Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH2:10][CH2:9][S:8][CH:7]=[C:6]1[CH2:11][C:12]([OH:14])=O.[CH3:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27]>C1C=CC=CC=1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:26]([C:17]1[N:18]2[CH:19]([S:24][CH2:25][C:16]=1[CH3:15])[CH:20]([NH:23][C:12](=[O:14])[CH2:11][C:6]1[S:5][CH2:10][CH2:9][S:8][CH:7]=1)[C:21]2=[O:22])([OH:28])=[O:27]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CC1=CSCCS1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 39.7 %

Procedure:
Thionyl chloride (3 cc.) is added to a solution of (5,6-dihydro-1,4-dithiin-2-yl)acetic acid (3.10 g.) in benzene (60 cc.), and the mixture is heated under reflux until gas ceases to be evolved. The reaction mixture is then concentrated to dryness under reduced pressure (20 mm.Hg). A brown oil is obtained and is dissolved in chloroform (60 cc.). The solution is added dropwise, over the course of one hour, to a suspension of 7-aminodesacetoxycephalosporanic acid (4.28 g.) in chloroform (50 cc.) and triethylamine (5.5 cc.) kept at 5° C. The mixture is stirred for a further 45 minutes at a temperature of about 20° C. and is concentrated to dryness under reduced pressure (20 mm.Hg). The residue is taken up in water (100 cc.) and ethyl acetate (100 cc.) and the aqueous phase is brought to pH 8.5 by addition of triethylamine. The organic phase is separated by decantation. Ethyl acetate (300 cc.) is added to the aqueous phase and 4N hydrochloric acid is added until the pH is 2. The organic phase is separated, the aqueous phase is washed with ethyl acetate (100 cc.), and the organic phases are combined, dried over magnesium sulphate, treated with decolourizing charcoal and concentrated to 50 cc. under reduced pressure (20 mm.Hg). After cooling to about 0° C., the solid is filtered off and washed with ethyl acetate (2 × 20 cc.). 2-Carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl)acetamido]-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (2.6 g.) is obtained in the form of a light beige powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Br[C:17]1C=C(C)C(F)=C([CH:24]=1)C#N.C([O-])([O-])=O.[K+].[K+].N1C=NC=N1>CN(C=O)C.O>[CH3:15][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=[C:2]([CH:17]=[CH2:24])[CH:3]=1)[C:7]#[N:8]
Reactant: Cc1cc(Br)cc(C#N)c1F
Reactant: Cc1cc(Br)cc(C#N)c1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1nc[nH]n1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cc(C)c(-n2cncn2)c(C#N)c1
Temperature: 140 °C
Yield: 49 %

Procedure:
5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71): To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added K2CO3 (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% EtOAc/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br
Reactant: CCc1cc2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCc1oc2ccccc2c1C(=O)c1ccc(Br)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10.9 g 4-bromo-3-sulfamoylbenzoyl chloride and 6 g 2-ethylbenzo[b]furan in the presence of 11.7 g aluminum chloride. Colorless crystals, m.p. 202°-206° C. (ether).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8](=[O:14])[CH2:9][O:10][C:11](=[O:13])[NH2:12])(=O)C>CO>[OH:6][CH2:7][C:8](=[O:14])[CH2:9][O:10][C:11](=[O:13])[NH2:12]
Reactant: CC(=O)OCC(=O)COC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)OCC(=O)CO

Procedure:
Aqueous sodium hydroxide (35 ml. of a 2.5N solution) is added dropwise over 30 minutes to a stirred solution of 1-acetoxy-3-carbamoyloxy-2-propanone (14.9 g., 0.085 g.) in methanol (10 ml.). The methanol is evaporated under reduced pressure and the aqueous residue extracted with chloroform (3×25 ml.). The combined extracts are dried, and the solvent is removed in vacuo to afford 1-hydroxy-3-carbamoyloxy-2-propanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[O:11]C2=O)=[CH:4][CH:3]=1.[NH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([NH2:21])=[O:11])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=c1oc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Product: NC(=O)c1ccccc1NCc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
In 400 ml of concentrated aqueous ammonia, 14.4 g of 1-(4-chlorophenylmethyl)-2H-3,1-benzoxazine-2,4(1H)-dione were heated to 100° C. and stirred for 3 hours. After cooling, the crystals were collected by filtration, washed with water and dried. They were recrystallized from ethanol to obtain 8.6 g of title compound. m.p. 138°-139° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C@@H:23]4[CH3:35])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)([O-])O.[Na+]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]4[CH3:35])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNCCN1Cc1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-3-(S)-methylpiperazine-1-carboxylate (0.329 g, 0.672 mmol) in methylene chloride (8 mL) was added with trifluoroacetic acid (8 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, then the residue was added with methanol (20 mL) and a 5% solution of hydrogen chloride in methanol (5 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and then the residue was suspended in acetonitrile and thereby washed to obtain orange solid. This solid was dissolved in saturated aqueous sodium hydrogencarbonate, and the solution was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-{[2-(S)-methylpiperazin-1-yl]methyl}benzofuran-3(2H)-one (0.0460 g, 17%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:44]2[C:43](=[CH:45][CH2:46][OH:47])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]>C1COCC1.O>[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:47][CH2:46][CH:45]=[C:43]2[C:44]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:62][CH:63]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCC=C1c2ccccc2-c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3-c3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0°C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 2-fluoren-9-ylidene-ethanol (0.208 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 72 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (3×20 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to a yellow gum. This was then purified by column chromatography on silica gel (15% Et2O in petroleum eluent) to give ethyl 2-ethoxy-3-[4-(2-fluoren-9-ylidene-ethoxy)-phenyl]-propionate as a yellow gum; 0.28 g (60%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=O)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=O)C.[CH3:27][NH:28][NH2:29].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:20]([C:6]12[C:4](=[O:3])[N:28]([CH3:27])[N:29]=[C:11]1[CH2:10][CH2:9][NH:8][CH2:7]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CNN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1N=C2CCNCC2(Cc2ccccc2)C1=O
Temperature: 65 °C
Reaction time: 7.5 h
Yield: 84.8 %

Procedure:
To a solution of 3-benzyl4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1935.97 g, 5.36 mol) in toluene (9700 mL) was added methylhydrazine (299.2 mL, 5.63 mol), followed by acetic acid (325 mL, 5.68 mol) slowly at about 8° C. The reaction mixture was heated slowly to about 65° C. and stirred for about 7.5 hours. After cooling to room temperature, the organic layer was washed with 10% sodium bicarbonate, water and saturated NaCl solution and concentrated in vacuo to a low volume. The reaction was repeated at same scale twice. The concentrated product solutions from the three reactions were combined and mixed with IPE (50 L), cooled to about 0° C., HCl gas was introduced repeatedly and stirred at room temperature overnight until the deprotection was complete. The mixture was concentrated in vacuo to about half of the original volume, methylene chloride (24 L) was added, followed by NH4OH (22 L). The mixture was then extracted with methylene chloride and concentrated to a low volume (6 to 7 L). Hexane (20 L) was added and the mixture was cooled to about 15-20° C. The free base product was collected as crystals and dried under vacuum (2985 g total, yield 84.8%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[C:46]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][O:40][C:41]1[C:46]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:43][N:42]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NS(C)(=O)=O
Yield: 68.2 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (132 mg, 0.4 mmol), sodium carbonate (43 mg, 0.41 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 83 mg (68% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38](N1C=CN=C1)(=[O:40])[CH3:39].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:38](=[O:40])[CH3:39])[CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1

Procedure:
Dissolve 2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (144 mg, 0.29 mmol)) in dry dichloromethane (3 mL). Add 1-acetylimidazole (48 mg, 0.43 mmol) and triethylamine (0.081 mL, 0.58 mmol) and stir for 2 h. Dilute with ethyl acetate and wash with 1 N HCl and saturated aqueous sodium bicarbonate, dry (magnesium sulfate), and concentrate to give the title compound which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(NC(C)C)(C)C.C([O-])(O)=O.[Na+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cncc(-c2ccc(C)cc2F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of ethyl 5-bromonicotinate (0.58 g, 2.53 mmol) in acetonitrile (15 mL) and water (5 mL) were added (2-fluoro-4-methylphenyl)boronic acid (0.47 g, 3.04 mmol), 3,3′,3″-phosphinidynetris(benzenesulfonic acid) trisodium salt (0.22 g, 0.38 mmol), palladium(II)acetate (28.4 mg, 0.13 mmol) and diisopropylamine (0.90 mL, 6.32 mmol). The mixture was heated to 80° C. After 1 h, the mixture was cooled to ambient temperature and saturated aqueous NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (0.67 g). MS 260.1 (M+1).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:12]=C[C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])#N.Cl.O.[C:18]([OH:24])([C:20](F)(F)F)=[O:19]>CC#N>[C:18]([C:20]1[CH:12]=[C:5]([CH:4]=[CH:3][C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([OH:24])=[O:19]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cc(C[C@H](N)C(=O)O)ccc1O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: N[C@@H](Cc1ccc(O)c(C(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 250 mL 3-necked flask equipped with a reflux condenser and a magnetic stirrer was charged with 1.45 g of 3-cyano-L-tyrosine, 50 mL of concentrated HCl, and 50 mL of water. The solution was heated to reflux with stirring. After 2 days, analysis of the reaction mixture by HPLC (C18, 90:10:0.1 H2O:MeCN:TFA) indicated a major component at k1 =2.23 (75%) and a minor component at k1 =1.59 (25%). After 4 days HPLC indicated only the k1 =2.23 material. The reaction mixture was cooled to RT, filtered, and the filtrate was concentrated in vacuo to dryness to give 1.2 g of 3-carboxy-L-tyrosine as a dark brown solid. IR analysis (nujol) indicated loss of the nitrile stretch of 3-cyano-L-tyrosine, at 2223 cm-1. The crude solid was added to 60 mL of anhydrous MeOH in a 250 mL 3-necked flask equipped with a condenser and a magnetic stirrer. The mixture was acidified by bubbling HCl gas through for 5 min and heated to reflux with stirring. After 6 h, the reaction mixture was cooled to RT and neutralized with solid NaHCO3. The mixture was concentrated in vacuo to dryness, mixed with 100 mL of water, and extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with 5% aqueoous NaHCO3 (2×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to 10 mL. The solution was diluted with 35 mL of ether and treated with 5.5 mL of 1 M etheral HCl. A solid precipitated which was collected by filtration, washed with ether, and dried in vacuo to afford 0.90 (50%) of methyl 3-(methoxycarbonyl)-L-tyrosinate.HCl as an off-white powder, m.p. 211-213° C.
Reaction SMILES: C([O:3][CH2:4][C:5]([O:7][C:8]([CH3:22])([CH2:10][CH2:11][C:12]([O:15][C:16](=[O:21])[CH2:17][O:18]C=O)([CH3:14])[CH3:13])[CH3:9])=[O:6])=O>C(=O)(O)[O-].[Na+]>[OH:3][CH2:4][C:5]([O:7][C:8]([CH3:22])([CH2:10][CH2:11][C:12]([O:15][C:16](=[O:21])[CH2:17][OH:18])([CH3:13])[CH3:14])[CH3:9])=[O:6]
Reactant: CC(C)(CCC(C)(C)OC(=O)COC=O)OC(=O)COC=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CCC(C)(C)OC(=O)CO)OC(=O)CO
Reaction time: 72 h

Procedure:
[see Kodadeck et. al. J. Am. Chem. Soc. (2004), 126(13), 4088-4089.] The crude product (68) was combined with aqueous sodium bicarbonate solution (20 mL, 0.75 N) and stirred for 3 days. The compound was then removed from the aqueous phase using continuous distillation in ether overnight. The organic phase was then evaporated to get a white solid. (0.032 g) 1H NMR (400 MHz, CDCl3): δ 1.36 (s, 12H), 1.84 (s, 4H), 3.41 (b, 2H), 4.00 (s, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(c2cccnc2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine with TBTU and DIPEA in THF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].Br[C:26]1[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=1.CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=3)[CH2:20][CH2:19]2)[C:14]1=[O:24]
Reactant: COc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)cn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
(S)-3-(2-Fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.050 g, 0.14 mmol), 2-bromo-5-methoxypyrazine (0.032 g, 0.17 mmol), NaOtBu (0.041 g, 0.42 mmol), Pd(OAc)2 (0.005 g, 0.02 mmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (DavePHOS) (0.017 g, 0.042 mmol) were added to an argon-filled sealable flask. Toluene (1.5 mL) was added and the mixture was purged with bubbling argon for 5 minutes. The vessel was sealed and the mixture was stirred at 110° C. overnight. The mixture was cooled to ambient temperature, diluted with THF (12 mL), and stirred for 15 minutes. The mixture was filtered through GF/F paper and concentrated. The residue was purified by silica chromatography (EtOAc) to afford (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(5-methoxypyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.031 g, 0.067 mmol, 48% yield). Mass spectrum (apci) m/z=464.2 (M+H). Optical purity was not determined.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[S:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[CH:20][C:19]=1[Cl:30].C([O-])([O-])=O.[Cs+].[Cs+].N#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[Cl:30][C:19]1[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[S:22][C:18]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: Cc1cccc(-c2cc(Cl)c(Br)s2)n1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3Cl)c(C)nc12
Temperature: 110 °C
Yield: 10.1 %

Procedure:
A solution of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.39 g, 1.78 mmol), 2-(5-bromo-4-chloro-thiophen-2-yl)-6-methyl-pyridine (0.59 g, 2.04 mmol), Cs2CO3 (1.23 g, 3.77 mmol), and DMF (5 mL), is de-gassed with N2 for 15 minutes. PPh3 (0.089 g, 0.34 mmol) and Pd2(dba)3 (0.079 g, 0.86 mmol) is added and the solution heated at 110° C. for 48 hours. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (25 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) and is chromatographed (19×300 C18 Symmetry column, 20-45% water: 0.1% TFA/ACN: 0.1% TFA gradient) furnish the title compound (0.078 g, 0.18 mmol, 10%). Spectrum identical to Method A.