Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:33])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:15]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=2)[CH:4]=1.O.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[CH3:2][N:3]1[CH:8]=[CH:7][CH2:6][C:5]([C:9](=[O:33])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:15]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=2)=[CH:4]1
Reactant: C[n+]1cccc(C(=O)NCCc2ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c2)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN1C=CCC(C(=O)NCCc2ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c2)=C1
Reaction time: 0.33 h

Procedure:
To a cold mixture of 2.0 g (3.5 mmol) of compound 6c, 200 ml of deaerated water and 100 ml of ethyl acetate, 1.14 g (14 mmol) of sodium bicarbonate and 2.43 g (14 mmol) of sodium dithionite were added. The mixture was stirred under N2 for 20 mins. The ethyl acetate layer was separated and the aqueous layer was re-extracted with 100 ml of ethyl acetate. The combined ethyl acetate was washed with cold deaerated water, dried over anhydrous Na2SO4 and distilled on rotovapor. The viscous yellow oily residue was dissolved in 5 ml of acetone, filtered under N2 atmosphere and then evaporated under reduced pressure. The solid residue was dried under vacuum over P2O5 in N2 atmosphere. It reduced alcoholic AgNO3 instantaneously and gave no color with DeCl3 test. Yield, 1.3 g (83%) m.p. 45°-48° C.; UV (CH3OH) 210 and 355 nm; NMR (CDCl3) δ 7.04-6.92 (m, 4H, C6H3 +C2 dihydropyridine proton), 5.71-5.61 (doublet of doublets, 1H, C6 dihydropyridine proton), 4.81 (bs, 1H, CONH), 4.60-4.51 (m, 1H, C5 dihydropyridine proton), 3.53 (q, 2H, J=6.3 Hz, --N--CH2), 2.36 (bs, 2H, C4 dihydropyridine proton), 2.91 (s, 3H, N--CH3), 2.79 (t, 2H, J=6.3 Hz, CH2), 1.33 (s, 18H, CO--C(CH3)3). Anal. Calcd for C25H34N2O5. 11/2H2O: C, 63.9; H, 7.93; N, 5.96. Found: C, 63.4; H, 7.81; N, 5.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[Si](C)(C)N[Si](C)(C)C.[I:25][Si](C)(C)C.[I-].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[I:25][CH:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][C:12]1=[O:15]
Reactant: C[Si](C)(C)I
Reactant: COc1ccc(C2CCC(=O)CC2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCC(=O)C(I)C2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4-methoxyphenyl)cyclohexanone (INTERMEDIATE 7, Step A) (219.6 mg, 1.075 mmol) in DCM (5 ml), under nitrogen at 0° C., was added hexamethyldisilazane (0.272 ml, 1.290 mmol) followed by dropwise addition of iodotrimethylsilane (0.161 ml, 1.183 mmol). A solution of sodium iodide (161 mg, 1.075 mmol) in THF (3.3 ml) was then added, followed by addition of a cloudy mixture of m-CPBA (318 mg, 1.290 mmol) in DCM (3 ml). At 10 minutes, added ethyl acetate and washed with 1M aqueous hydrochloric acid (added brine to help break emulsion). The aqueous layer was extracted with EtOAc and the combined organics were washed with saturated aqueous sodium thiosulfate, followed by saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford each diastereomer of the titled compound. Either one can be used on Step B. 1H NMR (500 MHz, CDCl3) (trans): δ 7.19-7.14 (m, 2H); 6.90-6.85 (m, 2H); 4.73-4.71 (m, 1H); 3.80 (s, 3H); 3.54 (td, J=14.6, 6.2 Hz, 1H); 3.46-3.40 (m, 1H); 2.42-2.37 (m, 1H); 2.30-2.25 (m, 1H); 2.23-2.09 (m, 2H); 1.93 (qd, J=13.3, 4.2 Hz, 1H). 1H NMR (500 MHz, CDCl3) (cis): δ 7.16-7.11 (m, 2H); 6.88-6.83 (m, 2H); 5.05 (dd, J=13.5, 5.9 Hz, 1H); 3.78 (s, 3H); 3.12-3.08 (m, 1H); 2.88-2.77 (m, 2H); 2.68 (dd, J=14.1, 6.1 Hz, 1H); 2.48 (q, J=12.9 Hz, 1H); 2.29-2.25 (m, 1H); 1.98 (dd, J=13.2, 4.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:29][C:26]3[N:25]=[CH:24][C:23]([C:22]([F:31])([F:21])[F:30])=[CH:28][N:27]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2)C1
Temperature: 120 °C
Yield: 108.3 %

Procedure:
To a 10 ml glass vial was added (S)-2-(4-bromo-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (70 mg, CAS 1131220-37-5) and 5-trifluoromethyl-pyrimidin-2-ylamine (66.7 mg, CAS 69034-08-8) in dioxane (2 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (14.3 mg), tris(dibenzylideneacetone)dipalladium(0) (7.49 mg) and sodium tert-butoxide (21.6 mg) were then added. The vial was capped and heated at 120° C. for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (S)-2-[4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (94 mg, quant.) as an off-white solid. MS (ISP): 425.2 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([S:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O>[CH2:3]([S:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(SCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Sodium borohydride (2.7 g, 67 mmol) was added slowly in three portions to an ice cold mixture of 4-(benzylsulfanyl)-benzaldehyde (7.70 g, 33.7 mmol) and methanol (150 mL). After the addition was complete, the reaction mixture was warmed to room temperature, then stirred for 1 hour. The reaction mixture was cooled again in an ice bath, then 1 N aqueous HCl (80 mL) was added. The resulting mixture was diluted with water (600 mL), then extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (Analogix SuperFlash™ column, 5%-50% ethyl acetate in hexanes) gave 6.33 g (81%) of (4-benzylsulfanyl-phenyl)-methanol as a white solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].I[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])I>>[F:12][C:10]1([F:13])[C:9]([F:15])([F:14])[C:8]([F:17])([F:16])[C:7]([F:19])([F:18])[O:2]1
Reactant: O=S(=O)(O)O
Reactant: FC(F)(I)C(F)(F)C(F)(F)C(F)(F)I
Product: FC1(F)OC(F)(F)C(F)(F)C1(F)F
Temperature: 85 °C
Yield: 62 %

Procedure:
Into a four necked flask equipped with a thermometer, a reflux condenser, a dropping funnel and a stirrer, 190 g (0.7 mole as SO3) of fuming sulfuric acid containing 30% of SO3 were charged and were heated at 85° C. and then 100 g (0.22 mole) of 1,4-diiodoperfluorobutane having the formula I(CF2)4I were added dropwise to the flask. The reaction was conducted while maintaining the temperature in the reactor at 80° to 90° C. The collection and the separation of the product were conducted in accordance with the process of Example 4. As a result, the conversion was 52% and perfluorotetrahydrofuran (62% yield) and perfluoro- γ-butyrolactone (7% yield) were obtained based on the starting material.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(F)cc3)oc2C)C2CCCCC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid (694 mg), ethyl 3-(methylamino)propanoate (223 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), hydroxybenzotriazole monohydrate (260 mg) and triethylamine (237 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give ethyl 3-[{[5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (263 mg) as an amorphous compound. Ethyl 3-[{[5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (246 mg, 30%).
Reaction SMILES: ClC1C=CC(C=C([N+]([O-])=O)C2C=CC=CC=2)=CC=1.[Na].C(OCC)(=O)CC(OCC)=O.[C:31]([CH:36]([CH:42]([C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=1)[CH:43]([N+:50]([O-])=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37](OCC)=[O:38])([O:33]CC)=[O:32]>>[C:31]([CH:36]1[CH:42]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=2)[CH:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:50][C:37]1=[O:38])([OH:33])=[O:32]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(Cl)cc1)C(c1ccccc1)[N+](=O)[O-]
Agent: O=[N+]([O-])C(=Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Na]
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C(O)C1C(=O)NC(c2ccccc2)C1c1ccc(Cl)cc1

Procedure:
The 3-carboxy-4-p-chlorophenyl-5-phenyl-2-pyrrolidinone (after recrystallization from ethanol M.P. : 184°C. (decomposition)) was prepared by condensing 1-p-chlorophenyl-2-nitro-2-phenyl-ethylene with the sodium derivative of diethyl malonate, reduction of the obtained ethyl 2-carbethoxy-3-p-chlorophenyl-4-nitro-4-phenyl-butanoate (M.P. : 148°-149°C. (recrystallized from ethanol) by means of hydrogen under pressure in presence of Raney cobalt and hydrolysis of the resulting 3-carbethoxy-4-p-chlorophenyl-5-phenyl-2-pyrrolidinone (M.P. : 198°C. (recrystallized from toluene)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>C1COCC1>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Yield: 35.1 %

Procedure:
5-Nitroindazol (10.0 g, 61.3 mmol) was dissolved in THF (100 mL). Potassium carbonate (25.4 g, 184 mmol) and 3-fluorobenzylbromide (12.7 g, 67.4 mmol) were added, and the mixture was heated to reflux for 3 h. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL) and extracted with water (200 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL each). The combined organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to yield 6.55 g (39%) of the title compound (less polar component) and 5.84 g (35%) of the regioisomeric 2H-indazole derivative (more polar component).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH2:19])=[N:9]3)[CH:7]=1.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:9]3)[CH:7]=1
Reactant: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(4aS,5S,7aS)-7a-(5-Bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (620 mg, 1.63 mmol) was dissolved in THF (10 mL). (BOC)2O (0.45 mL, 1.95 mmol) and Et3N (0.27 mL, 1.95 mmol) were added and the reaction was stirred at 100° C. After 1 hour, the solvents were removed in vacuo. The residue was purified using column chromatography (Biotage SNAP 25 g, 20 mL/min eluting with 20-80% EtOAc in n-hexane) to leave the title compound as a foam. (704 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.54 (t, J=1.00 Hz, 1H), 6.86-7.01 (m, 1H), 4.49-4.71 (m, 3H), 4.45 (dd, J=1.22, 8.56 Hz, 1H), 3.68-3.92 (m, 1H), 2.95-3.20 (m, 2H), 2.73 (t, J=1.00 Hz, 1H), 1.46-1.64 (m, 9H)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH:10]([C:22]([OH:24])=[O:23])[NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.[CH3:25]O>>[CH3:25][N:11]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:10]([C:4]1[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])[C:22]([OH:24])=[O:23]
Reactant: CO
Reactant: O=C(O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Agent: Cl
Product: CN(c1ccc2ccccc2c1)C(C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Gaseous hydrogen chloride is introduced for 11 hours through a stirred and refluxing solution of 17.3 parts of (±)-2-(2,6-dichlorophenyl)-N-(2-naphthyl)glycine in 96 parts of methanol. The reaction mixture is allowed to cool overnight to room temperature. The precipitated product is filtered off and crystallized from methanol, yielding 6.4 parts of (±)-methyl 2-(2,6-dichlorophenyl)-N-(2-naphthyl) glycine; mp. 143.5° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCN
Reaction time: 24 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 hours. The solution was then filtered through a Celite pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][N:17]2[C:20](=[O:37])[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:37]=[C:20]([N:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[CH:19]=2)[CH2:15][CH2:16]1)[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3cncnc3)cc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Pyrimidin-5-ylboronic acid (28 mg, 230 μmol), (S)-tert-butyl 1-(6-bromoindolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (100 mg, 230 μmol), (Pd(dppf)Cl2) (18 mg, 22 μmol) were dissolved in DMF (1.1 mL) and 1M sodium carbonate solution (630 μl, 630 μmol) was added. The resulting slurry was stirred in a sealed tube for one hour at 85° C., allowed to cool to room temperature and diluted with water. The mixture was extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with 1M lithium chloride solution (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The residue was purified by medium pressure chromatography (silica, 0 to 100% ethyl acetate:hexanes) to give (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyrimidin-5-yl)indolin-1-yl)propan-2-ylcarbamate (74 mg, 74% yield). MS ESI (pos.) m/e: 445.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:15])=[C:7]([CH3:14])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:16]>C(Cl)(Cl)Cl.C(OCC)(=O)C.[Cu](Br)Br>[Br:16][CH2:12][C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH3:14])[CH:8]=1)=[O:13]
Reactant: CC(=O)c1cc(C)c(O)c(C(C)(C)C)c1
Reactant: Br
Agent: Br[Cu]Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 82.5 g (0.4 mol) of 1-(5-tert.butyl-3-methyl-4-hydroxyphenyl)-ethanone in 360 ml of chloroform was added dropwise while stirring to a suspension, heated to boiling, of 179 g (0.8 mol) of copper(II) bromide in 360 ml of ethyl acetate. The mixture was subsequently refluxed for 4 hours until the evolution of hydrogen bromide was complete. After the mixture had been cooled to room temperature, the copper salts were filtered off under suction, the filter residue was washed repeatedly with ethyl acetate, the filtrate was evaporated under reduced pressure, and the solid residue was recrystallized from cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[N+](C1C=CC(S(O[CH:29]([I:32])[C:30]#[CH:31])(=O)=O)=CC=1)([O-])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:31][C:30]#[C:29][I:32])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nnn[nH]2)cc1
Reactant: C#CC(I)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn(CC#CI)n2)cc1
Reaction time: 4 h

Procedure:
In anhydrous dimethylformamide were stirred well 1.86 g (10 mmoles) of 5-(p-methoxyphenyl)tetrazole and 420 mg (10 mmoles) of sodium hydroxide to form a homogeneous solution. To this solution were added under ice-cooling 3.67 g (10 mmoles) of iodopropargyl p-nitrobenzenesulfonate and the reaction was continued for 4 hours. The reaction mixture was extracted with 200 ml of ethyl acetate and 100 ml of water, the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure. The solid residue, thus obtained was recrystallized twice from methanol to give 2-(1'-iodopropyn-3'-yl)-5-(p-methoxyphenyl)tetrazole, Yield 2.06 g (60%), mp. 146.7°-149.8° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=O)[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A suspension of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.00963 mole) and 1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) in tetrahydrofuran (100 ml) was refluxed for 3.25 hours under nitrogen, cooled to room temperature, a stream of nitrogen was bubbled through the solution for 0.75 hr then a solution of dipropylamine (2.92 g, 0.0289 mole) in tetrahydrofuran (4 ml) was added. The reaction mixture was refluxed overnight under nitrogen and evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers were separated, sodium chloride was added to the aqueous layer and it was re-extracted with ethyl acetate. The combined organic layers were washed twice with a saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered and evaporated under reduced pressure to a solid (3.7 g, 95% yield). The solid was recrystallized from isopropyl alcohol/water and dried under high vacuum at 58° C. to give 2.11 g of title compound, mp 170°-173.5° C.
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCC[C@@H](O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H](O)c1ccc(C(=O)NC=CC(=O)OCC)cc1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propenoate (3.97 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.75 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J=8.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (q, J=5.9 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84-1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J=107.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1): 294.