(C(=O)OC)C(=O)C(=O)OC)cc1OC
Agent: C=O
Agent: CCc1c(OC)cc(CC(=O)OC)cc1OC
Agent: COC(=O)C(=O)OC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)c1cc(OC)c(CC)c(OC)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 56.6 %

Procedure:
c 1) A solution of 80.43 g (337.5 mmol) of methyl (4-ethyl-3,5-dimethoxy-phenyl)-acetate in 400 ml of toluene was added dropwise to a suspension of 22.1 g (506 mmol) of NaH (55% in mineral oil) in 400 ml of tetrahydrofuran and 40.86 g (346 mmol) of dimethyl oxalate and the mixture was stirred at room temperature for 65 hours. The reaction mixture was poured on to 300 ml of ice-water and washed twice with 250 ml of diethyl ether. The aqueous phase was adjusted to pH 1 with 25% HCl and extracted three times with 300 ml of diethyl ether. The combined phases were dried (MgSO4), filtered and evaporated. The thus-obtained dimethyl 2-(4-ethyl-3,5-dimethoxy-phenyl)-3-oxo-succinate (101.9 g, 314.3 mmol) was suspended in 150 ml of water and treated with 61 ml (812 mmol) of formaldehyde solution (37% in water). Subsequently, a solution of 43.4 g of potassium carbonate in 150 ml of water was slowly added dropwise thereto and the mixture was stirred at room temperature for 12 hours and then extracted three times with 250 ml of diethyl ether. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography of the resulting residue (silica gel, hexane/methylene chloride 1:2) gave 44.5 g (53%) of methyl 2-(4-ethyl-3,5-dimethoxy-phenyl)-acrylate as a colorless wax, Rf=0.635 (silica gel, methylene chloride/hexane 2:1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[C:12]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O-:27].[Na+]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[C:12]([S:15]([C:18]2[CH:19]=[N:20][C:21]([O:27][CH3:26])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(Cl)nc2)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)C)on2)cn1
Temperature: 60 °C
Yield: 31.5 %

Procedure:
To a solution of 115 mg (0.30 mmol) N-(5-tert-butyl-isoxazol-3-yl)-2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionamide in methanol (3 mL) were added 0.14 mL (0.6 mmol, 25 wt % solution in methanol) of sodium methoxide solution. The reaction mixture was heated in a sealed tube to 60° C. for 4 h. The solution was concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent DCM, 0-20% ethyl acetate) to afford 36 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(6-methoxy-pyridine-3-sulfonyl)-2-methyl-propionamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].CCN(CC)CC.[CH:31]1([C:34]#[C:35][Si](C)(C)C)[CH2:33][CH2:32]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:35]#[C:34][CH:31]3[CH2:33][CH2:32]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)C#CC1CC1
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(C#CC3CC3)c2c1C
Temperature: 80 °C
Yield: 15 %

Procedure:
To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (1.8 g, 5.1 mmol, 1 eq), in 2 mL of DMF under nitrogen was added 200 mg of PdCl2(PPh3)2 (0.28 mmol, 0.05 eq), Et3N (2.85 mL, 20.4 mmol, 4 eq), cyclopropylethynyl-trimethylsilane (1 g, 7.2 mmol, 1.4 eq), and tetrabutylammonium fluoride (5.1 mL, 1.0 M in THF, 5.1 mmol, 1 eq). The reaction mixture was sealed and heated to 80° C. for 12 h. After workup and column chromatography (2% ethyl acetate/hexane), 4-cyclopropylethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 15% yield (202.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm 0.7 (m, 2 H) 0.9 (m, 2 H) 1.3 (t, J=7.1 Hz, 3 H) 1.5 (m, 1 H) 2.7 (s, 3 H) 4.3 (q, J=7.2 Hz, 2 H) 7.2 (m, 1 H) 7.3 (dd, J=8.3, 7.3 Hz, 1 H) 7.4 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[Cu][C:11]#[N:12].[C-]#N.[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:11]#[N:12])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)ncc1C#N
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-bromo-4-methylpyridine (4.0 g, 21.4 mmol) and copper(I) cyanide (2.2 g, 24.6 mmol) in N,N-dimethylformamide (5 mL) was stirred for 4 h at reflux temperature. The hot mixture was poured into a warm solution of sodium cyanide (4.3 g) in water (13 mL). After the mixture was vigorously shaken, the mixture was extracted with ethyl acetate. The organic extract was washed with 10% aqueous sodium cyanide, saturated brine solution and evaporated. The title compound was obtained as a solid after chromatography on silica gel (15% acetone/hexane); yield 1.81 g (64%).
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.[CH2:14]([N:16]([CH2:26][CH3:27])[C:17](=[O:25])[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:15].[Br:28]CCBr>C1COCC1.[Cl-].[Na+].O>[CH2:26]([N:16]([CH2:14][CH3:15])[C:17](=[O:25])[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[Br:28])[CH3:27]
Reactant: BrCCBr
Reactant: CCN(CC)C(=O)Oc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a cooled (-78° C.) solution of TMEDA (787 mg, 6.6 mmol) in anhydrous THF (15 mL) was slowly added sec-butyl lithium (1.30 M, 5.08 mL, 6.6 mmol), and the resultant solution was stirred at -78° C. for 10 minutes. 3-Pyridyl diethylcarbamate (1.16 g, 6.0 mmol, from step 20a) in THF (3 mL) was slowly added, and the mixture was stirred at -78° C. for 30 minutes. 1,2-Dibromoethane (0.575 mL, 6.6 mmol) was then added, and the mixture was stirred for an additional 2 hours. Brine (1 mL) was added and the mixture was slowly warmed up to room temperature. The organic layer was decanted, and the residue was washed with ethyl acetate (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with hexane/EtOAc (1:1 and 1:2) to provide 1.25 g (76% yield) of the title compound. TLC Rf 0.48 (1:2 hexane/EtOAc). MS (DCI/NH3) m/e 290 with 79Br and 292 (M+NH4)+ with 81Br, 273 with 79Br and 275 (M+H)+ with 81Br. 1H NMR (CDCl3, 300 MHz) δ: 8.47 (s, 1H, ArH), 8.27 (d, J=7.2 Hz, 1H, ArH), 7.16 (d, J=7.2 Hz, 1H, ArH), 3.52 (q, J=7.5 Hz, 2H, NCH2), 3.41 (q, J=7.5 Hz, 2H, NCH2), 1.33 (t, J=7.5 Hz, 3H, CH3), 1.24 (t, J=7.5 Hz, 3H, CH3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)=O)(C)(C)C.[CH:16]([N:19](CC)C(C)C)([CH3:18])[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CC(N)C>CN(C)C=O.C(OCC)(=O)C>[CH:16]([NH:19][C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:15])([CH3:18])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
To (3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (150 mg, 0.70 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 1-hydroxybenzotriazole (94 mg, 0.70 mmol) were added. The mixture was stirred at room temperature for 5 min, followed by addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.77 mmol). The mixture was then stirred for 20 min. 2-Propanamine (59 μL, 0.69 mmol) was added and the mixture was stirred overnight. The mixture was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated, and purified by preparative LCMS using pH 2 buffer to give desired boc-protected intermediate. The product fractions were concentrated and treated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 30 min, at which time the mixture was concentrated and dissolved in DCM/MeOH and treated with Trisamine resin (Silicycle) for 30 min. The resulting mixture was filtered and the solvents were evaporated to give the desired compound (63 mg, 58%) which was used in the next step without further purification. LCMS calc. for C8H17N2O (M+H)+: m/z=157.1. found: 157.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH2:11]O)[CH3:10])[CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(CO)c1cc(Cl)ccc1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1cc(Cl)ccc1O
Yield: 79.7 %

Procedure:
To a −10° C. solution of 4-chloro-2-(hydroxypropan-2-yl)phenol (6.00 g, 32.15 mmol) in 100 mL of methylene chloride add triethylsilane (31.0 mL, 194.08 mmol) and boron trifluoride diethyl etherate (66 mL, 520.82 mmol) dropwise over a period of 10 minutes. Keep the reaction mixture cold and stir for an additional hour before quenching with aqueous sodium bicarbonate. Separate the mixture, and extract the aqueous phase with methylene chloride. Wash combined organic phases with aqueous sodium bicarbonate and brine, dry over anhydrous magnesium sulfate, filter, and concentrate to give a purple oil. Purify by flash chromatography using 25% ethyl acetate in hexanes to give 4.37 g (80%) of pure 4-chloro-2-isopropylphenol as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.5, 2.6 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 4.77 (s, 1H), 3.17 (sept, 1H), 1.24 (d, J=6.9 Hz, 6H). 3C NMR (101 MHz, CDCl3) δ 151.26, 136.37, 126.56, 126.36, 125.81, 116.46, 27.14, 22.33. MS: m/e 171.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](Cl)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[CH:31]=[CH:32][N:33]=[C:27]2[CH:26]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.O>C(Cl)Cl.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.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:31]1[N:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:26][C:27]3=[N:33][CH:32]=1)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccn2ccnc2c1
Reactant: Clc1ccc2cccc(OCc3ccccc3)c2n1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccn2c(-c3ccc4cccc(OCc5ccccc5)c4n3)cnc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
8-(Benzyloxy)-2-chloroquinoline (5.0 g, 18.5 mmol), 7-(2-methoxyethoxy)-imidazo[1,2-a]pyridine (3.56 g, 18.5 mmol), Pd(PPh3)4 (1.07 g, 0.927 mmol), K2CO3 (5.12 g, 37.1 mmol), and Pd(OAc)2 (0.208 g, 0.927 mmol) were added into dioxane (74.1 ml, 18.5 mmol) and water (0.735 ml, 40.8 mmol) and heated to 100° C. overnight under nitrogen. The reaction was diluted with DCM and carbon (5 g) was added, followed by filtration. The filtrate was concentrated and then triturated with 1:1 EtOAc/MTBE (30 mL). The resulting solids were allowed to stir for 5 hours and then filtered to isolate of the desired product as a solid (5.4 g, 69% yield).
Reaction SMILES: C1C(I)=C(O)C(I)=C2OC3C([C:17]4(O[C:28](=O)[C:19]5[C:20](Cl)=[C:21](Cl)[C:22](Cl)=[C:23](Cl)[C:18]4=5)C=12)=CC(I)=C(O)C=3I.CN([C:37]1[CH:38]=[CH:39][C:40]2N=C3C(=CC(C=C3)=[N+](C)C)S[C:41]=2[CH:42]=1)C>>[CH:20]1[C:19]2[C:18](=[CH:17][C:37]3[C:38]([CH:28]=2)=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Product: c1ccc2cc3ccccc3cc2c1

Procedure:
(8.3 mmol) and 500 mg. of photosensitizing resin were mixed in 100 ml. of chloroform and irradiated. After 148 cc. (6.6 mmol) of oxygen was absorbed the resin was filtered off, the solution was decolorised with charcoal and evaporated to dryness. The residue was fractionally recrystallized from chloroform to yield anthracene endoperoxide, mp 137°-143°. Rose bengal attached to IRA-400 and methylene blue attached to IRC-200 both gave the same results.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH:8]1[CH2:12][CH3:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[CH2:12]([CH:8]1[CH:7]([CH2:6][CH2:5][OH:4])[NH:10][C:9]1=[O:11])[CH3:13]
Reactant: CCC1C(=O)NC1CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC1C(=O)NC1CCO

Procedure:
The crude 4-[2-(acetyloxy)ethyl]-3-ethyl-2-azetidinone is stirred with 9.7 g of potassium carbonate in 880 ml of absolute methanol at room temperature for 30 minutes. The mixture is neutralized with acetic acid and then evaporated to dryness at 50° C. under vacuum. The residue is suspended in a saturated aqueous solution of sodium chloride and the mixture is extracted with four 150-ml portions of ethyl acetate. The combined organic layers are dried over MgSO4 and then evaporated to dryness yielding 34 g of 3-ethyl-4-[2-(hydroxy)ethyl]-2-azetidinone which contains 80% of the trans isomer (estimated by N.M.R.). The I.R. and N.M.R. data confirm the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].N1([CH:22]=[O:23])C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][CH:22]=[O:23]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: O=CNc1ccc(C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-4-(trifluoromethyl)aniline (500 mg, 2.56 mmol) in tetrahydrofuran (THF) (8 mL) was added 1H-1,2,3-benzotriazole-1-carbaldehyde (489 mg, 3.32 mmol, Sigma-Aldrich). The reaction mixture was heated to 70° C. and stirred for 18 hours. To the reaction mixture was added 1H-1,2,3-benzotriazole-1-carbaldehyde (1.16 mmol, 245 mg) and the reaction mixture heated to 70° C. for a further 5 hours. The reaction mixture was concentrated under vacuum and the residue partitioned between DCM (20 mL) and 2N HCl (10 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].NC1C=CC=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:19]=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Agent: Nc1ccccn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccccn1

Procedure:
The product from Example 11, Part D (100 mg, 0.3 mmol) and 2-aminopyridine (43 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (39 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 8.11 (m, 3H), 7.67 (m, 2H), 7.44 (m, 1H), 7.31 (m, 2H), 7.19 (t, J=8 Hz, 1H), 7.00 (t, J=7 Hz, 3H), 5.28 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.22 (d, J=15 Hz, 1H), 2.54 (m, 2H), 1.96 (m, 2H). MS: m/z (MH+) 408.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:9][C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1>C(Cl)Cl.CCOCC>[C:1]([C:12]1[CH:11]=[C:10]([CH3:9])[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]=1[OH:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1cc(C)cc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (14.7 ml, 5 eq.) is added slowly to an ice cooled suspension of AlCl3 (27.7 g, 5 eq.) in dry CH2Cl2 (125 ml). The reaction is stirred until most of the solid is dissolved, then 5-methyl salicylic acid 236 (6.31 g, 41 mmol) is added. The reaction is stirred at 0° C. for 1.5 hr, then at room temperature for 1.5 hr. The reaction is poured onto ice, diluted with Et2O, and washed with water, brine, dried (MgSO4). Concentration in vacuo afforded a slowly crystallizing oil. Recrystallization (CH2Cl2/hexanes) yielded pure 3-Acetyl-5-methyl salicylic acid (Example 529, Table IIIa) as 3.29 g of off white powder (41% recrystallized yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][C:37]=2[O:46][CH3:47])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:33]([NH:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][C:37]=2[O:46][CH3:47])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1NC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A mixture of 243 mg of methyl 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)-3-methoxybenzoate and 6.0 ml of a THF-methanol (2:1) mixed solvent was mixed with 1.0 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the residue was mixed with 1 M hydrochloric acid, extracted with chloroform and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 227 mg of 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)-3-methoxybenzoic acid as a pale brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=C1Nc2cccc(-c3cccc(NS(=O)(=O)c4cccs4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (27 mg, 0.090 mmol) (from Example 4 supra) in 1.5 mL of pyridine (Fisher Scientific) was treated dropwise with 2-thiophenesulfonyl chloride (19 mg, 0.104) (Aldrich). The reaction mixture was stirred at room temperature for 30 min and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes then 40% ethyl acetate-hexanes elution) to provide a crude yellow solid. Recrystallization from chloroform-pentane provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]-2-thiophenesulfonamide (17 mg, 42%) as an orange solid (mp 218-220° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)CCc2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), ethyl piperidine-4-carboxylate (16.77 mg, 0.107 mmol), and TEA (0.025 mL, 0.178 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (2 mL) and purified by HPLC to give the title compound. LCMS m/z=477.5 [M+H]+; 1.19 (t, J=7.1 Hz, 3H), 1.25 (d, J=6.8 Hz, 0.3H), 1.37-1.50 (m, 2H), 1.44 (d, J=6.7 Hz, 2.7H), 1.67-1.77 (m, 1H), 1.77-1.89 (m, 2H), 1.99-2.09 (m, 2H), 2.20-2.31 (m, 1H), 2.45-2.56 (m, 1H), 2.57-2.79 (m, 3H), 2.92 (t, J=6.6 Hz, 2H), 3.00-3.19 (m, 5H), 3.34-3.47 (m, 1H), 3.50-3.59 (m, 1H), 3.70-3.86 (m, 2H), 4.06 (q, J=7.0 Hz, 2H), 3.70-3.86 (m, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).