Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]1[C:18]([NH2:20])=[O:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]1[C:18]([NH2:20])=[O:19]
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](CN=[N+]=[N-])[C@H]1C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@@H](CN)[C@H]1C(N)=O
Reaction time: 25 h

Procedure:
A mixture of (2S,3S)-3-azidomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Step 5.3) (0.723 mmol) and triphenylphosphine (0.867 mmol) in THF (3 mL) was stirred at it for 25 h. The reaction mixture was concentrated to afford the crude title compound as a light brown solid. HPLC: tR 3.53 min (method B); ESI-MS: [M+H]+ 248.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH:20]=[CH2:19])=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCBr
Reactant: Oc1ccc2c(CCc3ccccc3)coc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(CCc3ccccc3)coc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of the product from Step C (1.128 grams) in dry DMF (15 mL) was exposed to allyl bromide (0.43 mL) followed by cesium carbonate (1.620 grams). After stirring overnight at ambient temperature, the reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Evaporation gave the title compound, which did not require further purification.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:22]O>>[C:2]1([C:1]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:22])=[O:14])=[CH:16][CH:17]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A stirring solution of MeOH, 4-benzoylbenzoic acid and thionyl chloride was refluxed for 7 h under a nitrogen atmosphere. The reaction was cooled to RT and a white solid precipitated. The mixture was refrigerated overnight then filtered, rinsed with ice chilled MeOH and air-dried to yield 6.10 g (64%) of the title compound 19 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ8.09 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.1 Hz, 2H), 7.54-7.74 (m, 5H), 3.88 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:13][C:14]1[C:15]([F:20])=[C:16]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:19]=1[Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
step 1—To a solution of di-iso-propylamine (150 mL, 108.3 g, 1.07 mol) in THF (500 mL) cooled to −78° C. and maintained under a N2 atmosphere was added over 1 15 min period, n-BuLi (100 mL, 1.00 mol, 10M in hexanes). The resulting mixture was stirred for 30 min at −78° C. A mixture of 23a (45 mL, 52.110 g, 0.457 mol) and chlorotrimethylsilane (130.0 mL, 111.28 g, 1.024 mol) was added at a rate which maintained the internal reaction temperature below −50° C. The solution was stirred at −78° C. for 1 h. The reaction was quenched at −78° C. by addition of 1M H2SO4, diluted with MTBE and the mixture was saturated with solid NaCl. The phases were separated and the aqueous phase was extracted with MTBE (300 mL). The combined organic extracts were dried (MgSO4), filtered and the solvents evaporated to afford 118 g (100%) of 23b as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C>CCOCC>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([B:20]([OH:21])[OH:19])=[CH:12][C:11]=2[CH:15]=1
Reactant: Cc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc2oc(B(O)O)cc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (35.16 ml) was added dropwise to a stirred solution of THEDA (9.58 ml) and 5-methylbenzofuran (8.22 g) in ether (250 ml) maintaining the temperature below -60° C. throughout. The solution was warmed to about -10° C. over 45 minutes and stirred at this temperature for 30 minutes. A precipitate formed on warning. The suspension was cooled and triisopropylborate (43 ml) was added, maintaining the temperature below -60° C. The solution was warmed gradually to room temperature before quenching with 2N HCl (70 ml). The mixture was extracted with ether (3×50 ml) and the combined organic extracts washed with 2N HCl (4×30 ml), water (2×30 ml) and dried before evaporation to give the title compound as an orange solid (12.75 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:11]1([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([C:17]([F:19])([F:20])[F:18])=[N:8]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (160 mg, 0.56 mmol) and 1N aqueous sodium hydroxide solution (2.3 mL, 2.3 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH˜2 with 1N aqueous hydrochloric acid and concentrated to give 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as an off-white solid, which was directly used without further purification. LCMS calcd for C11H7F3N2O (m/e) 256, obsd 257 (M+H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(O[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>ClCCl>[CH3:40][N:42]1[CH2:47][CH2:46][CH:45]([NH:48][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:1]=[CH:2][NH:3][C:4]=3[CH:9]=2)=[O:12])[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc3nc[nH]c3c2)CC1
Reaction time: 3 h

Procedure:
Step 1 (Amide Coupling): 5-Benzimidazole carboxylic acid (0.50 g, 3.1 mmol), EDC.HCl (0.72 g, 3.7 mmol) and HOBt (0.58 mg, 3.7 mmol) in dichloromethane (11 mL) was stirred at room temperature for 10 minutes. 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.70 g, 3.4 mmol) and DIPEA (0.59 ml, 3.4 mmol) were added and the mixture was stirred for 3 hours. The mixture was then partitioned between EtOAc and sat. aqueous Na2CO3. The layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo to give 3H-benzoimidazole-5-carboxylic acid (1-methyl-piperidin-4-yl)-amide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(O)(=O)C>[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33]3[NH:10][C:5]4[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=4[N:9]=3)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, 1.0 mL (5.0 mmol) diisopropylethylamine and 1.1 g (6 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyleuronium hexafluorophosphate were added to a solution of 0.59 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 mL dimethylformamide, which was then stirred for 5 min, irradiated for 15 min with microwaves in a microwave reactor (Initiator Sixty, Biotage) and concentrated in a vacuum. The concentrate was dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, and dried over magnesium sulfate, followed by vacuum concentration. The residue thus obtained was dissolved in acetic acid (15 mL) and stirred for 5 min before irradiation for 15 min with microwaves in a microwave reactor (Initiator Sixty, Biotage). Again, the reaction solution was cooled to room temperature, vacuum concentrated, dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, and dried over magnesium sulfate, followed by vacuum concentration. The residue was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.81 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH2:18][CH2:19][OH:20])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH2:18][CH:19]=[O:20])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCCO)Cc1ccc(Cl)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCC=O)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
3.00 g (9.97 mmol) of tert-butyl [(6-chloropyridin-3-yl)methyl](3-hydroxypropyl)carbamate are dissolved in 50 ml of dichloromethane, 56.38 g (19.94 mmol) of a 15 percent strength solution of Dess-Martin periodinane in dichloromethane are added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed with 1N aqueous sodium hydroxide solution and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:1) gives 2.75 g (92% of theory) of tert-butyl [(6-chloropyridin-3-yl)methyl](3-oxopropyl)carbamate.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:12]=[C:11]2[C:23]1[N:28]=[C:27]([O:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[CH:26]=[N:25][CH:24]=1.[CH:43]([O:46][C:47]1[CH:52]=[N:51][CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[N:48]=1)([CH3:45])[CH3:44]>Cl[Cu].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:44][CH:43]([O:46][C:47]1[N:48]=[C:49]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:12]=[C:11]3[C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:31]3)[CH:26]=[N:25][CH:24]=2)[CH:50]=[N:51][CH:52]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: CC(C)Oc1cncc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Product: CC(C)Oc1cncc(-c2ccc3c(c2)c(-c2cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n2)nn3C2CCCCO2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
To a 50 mL round bottom flask was added CuCl (0.035 g, 0.36 mmol), Cs2CO3 (0.467 g, 1.43 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.020 g, 0.04 mmol), tert-butyl (3R)-3-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate 10a (0.200 g, 0.36 mmol), Pd(OAc)2 (4.02 mg, 0.02 mmol), and 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (0.189 g, 0.72 mmol, CombiPhos Catalysis). The flask was sealed and evacuated under vacuum and backfilled with N2. DMF (2.7 mL) was added, and the reaction mixture was stirred at 80° C. for 18 h. The reaction was filtered through a 0.45 M filter and then diluted in water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl (3R)-3-((6-(5-(6-(1-methylethoxy)-2-pyrazinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.130 g, 0.21 mmol, 59% yield) as a light-yellow oil. MS (ESI, pos. ion) m/z: 616.2 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([O:23][CH:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([O:27]C)=[O:26])[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([O:23][CH:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([OH:27])=[O:26])[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A mixture of methyl 2-{[6-(2-benzyl-1,3-oxazol-5-yl)-2-naphthyl]oxy}-3-phenylpropanoate (578 mg, 1.25 mmol), prepared in the previous step, and 1 N NaOH (1.87 mL, 1.87 mmol) in 20 mL of THF, 20 mL of methanol and 10 mL of H2O was stirred at room temperature for 16 h (overnight). The reaction was acidified by the addition of 2.0 mL of 1N HCl and then concentrated under reduced pressure to remove the THF and the methanol. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (144 mg, 26%) as a white solid, mp 78-82° C. Elemental Analysis for C29H23NO4+0.50 H2O Calc'd: C, 75.97; H, 5.28; N, 3.05. Found: C, 75.29; H, 5.02; N, 2.91.
Reaction SMILES: [CH:1]1([CH:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]2[C:19](=O)[O:18][C:16](=[O:17])[C:13]2=[N:14][CH:15]=1)([O-:9])=[O:8].S(Cl)(Cl)=O>ClCCCl.C(Cl)Cl>[CH:1]1([CH:4]([N:6]2[C:19](=[O:18])[C:12]3[C:13](=[N:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=3)[C:16]2=[O:17])[CH3:5])[CH2:3][CH2:2]1
Reactant: O=C1OC(=O)c2ncc([N+](=O)[O-])cc21
Reactant: CC(N)C1CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C1CC1)N1C(=O)c2cc([N+](=O)[O-])cnc2C1=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
11.2 g (0.132 mol) of 1-cyclopropylethylamine were added to a mixture of 22.3 g (0.115 mol) of 5-nitropyridine-2,3-dicarboxylic anhydride in 150 ml of 1,2-dichloroethane at 25° C. with stirring in the course of 8 minutes and the mixture was stirred at 70° C. for 3 hours. After cooling to 25° C., 19.6 g (0.165 mol) of thionyl chloride were added with stirring in the course of 10 minutes and the mixture was stirred at 25° C. for 10 hours and at 70° C. for 1 1/2 hours. The reaction mixture was diluted with 100 ml of methylene chloride and added with stirring to 500 ml of ice-water. The aqueous phase was extracted twice more with methylene chloride. The organic phase was then washed successively with water, saturated sodium hydrogencarbonate and sodium chloride solution and filtered off with suction over neutral alumina. After concentrating, 21.5 g (72% of theory) of the title compound of m.p. 96°-99° C. were obtained (active compound Example 1.020).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[C:19]([Zn]C#N)#[N:20].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O>[C:19]([C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1)#[N:20]
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a 10 ml microwave vial was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), dicyanozinc (150 mg, 1.277 mmol) and DMF (5 mL). The mixture was degassed and stirred at rt under N2 for 15 min. To the mixture was added palladium tetrakis (118 mg, 0.102 mmol) and the reaction was stirred at 95° C. for 1 h. The reaction was allowed to cool and poured into saturated aqueous Na2CO3 (50 mL) and EtOAc (50 mL) and stirred for 20 min. The mixture was extracted with ether (100 ml) and EtOAc (100 ml) (1:1), followed by filtration and evaporation to yield a residue. The residue was purified by silica gel chromatography (Analogix IF280, 0-8% EtOAc/hexanes, SF25-40 g, 30 minutes) to give methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (130 mg, 0.497 mmol, 38.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J=1.52 Hz, 1H) 7.82 (s, 1H) 7.71 (d, J=1.52 Hz, 1H) 4.85-4.97 (m, 1H) 3.90 (s, 3H) 2.29 (s, 3H) 1.45 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 257.4.
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].O.C1(C)C=CC(S(O)(=O)=[O:50])=CC=1.P(=O)(O)(O)O>CS(C)=O.C(OCC)(=O)C>[OH:50][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in dimethylsulfoxide (160 ml), there were successively added water (40 ml), cuprous oxide (6.76 g) and p-toluenesulfonic acid (7.6 g), and the resultant mixture was warmed to 50 to 55° C. and stirred for 2 hours at the same temperature. After cooling down to room temperature, 1% aqueous phosphoric acid (90 ml) and ethyl acetate (200 ml) were poured into the reaction mixture, followed by stirring for 0.5 hour. An insoluble material was removed by filtration over celite and washed 3 times with ethyl acetate (20 ml). The filtrate and the washings were combined together, and the aqueous layer was separated from the organic layer and extracted with ethyl acetate (200 ml). The organic layer and the extract were combined together, washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and the concentrate was crystallized from a mixture of toluene and n-hexane (1 : 1) to give crystals of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 118°-120° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[CH:8][C:7]=1[CH3:29].[OH-].[Na+].C1COCC1>CO>[CH3:29][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)ccc1CCC(=O)O

Procedure:
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionic acid methyl ester (0.170 g, 0.390 mmole) is treated with a mixture of NaOH(aq) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight. The organic solvents are removed on rota-vapor. The residue is diluted with water (10 mL), acidified to pH=2 with 6N HCl(aq). The precipitate is collected through filtration, washed with cold water (30 mL) and dried to provide the titled compound as white solid. MS (ES):419 (M+H)−, the structure is also confirmed by proton NMR.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]([OH:11])=[O:10])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)CNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CN(c1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
7.7 Parts of N-phenylglycine and 5 parts of sodium hydroxide are dissolved in 30 parts of water. Into the resulting solution, 5 parts of chloroform containing 10 parts of benzenesulfonyl chloride is dropped with stirring. After the dropping, the resulting mixture is stirred at room temperature for 4 hours and then at 50° C for 30 minutes. Subsequently, the aqueous layer is separated from the reaction mixture and then acidified with hydrochloric acid to form an oily substance. By rubbing on the inner wall of a flask with spatula, crystallized products are formed. The crystals are recrystallized from a mixed solvent comprising methanol and water to obtain 4.2 parts of N-benzenesulfonyl-N-phenylglycine, m.p. 166°-167° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(F)cc1C(=O)O
Yield: 75.6 %

Procedure:
Reaction of 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine-4-carboxylic acid (1.0 g, 3.9 mmol) with TFA as described above gives 5-amino-2-fluoropyridine-4-carboxylic acid(0.46 g, 74%). 1H NMR (DMSO) δ 7.85 (1H, d, J=1.5 Hz), 7.23 (1H, d, J=2.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([O:15][C:16](=[O:19])[CH2:17]I)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: CCOC(=O)CI
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Product: CCOC(=O)Cc1c[nH]c2cc(N)ccc12

Procedure:
(6-Amino-1H-indol-3-yl)-acetic acid ethyl ester (B-17) was synthesized following the general scheme above starting from 6-nitroindole and iodo-acetic acid ethyl ester. Overall yield (24%).