Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[N:20]=[C:19]([I:21])[C:18]([O:22][CH3:23])=[CH:17][CH:16]=1)=O.C(O)(C)C.O>C1(C)C=CC=CC=1.O1CCCC1>[OH:12][CH2:13][C:15]1[N:20]=[C:19]([I:21])[C:18]([O:22][CH3:23])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(I)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc(CO)nc1I
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
40 ml of a 25% solution of diisobutylaluminum hydride in toluene is added drop by drop to a solution of 7 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester in 95 ml of toluene and 50 ml of tetrahydrofuran at -70° C. The reaction mixture is stirred for 30 minutes at -70° C., heated to -5° C. within two hours and stirred for 2 hours at this temperature. The reaction mixture is cooled to -70° C., mixed in succession with 20 ml of isopropanol and 20 ml of water and stirred for three hours at room temperature. The precipitate is suctioned off on diatomaceous earth, the filter residue is washed with dichloromethane and the filtrate is concentrated by evaporation. 6.54 g of 6-hydroxymethyl-2-iodo-3-methoxypyridine of melting point 106°-108° C. is obtained.
Reaction SMILES: [OH:1][C@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: CON(C)C(=O)[C@](C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CON(C)C(=O)[C@@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
(R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol) and 4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added and stirred at ambient temperature overnight. The reaction was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (R)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (22.9 g, 113 mmol, 57.5% yield).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.[O-]CC.[K+].C(=O)(O)[O-].[Na+]>>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:13][CH2:12][CH2:11][C:10]([OH:15])=[O:14]
Reactant: O=C1CCCO1
Reactant: COc1ccccc1O
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [K+]
Product: COc1ccccc1OCCCC(=O)O
Temperature: 110 °C
Reaction time: 10 h
Yield: 55 %

Procedure:
To the mixture of guaiacol (2-methoxyphenol, 1.0 equivalent) and γ-butyrolactone, cooled in an ice-water bath, was added potassium ethoxide in small portions. The reaction mixture was heated at 110° C. overnight, and then at 155° C. for an additional 10 hours. The mixture was then poured into ice water, basified to pH 9.5 with saturated sodium bicarbonate, and extracted with chloroform. The aqueous phase was separated, acidified to pH 2.5 with 2N HCl, and extracted with a mixture of chloroform:isopropyl alcohol (3:1). The organic phase was dried over anhydrous sodium sulfate and evaporated to afford 4-(2-methoxyphenoxy)butanoic acid as a light brown oil in 55% yield. The crude product was used for next reaction without further purification: 1H NMR δ 6.90 (m, 4H), 4.08 (t, 2H, J=6.2 Hz), 3.85 (s, 3H), 2.62 (t, 2H, J=7.2 Hz), 2.16 (p, 2H, J=6.6 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[N:20][N:21]=2)[N:18]=1)(=O)=O.[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:35]1([CH:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]2[CH2:30][CH2:31][N:32]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[N:20][N:21]=4)[N:18]=3)[CH2:33][CH2:34]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)OCCCCCCNc1ccc2nncn2n1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CCN(CCCCCCNc3ccc4nncn4n3)CC2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.6 %

Procedure:
796 mg of 6-[6-(methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine was dissolved in 15 ml of N,N-dimethylformamide; 769 mg of 1-(diphenylmethyl)piperazine, 422 mg of potassium carbonate, and 506 mg of potassium iodide were added, followed by stirring at 60° C. for 4 hours. After cooling, saline was added; the reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethyl acetate, washed with diethyl ether, recrystallized in the same manner, and dried, to yield 353 mg of the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](O)[CH3:8])(=[O:4])[CH:2]=[CH2:3].[C:10]([O:14][CH2:15][CH2:16][CH2:17]O)(=[O:13])[CH:11]=[CH2:12]>>[CH2:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:8][CH2:7][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4])=[O:13].[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)OCC(C)O
Reactant: C=CC(=O)OCCCO
Product: C=CC(=O)OCCCCCCOC(=O)C=C

Procedure:
HPA—an isomeric mixture of 2-hydroxypropyl acrylate and 3-hydroxypropyl acrylate (available as ROCRYL 430 from Rohm and Haas, Philadelphia, Pa.)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH:8]3[O:15][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][C@@H:7]([OH:15])[C@H:8]([N:27]1[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]1)[CH2:9]2
Reactant: COc1cc2c(cc1OC)CC1OC1C2
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC(C)O
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1OC)C[C@@H](N1CCN(c3ccccc3OC)CC1)[C@H](O)C2
Yield: 22.9 %

Procedure:
A solution of 2.94 g of 2,3-dimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.9 g of 1-(o-methoxyphenyl)piperazine, and 1 ml of isopropanol in 30 ml of xylene is refluxed for 5 days. The reaction mixture is concentrated in vacuo, the residue taken up in ethyl acetate, and this is thoroughly extracted with dilute hydrochloric acid. The combined acid extracts are made basic with dilute sodium hydroxide solution, and this is thoroughly extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated in vacuo to an oil, which gives 1.3 g of solid on trituration with ethyl acetate. Recrystallization from ethyl acetate gives 600 mg of the title compound, melting point 172°-174° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:77])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][NH:59][CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C>[F:77][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][N:59]([C:4](=[O:6])[C@@H:3]([O:2][CH3:1])[CH3:7])[CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:66][CH2:67]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Reactant: CO[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Reaction time: 8 h

Procedure:
A solution of (S)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA (3.9 mg, 0.028 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL) was stirred at room temperature for 10 min then treated with N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol). Stirring was continued overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.6 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.76 (t, J=6.2 Hz, 0.9H), 2.84 (t, J=5.4 Hz, 1.1H), 2.95-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J=14.6, 4.3 Hz, 2H), 3.83-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.49 (m, 1H), 4.56 (m, 1.1H), 4.68 (m, 0.9H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:22]([O:24][C:25](=[O:49])[CH2:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[CH2:45][NH:46][CH2:47][CH3:48])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:23].O>C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:49])[CH2:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][C:36]=2[CH2:45][N:46]([C:12]([C:9]2([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:11][CH2:10]2)=[O:13])[CH2:47][CH3:48])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:23]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2(c3ccc(Cl)cc3Cl)CC2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(2,4-dichloro-phenyl)-cyclopropanecarbonyl chloride (0.37 mmol) in CH2Cl2 was added triethylamine (0.16 mL, 1.12 mmol), and the mixture was stirred for 10 minutes. (2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.146 g, 0.37 mmol) in CH2Cl2 was then added, and the reaction was stirred for 30 minutes at room temperature. Additional triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred for another 30 minutes. Analytical LCMS indicated that starting material was still present, so another portion of triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred for 1 hour and then worked-up with CH2Cl2 and H2O. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30].CN(C)C=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>>[CH3:26][N:27]([CH3:32])[CH2:28][C:29]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:20]=1)=[O:30]
Reactant: COc1ccc(-c2ccc3cnc(Nc4cccc(N)c4)nn23)cn1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(NC(=O)CN(C)C)c4)nn23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-benzene-1,3-diamine (50.0 mg, 0.150 mmol; N,N-Dimethylglycine (18.6 mg, 0.180 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34.6 mg, 0.180 mmol; and N,N-Dimethylformamide (0.999 mL, 12.9 mmol) were combined in a vial and stirred at rt for 1 hour. LCMS showed partial conversion to product. Stirred an additional 2 hours. Added 5 extra eq of acid, DIEA, HOBT, and EDCI and stirred for 18 h. Reaction went to completion. Diluted reaction mixture with sat'd NaHCO3 and filtered off resulting ppt. Ppt was purified by ISCO silica gel chromatography (0-100% EtOAc in hexanes). Conc down to recover title compound as a yellow solid (11 mg, 13%). LCMS=418.0 (M+H), HPLC purity=93%, rt=2.218 min. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.03 (s, 1H), 8.72 (s, 2H), 8.52 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.85 (s, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.32-7.28 (m, 2H), 6.95 (d, J=4.6 Hz, 1H), 6.90-6.87 (m, 2H), 6.85 (d, J=4.5 Hz, 1H), 4.00 (s, 3H), 3.09 (s, 2H), 2.37 (s, 6H).
Reaction SMILES: I[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(NC(C)C)(C)C.O>O1CCCC1.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.[Cu](I)I>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=[C:2]1[C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cc2ccccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cc2ccccc2o1

Procedure:
A solution of Example 651 (1.00 g, 4.10 mmol), (trimethylsilyl)acetylene (0.80 mL, 5.68 mmol), dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.13 mmol), diisopropylamine (1.08 mL, 7.74 mmol) and copper iodide (3 mg, 0.258 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for about 16 h. The solution was poured into water and was extracted with dichloromethane. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9:1) as eluent to provide Example 652. 1H NMR (300 MHz, CDCl3) δ 0.29 (m, 9H), 6.94 (s, 1H), 7.23 (m, 1H), 7.33 (m, 1H), 7.43 (m, 1H), 7.54 (d, J=7.8 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[C:9]1([CH:4]([CH2:3][CH2:2][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(CCCl)c1ccccc1
Reactant: c1cn[nH]c1
Product: COC(=O)C(CCn1cccn1)c1ccccc1
Yield: 32.2 %

Procedure:
Methyl (RS)-4-chloro-2-phenylbutanoate (prepared as described in J. Amer. Chem. Soc., 443, 73, 1951) (1 g) and pyrazole (1 g) were heated together at 120° C. for 5 hour, cooled and the residue partitioned between ether and water. The organic layer was washed with water and extracted with 2M hydrochloric acid. The acid extracts were basified with sodium carbonate and extracted with ether. The organic layer was dried over magnesium sulphate and evaporated to give the title compound (0.37 g, 33%) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 35, the configuration of the stereocenter is arbitrarily assigned) and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 7. LC (method 5): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:18][C:14]1[C:15]([OH:17])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CNCCc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.655 g, 1.89 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.460 g of a clear oil. 1H NMR (400 MHz, DMSO-d6) d 7.11 (s, 1 H), 6.65 (s, 1 H), 2.90 (m, 1 H), 2.73 (m, 5 H), 2.55 (m, 1 H), 1.19 (d, J=7 Hz, 3 H). MS calculated for C11H14BrNO+H: 256, observed: 256.
Reaction SMILES: Cl.[CH:2]1([S:5]([NH:8][C:9]([C@@:11]2([NH:16][C:17]([C@H:19]3[NH:23][CH2:22][C@H:21]([O:24][C:25]([N:27]4[CH2:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][C:33]=5[F:36])[CH2:28]4)=[O:26])[CH2:20]3)=[O:18])[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C@@H:45]([CH:49]([CH3:51])[CH3:50])[C:46](O)=[O:47])=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl.O>[F:36][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:34]=1[CH2:35][N:27]([C:25]([O:24][C@@H:21]1[CH2:20][C@@H:19]([C:17](=[O:18])[NH:16][C@:11]3([C:9](=[O:10])[NH:8][S:5]([CH:2]4[CH2:3][CH2:4]4)(=[O:6])=[O:7])[CH2:13][C@H:12]3[CH:14]=[CH2:15])[N:23]([C:46](=[O:47])[C@@H:45]([NH:44][C:41]3[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=3)[CH:49]([CH3:51])[CH3:50])[CH2:22]1)=[O:26])[CH2:28]2
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)[C@H](Nc1ccc(F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
[(3R,5S)-5-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-3-yl]4-fluoroisoindoline-2-carboxylate hydrochloride (0.050 g, 0.092 mmol), (S)-2-(4-fluorophenylamino)-3-methylbutanoic acid (0.021 g, 0.10 mmol) and HATU (0.042 g, 0.11 mmol) in DCM (3 mL) was added DIEA (0.048 mL, 0.28 mmol) and the reaction was stirred at rt for 5 hr. H2O (5 mL) and saturated KHSO4 solution (3 mL) was added. The mixture was extracted with ether (15 mL), washed with brine (10 mL) and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (hexane:Ethyl acetate=1:2) to give the (3R,5S)-5-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-1-((S)-2-(4-fluorophenylamino)-3-methylbutanoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate (0.042 g, 65%) as white solid. MS: Calcd.: 699; Found: [M+H]+ 700. 1H NMR (400 MHz, d6-DMSO) δ 10.91, 10.85 & 10.58 (s, 1H), 9.16, 9.05 & 8.84 (s, 1H), 7.40 (m, 1H), 7.04-7.21 (m, 2H), 6.71 (m, 2H), 6.60 (m, 2H), 5.62 (m, 1H), 5.10-5.17 (m, 4H), 4.68 (s, 2H), 4.41-4.60 (m, 2H), 4.32 (m, 1H), 4.09 (m, 1H), 3.97 (m, 1H), 3.80 (m, 1H), 2.94 (m, 1H), 2.22 (m 1H), 2.00-2.18 (m, 3H), 1.71 (m, 1H), 1.20-1.31 (m, 2H), 0.87-1.10 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:16]([C:18](O)=[O:19])[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N:48]12[CH2:53][CH2:52][CH:51]([CH2:50][CH2:49]1)[CH:46]([NH:45][C:18]([C:16]1[CH:17]=[C:2]([Br:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=4)=[N:6][C:5]=13)=[O:19])[CH2:47]2
Reactant: NC1CN2CCC1CC2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Br)cc3o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cc(Br)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol), 1-hydroxybenzotriazole (60 mg, 0.31 mmol) and 3-aminoquinuclidine dihydrochloride (61 mg, 0.31 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.12 mL, 1.02 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide (60 mg, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.48 (d, J=7.3 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 4.35-4.25 (m, 1H), 3.60-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.82 (m, 2H),
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C:9](O)([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:15])[CH3:16])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC(O)(C#C[Si](C)(C)C)C1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: C=CCOC(=O)N1CC=C(C#C[Si](C)(C)C)C1
Yield: 43.2 %

Procedure:
To a solution of 1-allyloxycarbonyl-3-hydroxy-3-trimethylsilylethynylpyrrolidine (18.0 g) in pyridine (180 ml) was added dropwise thionyl chloride (29 ml) below 20° C. The resultant mixture was stirred for 1 hour and slowly poured into cooled water. The solution was extracted three times with n-hexane The extracts were combined, washed with 1N hydrochloric acid (4 times), saturated aqueous sodium hydrogen carbonate, water and brine successively, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel to give 1-allyloxycarbonyl-3-trimethylsilylethynyl-3-pyrroline (7.25 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[Li+].[Cl-].[NH4+]>CN(C)C=O>[NH:21]1[C:1]([CH2:3][C:4]2[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][C:10]3[N:15]4[CH:16]=[N:17][CH:18]=[C:14]4[CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:5]=2)=[N:2][N:23]=[N:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(CCc2cccc3cncn23)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1cc(CCc2ccc(Cc3nnn[nH]3)cc2)n2cncc2c1

Procedure:
A solution of 5-[p-(cyanomethyl)phenethyl]-imidazo[1,5-a]pyridine (6.0 g) in 16 ml of dry dimethylformamide is heated at 120° for 15 hours with sodium azide (2.15 g), lithium chloride (0.2 g) and ammonium chloride (1.80 g). After cooling and filtering, the solvent is evaporated and the residue is dissolved in 50 ml of water, extracted with 25 ml of ethyl acetate and brought to pH=5 with concentrated sulfuric acid. The precipitated solid is filtered, washed with water and dried to yield 5-[p-(5-tetrazolylmethyl)phenethyl]-imidazo[1,5-a]pyridine.