Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C:28]1=[O:37])[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:28]3=[O:37])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=NC2
Reaction time: 0.17 h

Procedure:
A mixture of 0.84 g (2 mmol) of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, 0.48 g (2.6 mmol) of 3,4-dihydro-1-(2-propynyl)-2(1H)quinolinone, 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 1.5 ml of triethylamine and 50 ml of dimethylformamide was deqassed with argon for 10 minutes. Palladium acetate, 25 mg, was then added and stirring was continued for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated. dried and evaporated and the residue was chromatographed over 50 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate gave colorless crystals of 1-{3-[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][ 1,4]benzodiazepin 8-yl]-2-propynyl}3,4 dihydro-2(1H)-quinolinone with m.p. 236°-239°.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[NH3:12]>>[NH2:12][C:4]1[C:3]([F:11])=[C:2]([F:1])[N:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: N
Reactant: Fc1nc(F)c(F)c(F)c1F
Product: Nc1c(F)c(F)nc(F)c1F
Temperature: 25 °C

Procedure:
A mixture of 20.0 g (118 mmol) of pentafluoropyridine (Aldrich Chemical Company, Milwaukee, Wis., USA) and 40 ml of concentrated aqueous ammonia was heated on a steam bath for two hours in a sealed stainles steel reaction vessel. The vessel and contents were cooled to room temperature and the resulting suspension suspension was partitioned between water and diethyl ether.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCO)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 125 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5 g, 29 mmol), 2-Methylamino-ethanol (7 mL, 87 mmol) and anhydrous potassium carbonate (5.3 g, 38 mmol) in N,N-dimethylacetamide (10 ml) were stirred at 125° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water (30 mL), stirred vigorously and incubated at 4° C. overnight. The resulting yellow precipitate was collected by filtration, washed well with water then dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-[(3-Amino-4-nitro-phenyl)-methyl-amino]-ethanol (5.4 g, 88% yield) as a yellow solid and used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:38]=[O:39].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[OH:1][C:2]1[C:3]([C:11]2([CH2:38][OH:39])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cccnc21
Reactant: C=O
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.75 g, 8.08 mmol) in anhydrous dichloromethane (40.0 mL) were added triethylamine (4.91 g, 48.5 mmol) and chlorotrimethylsilane (3.51 g, 32.3 mmol) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 2 h and diluted with anhydrous dichloromethane (50.0 mL). The organic layer was washed with water (2×25.0 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The gummy brown residue was dissolved in THF (40.0 mL) followed by the addition of formaldehyde solution (2.20 mL, 80.8 mmol, 37 wt % in water) and ytterbium (III) trifluoromethanesulfonate (1.25 g, 2.02 mmol). The reaction mixture was stirred at ambient temperature for 36 h and diluted with dichloromethane (100 mL). The organic layer was washed with saturated NaHCO3 (50.0 mL), saturated ammonium chloride (50.0 mL) and water (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound (2.85 g, 98%): 1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 8.29 (dd, 1H), 7.72 (dd, 1H), 7.13 (dd, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 5.86 (dd, 2H), 4.37 (dd, 2H), 3.77-3.84 (m, 2H), 3.25 (br, 1H), 1.63-1.77 (m, 2H), 1.36-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 179.9, 156.6, 152.3, 148.4, 147.5, 141.5, 133.8, 124.3, 118.7, 111.3, 107.9, 101.9, 101.4, 64.3, 59.1, 39.9, 31.6, 27.2, 22.3, 13.9; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[Cl:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][CH2:27][NH:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:7]([C:6]2[C:5]([O:4][C:3]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=3[Cl:1])=[N:13][CH:12]=[CH:11][CH:10]=2)=[O:9])=[CH:23][CH:22]=1
Reactant: Clc1ccc2c(c1)NCCC2
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccc(Cl)cc21
Temperature: 110 °C
Yield: 9.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1.5 mL) was added 7-chloro-1,2,3,4-tetrahydro-quinoline hydrochloride (33.7 mg, 0.17 mmol, 1.1 equiv; [CAS RN 90562-34-8]), triethylamine (30.4 mg, 42 μL, 0.3 mmol, 2.0 equiv; [CAS RN 121-44-8]) and HATU (62.7 mg, 0.17 mmol, 1.1 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 110° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 6 mg (10%) of the title compound. MS (ISP): 435.0 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][S:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1
Reactant: Sc1ccc(Br)cc1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CCSc1ccc(Br)cc1
Temperature: 40 °C
Yield: 95.4 %

Procedure:
3-Bromo-1,1,1-trifluoropropane (640 μl, 6 mmol) was added to a mixture of 4-bromothiophenol (945 mg, 5 mmol) and potassium carbonate (760 mg, 5.5 mmol) in DMF (5 ml) and the reaction mixture heated at 40° C. for 1 hour. The mixture was allowed to cool to ambient temperature and poured into water (50 ml) and extracted with EtOAc (2×30 ml). The extracts were combined, washed with brine (3×30 ml), dried (Chemelut column 1010) and evaporated to give the title compound (1.36 g, 95%) as a pale yellow oil. NMR 2.56 (m, 2H), 3.13 (t, 2H), 7.31 (d, 2H), 7.51 (d, 2H); m/z 285 (M+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([C:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]=1)[CH3:6].O>CCOCC>[CH2:1]([C:10]1([OH:13])[CH2:11][CH2:12][C:7]([CH2:5][CH3:6])=[CH:8][CH2:9]1)[CH3:2]
Reactant: CCC1=CCC(=O)CC1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CCC1=CCC(O)(CC)CC1

Procedure:
To a stirred solution of 35 ml of 3.2M ethereal ethyl magnesium bromide (Aldrich) in 75 ml of dry ether was added dropwise at gentle reflux a solution of 10.0 g of 4-ethyl-3-cyclohexen-1-one in 25 ml of ether. After one hour longer at reflux, the mixture was cooled and treated dropwise with 80 ml of water. The aqueous layer was extracted with ether and the combined ether layers were dried, concentrated, and Claisen-distilled to give 7.3 g of the desired product, b.p. 82°-86° C. (5 mm).
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)([O:16][CH2:17][CH2:18][O:19][Si](C)(C)C)C.[C:25]1(=O)[CH2:29][CH:28]=[CH:27][CH2:26]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:16]1[C:28]2([CH2:27][CH:26]=[CH:25][CH2:29]2)[O:19][CH2:18][CH2:17]1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: O=C1CC=CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1=CCC2(C1)OCCO2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of trimethylsilyl trifluoromethanesulfonate (CAS number 27607-77-8; 0.22 ml, 1.22 mmol) in DCM (12 ml) at −78° C. was successively added 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (CAS number 7381-30-8; 2.51 g, 12.18 mmol) and cyclopent-3-en-1-one (CAS number 14320-37-7; 1 g, 12.18 mmol). The reaction mixture was stirred at −78° C. for 3 hours, quenched with triethylamine (2 ml, 14.35 mmol), poured into a saturated solution of sodium bicarbonate and extracted with diethyl ether. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:26])[CH:10]=1.[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:22]([N:21]([CH2:24][CH3:25])[C:19]1[CH:18]=[CH:17][C:16]([NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[O:36])[CH:38]=2)=[C:15]([C:11]2[CH:10]=[C:9]([C:8](=[O:27])[NH:7][CH2:6][C:5]3[CH:28]=[CH:29][CH:30]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:20]=1)[CH3:23]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
A mixture of 80 mg of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(diethylamino)phenyl)isonicotinamide, 64 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 83 mg of HATU, and 190 μL of diisopropylethylamine in 0.5 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 17.6 mg of product. 1H NMR (400 MHz, CD3OD, ppm): δ 9.54 (t, J=5.9 Hz, 1H), 8.98 (dd, J=5.2, 0.6 Hz, 1H), 8.88 (d, J=9.0 Hz, 1H), 8.49 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.20 (s, 1H), 8.16-8.10 (m, 1H), 7.90 (dd, J=5.2, 1.5 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.75-7.63 (m, 4H), 7.63-7.50 (m, 2H), 4.74-4.67 (m, 2H), 4.21-4.03 (m, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.90-3.69 (m, 4H), 3.76 (q, J=7.2 Hz, 4H), 3.54 (t, J=5.9 Hz, 2H), 3.34-3.18 (m, 2H), 3.10 (s, 3H), 1.22 (t, J=7.2 Hz, 6H). MS (ESI, m/z) 717.24 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])/[CH:11]=[CH:28]/[C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(/C=C/C(C)=O)ccc1O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A suspension of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (600 mg, 3.1 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (863 mg, 6.2 mmol) in H2O (5 mL) was added and the reaction mixture was stirred for further 10 min at 0° C. After the dropwise addition of 4-(trifluoromethoxy)-benzaldehyde (473 μl, 3.3 mmol), the orange suspension was heated to reflux for 4 d at 40° C. The solvent was evaporated in vacuo and the resulting residue was purified by flash-chromatography on silica gel (Hexane/EtOAc 2:1) and dried in vacuo to obtain NW351 as a yellow solid (191 mg, 17%). mp: 93-95° C. 1H NMR (300 MHz, CD3OD) δ (ppm): 7.72 (d, 3J=8.4 Hz, 2H, HAr), 7.71 (d, 3J=15.9 Hz, 1H, Hvin), 7.68 (d, 3J=15.6 Hz, 1H, Hvin), 7.27 (d, 3J=8.3 Hz, 2H, HAr), 7.24 (d, 4J=1.9 Hz, 1H, HAr), 7.19 (d, 3J=16.0 Hz, 1H, Hvin), 7.15 (dd, 3J=8.4 Hz, 4J=2.0 Hz, 1H, HAr), 7.02 (dd, 3J=15.9 Hz, 5J=0.99, Hz, 1H, Hvin), 6.83 (dd, 3J=8.2 Hz, 5J=0.9 Hz, 1H, HAr), 3.89 (d, 5J=0.9, 3H, OCH3). 13C NMR (75 MHz, CD3OD) δ (ppm): 191.1 (C), 151.7 (q, 4J (C, F)=1.7 Hz), 151.2 (C), 149.4 (C), 146.4 (CH), 142.4 (CH), 135.4 (C), 131.3 (CH), 128.1 (C), 127.6 (CH), 125.0 (CH), 123.6 (CH), 122.3 (CH), 120.2 (C), 116.7 (CH), 112.2 (CH), 56.5 (OCH3). MS (FAB) m/z: 365.2 (M+). Anal. calcd for C19H15F3O4: C, 62.64; H, 4.15. Found: C, 62.45; H, 4.39%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][O-].[Na+].CI.Cl>CO>[CH3:17][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 120 °C

Procedure:
150 mg (0.57 mmol) of the compound of Example 24A were dissolved in 1.5 ml of methanol, 0.25 ml (1.14 mmol) of a 25% strength solution of sodium methoxide in methanol and 0.04 ml (0.62 mmol) of methyl iodide were added and the mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 120° C. for 30 min. After cooling, the reaction was acidified with 1 M hydrochloric acid and concentrated slightly on a rotary evaporator. The precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 96 mg (94% pure, 57% of theory) of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH2:16])[C:6]1=[O:7])[CH:3]=[CH2:4].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27](O)=[O:28])=[CH:21]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:2]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:16][C:27]([C:22]2[NH:23][C:24]3[C:20]([CH:21]=2)=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)=[O:28])[C:6]1=[O:7])[CH:3]=[CH2:4]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C=CCN1C(=O)[C@@H](N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 16 h
Yield: 53.7 %

Procedure:
(S)-1-allyl-3-amino-3,4-dihydrocarbostyril hydrochloride (7.6 mg) was added to a mixture of tetrahydrofuran (4 mL), 5-chloroindole-2-carboxylic acid (6.9 mg), 1-hydroxy-7-azabenzotriazole (5.5 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.7 mg) at room temperature. Diisopropylethylamine (12 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was evaporated under vacuum and the residue was directly purified by reverse phase preparative HPLC to provide the title compound (6.5 mg). HPLC/MS [M+H]+, 380; HPLC/MS [M+Na]+, 402.
Reaction SMILES: CC(=C)C.[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH:31]([CH3:38])[CH2:30][CH:29]([NH:39][C:40](=[O:50])[CH2:41][C:42]([NH:45][CH2:46][C@H:47]([OH:49])[CH3:48])([CH3:44])[CH3:43])[C:28]3=[O:51])=[CH:22][CH:21]=2)=[O:12])[CH2:7][CH2:6]1.C([O:54]CC)C>>[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH:31]([CH3:38])[CH2:30][CH:29]([NH:39][C:40](=[O:50])[CH2:41][C:42]([NH:45][CH2:46][C@H:47]([OH:49])[CH2:48][OH:54])([CH3:43])[CH3:44])[C:28]3=[O:51])=[CH:22][CH:21]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CC1CC(NC(=O)CC(C)(C)NC[C@@H](C)O)C(=O)N(Cc2ccc(-c3ccccc3NC(=O)N3CCOCC3)cc2)c2ccccc21
Reactant: CCOCC
Agent: C=C(C)C
Product: CC1CC(NC(=O)CC(C)(C)NC[C@H](O)CO)C(=O)N(Cc2ccc(-c3ccccc3NC(=O)N3CCOCC3)cc2)c2ccccc21

Procedure:
Reaction of isobutylene with N-chlorosulfonylisocyanate 57 in diethyl ether gives the azetidinone derivative 58. Removal of the chlorosulfonyl group with aqueous sodium sulfite followed by reaction with di-t-butyl-dicarbonate gives the BOC-protected intermediate 60. Alkaline hydrolysis gives the protected amino acid derivative 61 in good overall yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.O.[OH-].[K+].Br[C:15](P(=O)(OCC)OCC)([F:17])[F:16]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH:15]([F:17])[F:16])=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: OCc1cc(Br)ccc1S
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: OCc1cc(Br)ccc1SC(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(5-Bromo-2-sulfanylphenyl)methanol (0.50 g, 2.8 mmol) was dissolved in acetonitrile (11.4 mL) followed by the addition of water (11.4 mL) and solid potassium hydroxide (2.56 g, 45.6 mmol). The mixture was plunged into a −78° C. bath and when the mixture began to freeze diethyl [bromo(difluoro)methyl]phosphonate (1.22 g, 4.56 mmol) was added all at once and the cold bath was removed. The mixture was allowed to warm to ambient temperature and was stirred for 20 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[C:35]([Cl:34])[CH:36]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(Cl)c4)ccc3C)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (346.7 mg, 1.01 mmol) (from Example 23 supra) in THF (20 mL) were added diisopropylethylamine (258 mg, 2.03 mmol) (Aldrich) and then 3-chlorobenzoyl chloride (265 mg, 1.51 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (200 mL), washed with aqueous 1N NaOH (15 mL), brine (2×15 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 99/1 to 95/5) to give 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 468 mg, 97%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[O:9][CH:8]=[C:7]([C:15]1[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=1)[C:6]2=[O:25])[CH3:2].Cl.NO.C([N:31](CC)CC)C>CCO.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[C:7]1[CH:8]=[N:31][O:25][C:6]=1[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]([O:13][CH3:14])=[CH:11][C:10]=1[OH:9]
Reactant: CCN(CC)CC
Reactant: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1OC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2oncc2-c2ccc3ccccc3c2)c(O)cc1OC
Temperature: 140 °C

Procedure:
A mixture of 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36 g), hydroxylamine hydrochloride (0.6 g), triethylamine (0.5 mL) in EtOH (10 mL) was heated at 140° C. in microwave reactor for 4 h. The mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water and dried using a drying agent. The oil obtained on concentration was flash chromatograghed on silica gel to give 4-(naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole as white powder (f, 0.19 g). 1H-NMR (CDCl3) δ (ppm) 8.57 (s, 1H), 7.8 (m, 4H), 7.5 (m, 3H), 7.10 (s, 1H), 6.52 (s, 2H), 3.92 (s, 3H), 2.4 (q, 2H, J=7), 1.0 (t, 3H, J=7); ESMS clcd for C22H19NO3: 345.1. Found: 346.0 (M+H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:40])[C@@H:6]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][N:7]1[C:18](=[O:39])[C@H:19]([CH:36]([CH3:38])[CH3:37])[NH:20][C:21](=[O:35])[C@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:23][C:24](=[O:26])[CH3:25].Cl>O1CCCC1.O>[C:24]([NH:23][C@H:22]([C:21]([NH:20][C@H:19]([C:18]([N:7]1[CH2:8][CH:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C@H:6]1[C:5]([OH:40])=[O:4])=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)[C@@H]1CC(Oc2ccccc2)CN1C(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(Oc2ccccc2)C[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Lithium hydroxide (57 mg, 1.37 mmol) was added to a solution of N-Acetyl-tyrosinyl-valinyl-(4-phenoxy)proline methyl ester (360 mg, 0.685 mmol) dissolved in 8 ml of tetrahydrofuran/water (1:1) and stirred at room temperature for 1 hour. The mixture was acidified with 10% hydrochloric acid giving a white precipitate that was collected to give 175 mg of the title compound.