Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CS(O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.C(O)CCCCCCCCC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCOS(C)(=O)=O
Reactant: CCOC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCCCCCCO
Product: CCCCCCCCCCN1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Ethyl 1-piperazinecarboxylate (77.3 g, 0.28 mole), 1-decanol methanesulfonate (77.3 g, 0.28 mole) from the condensation of 1-decanol with methane sulfonyl chloride, K2CO3 (39.0 g, 0.28 mole), and 500 mL of EtOH were combined and refluxed for 2 days under N2. After cooling to room temperature, the reaction was partitioned between water and Et2O. The organic layer was separated, washed 3 times with water, dried over Na2SO4 and stripped of all solvent under reduced pressure to yield the crude product oil. Chromatographic purification of the crude oil gave 53.4 g of ethyl 4-decyl-1-piperazinecarboxylate.
Reaction SMILES: [OH:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10]O>OS(O)(=O)=O>[OH:1][C:2]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(O)CCCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(O)CCCC1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 1-hydroxycyclopentanecarboxylic acid (1.4 g, 10.76 mmol) in MeOH (10 mL) was treated with cone. H2SO4 (1 drop), heated at 65° C. for 2 h, cooled to RT and concentrated to dryness. The residue was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 1-hydroxycyclopentanecarboxylate (1.45 g, 92%). 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 3H), 2.92 (br s, 1H), 2.11-2.00 (m, 2H), 1.91-1.83 (m, 2H), 1.82-1.72 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)[C:39](=[O:41])[CH3:40])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (503 mg) and pyridine (0.14 ml) in dichloromethane (10 ml) was added acetic anhydride (0.13 ml) in an ice bath. The mixture was stirred at room temperature for 1 hour. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1→ethyl acetate as an eluant to afford yellow crystals. The crystals were washed with diisopropyl ether to give the desired compound (403 mg, yield 50%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:31]2>>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:31]2)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Yield: 72.6 %

Procedure:
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 70-4 (50 mg) was treated with tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (30 mg) to afford compound 72-1 (52 mg) as a light yellow solid after preparative LC purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+].C(N(CC)CC)C>O1CCOCC1.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>[CH:22]([C:11]1[C:5]2[C:4](=[O:20])[O:3][C:2]([CH3:21])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A mixture of 2,2-dimethyl-5-trifluoromethanesulfonyloxy-4H-1,3-benzodioxin-4-one (9.90 g, 30.3 mmol), tributyl(vinyl)tin (10.10 g, 31.9 mmol), lithium chloride (8.70 g, 205 mmol), and triethylamine (5.0 mL, 36.0 mmol) in 1,4-dioxane (300 mL) was deoxygenated by bubbling nitrogen through the mixture for 1 hour. To the mixture was added tetrakis(triphenylphosphine)palladium (3.40 g, 2.90 mmol) and the mixture was heated at 100° C. for 3 hours. The mixture was allowed to cool to room temperature and was filtered. The filtrate was concentrated and purified by flash chromatography (1:12, EtOAc/hexanes) to provide 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (5.00 g, 81%) as a yellow oil: H NMR: (CDCl3) δ1.72 (s, 6H), 5.43 (dd, J=11.0, 1.3 Hz, 1H), 5.72 (dd, J=17.5, 1.3 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.73 (dd, J=17.5, 11.0 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](O)=O)[CH2:4][CH2:3]1.[C:11]1([NH2:18])[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1.[CH3:19]N(C=O)C>N1C=CC=CC=1>[CH3:19][O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:18][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=2)[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CCC(O)CC1
Solvent: c1ccncc1
Product: COC1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
4-Hydroxy-cyclohexanecarboxylic acid (2 g, 13.8 mmol) in a mixture of DMF (4 mL) and pyridine (4 mL) was treated with 1,1-carbonyldiimidazole (2.26 g, 213.8 mmol) at RT and the resulting solution was stirred at 45° C. for 2 h. The mixture was treated with benzene-1,2-diamine (1.5 g, 13.8 mmol) and stirred at RT overnight. After completion, the mixture was concentrated and the obtained residue was treated with glacial acetic acid (20 mL) and heated at 110° C. for 0.5 h. The solution was allowed to cool to RT and concentrated to get a residue, which was purified by flash chromatography on silica gel to provide the title compound (3.0 g, 13.0 mmol, 71% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24](N3[C@H]4C5C=CC=CC=5C[C@H]4OC3=O)=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:46]O.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24]([OH:46])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: COc1ccc(-n2nc(C[C@H](C(=O)N3C(=O)O[C@@H]4Cc5ccccc5[C@@H]43)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
To a stirred solution of (2S,3aS,8aR)-3-{3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (20.7 g, 0.0323 mol) in THF (230 mL) and H2O (45 mL) at 0° C. was added 30% H2O2 (15.0 mL, 0.147 mol) followed by LiOH hydrate (2.75 g, 0.0655 mol) in H2O (15 mL). The reaction mixture was allowed to warm to rt and was stirred for 90 min. The mixture was cooled to 0° C. and then quenched with 1.5 N Na2SO3 (20 mL) maintaining pH 9-10. The mixture was concentrated to ¼ volume, then treated with H2O (200 mL) and acidified to pH 1-2 using 3 N HCl. The aqueous layer was washed with EtOAc (3×100 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to ¼ volume. Solid crystals that developed overnight were filtered and washed with cold 1:1 hexane/EtOAc. The chiral auxiliary was recovered in 66% yield (3.72 g). The filtrate was purified by flash chromatography (7:3 hexane/EtOAc with 0.3% MeOH) to afford 12.7 g (81.5%) of (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid as orange oil. HPLC: Rt=10.44 (Method E). MS (ES+): mass calculated for C26H22Cl2N3, 481.37; m/z found 503.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.12-7.31 (m, 9H), 6.90 (dd, J=6.3, 2.0 Hz, 1H), 6.86 (d, J=9.1 Hz, 2H), 6.21 (s, 1H), 4.07-4.15 (m, 1H), 3.82 (s, 3H), 3.53 (dd, J=9.3, 5.3 Hz, 1H), 3.10 (dd, J=9.1, 5.8 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: N[C@@H](C(O)=O)CC1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O[C:17]1[C:25]2N=N[NH:22][C:21]=2[CH:20]=[CH:19][CH:18]=1>>[CH:21]1([N:22]=[C:5]=[N:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:25][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
This is followed by coupling of the first D-tryptophan by the active ester technique with hydroxybenzotriazole (HOBt) obtained "in situ" by means of dicyclohexylcarbodiimide (DCC). 1.5 milliequivalents (3-fold excess with respect to the amine groups of the resin) of Fmoc-D-tryptophan (0.639 g) and 2 milliequivalents of HOBt (0.310 g) are dissolved in 12 ml of 2:1 DCM/DMF, transferred into the reactor of the apparatus and, after pre-equilibration for 2 minutes with stirring, 1.5 ml of 1 M DCC in 2:1 DCM/DMF (equal to 1.5 milliequivalents) are added, thus initiating the automatic coupling cycle (line 9 in Table 2). At the end of the cycle described in the table, the Kaiser test is carried out on an aliquot of resin; if the degree of incorporation of the amino acid is greater than 99%, the automatic protective group removal from the amine group is carried out; otherwise, the coupling is repeated. For the successive couplings, always according to the plan in Table 2, the following amino acids were used in the quantities indicated: Fmoc-DTrp (0.639 g for each of the 3 further couplings), Fmoc-valine (0.509 g), Fmoc-tyro-sine t-butyl ether (0.689 g) and Fmoc-t-butyl aspartate (0.617 g). After the last coupling, the protective group removal cycle is repeated, the resin is taken out of the reactor and dried in vacuo over potash, giving 1.650 g of product. This is then followed by the detachment of the peptide from the resin and simultaneous protective group removal from the side chains by trifluoroacetic acid (TFA). 1.5 g of peptide-resin are placed into a small flask containing 30 ml of a solution consisting of 27:1.5:1.5 (volume/volume) TFA/ethanedithiol/p-cresol and the mixture is maintained for 2 hours in a water bath at 35° C. with magnetic stirring. To precipitate the crude product, 10 volumes of ethyl ether and 5 volumes of petroleum ether, both cooled to 0° C., are added. The mixture is kept overnight at -78° C. and filtered over a porous funnel-shaped filter , giving 350 mg of crude crystalline product. For the purification by high-pres-sure liquid chromatography, the procedure of Example 1 is followed, giving 12 mg of product; characterization by HPLC analysis (conditions as described in Example 1): Rt=12.6 minutes, HPLC purity=98%.
Reaction SMILES: Cl[C:2]([CH3:8])([CH3:7])[CH:3]([N:5]=[O:6])[CH3:4].[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH3:14]O>O>[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]([CH3:8])([CH3:7])[C:3](=[N:5][OH:6])[CH2:4][CH3:14]
Reactant: NCCCN
Reactant: CO
Reactant: CC(N=O)C(C)(C)Cl
Solvent: O
Product: CCC(=NO)C(C)(C)NCCCN

Procedure:
A solution of 3-chloro-3-methyl-2-nitrosobutane (25.5 g) in methanol (180 cm3) was added dropwise to a stirred solution of 1,3-diaminopropane (47 cm3) in methanol (75 cm3) at 0° C. After the addition was complete the mixture was refluxed for 6 hours. Removal of the methanol in vacuo gave a yellow oil which was slurried in water (50 cm3). The white precipitate was removed by filtration and the pH of the aqueous solution adjusted to about 11. After saturating with salt the solution was continuously extracted with dichloromethane for 36 hours. The organic phase was dried (MgSO4) and concentrated in vacuo giving a yellow oil. Recrystallisation from ether/petrol gave pure product as a white crystalline solid, 9.9 g. Mpt. 69°-72° C.
Reaction SMILES: [O:1]=[C:2]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:69])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[CH:67]2[CH:63]([NH:64][C:65](=[O:68])[NH:66]2)[CH2:62][S:61]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[CH:38][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.O[N:71]1[C:75](=[O:76])[CH2:74][CH2:73][C:72]1=[O:77].C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:69])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[CH:67]2[CH:63]([NH:64][C:65](=[O:68])[NH:66]2)[CH2:62][S:61]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[CH:38][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([O:37][N:71]3[C:75](=[O:76])[CH2:74][CH2:73][C:72]3=[O:77])=[O:36])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCOCCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of crude 1-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (1.85 g, 1.89 mmol) in anhydrous DCM (43.0 ml) was added N-hydroxysuccinimide (239 mg, 2.08 mmol) followed by EDC (471 mg, 2.46 mmol). The reaction was stirred at r.t. for 4 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH, gradient) to provide 2,5-dioxopyrrolidin-1-yl 1-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([C:16]2[CH2:17][CH2:18][N:13]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cccc(C2=CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1

Procedure:
The reaction of tert-butyl N-(3-bromopropyl)carbamate and N-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide in refluxing dioxane with catalytic Bu4NI and base as described in Scheme A gave tert-butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11–12) gave the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[CH3:15][O:16]C(Cl)Cl.O>ClCCl>[CH3:14][O:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:15]=[O:16]
Reactant: COc1ccc(OC)c2ccccc12
Reactant: COC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C=O)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-dimethoxy-naphthalene (5 g, 26.6 mmol) in dichloromethane (100 mL) at 0° C. was added dichloromethyl methyl ether (3.66 g, 31.9 mmol) and stannic chloride (13.8 g, 53.1 mmol). The reaction mixture was stirred for 30 min at this temperature, allowed to warm to room temperature and stirred for an additional 30 min. Water (100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL) and the combined extracts dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, ethyl acetate/hexane: 2/8) to give a white solid: 1H NMR (DMSO-d6) δ 4.06 (s, 3H, CH3), 4.13 (s, 3H, CH3), 7.14 (s, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.29 (m, 2H, Ar—H), 10.54 (s, 1H, CHO).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:23]([O:26][C:27](Cl)=[O:28])([CH3:25])[CH3:24]>O>[CH:23]([O:26][C:27]([NH:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)OC(=O)Nc1ccc2nc(-c3ccccc3)oc2n1
Reaction time: 120 h

Procedure:
A mixture of 300 mg. of 5-amino-2-phenyloxazolo[ 5,4-b]pyridine and 3 ml. of pyridine was cooled in ice and to it was added 0.2 ml. of isopropylchloroformate. The mixture was allowed to age in the refrigerator for 5 days, and diluted with ice and water. The precipitate was collected and recrystallized from isopropanol to give 5-isopropoxycarbonylamino-2-phenyloxazolo[ 5,4-b]pyridine, m.p. 210°-211° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 11b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 11c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+−Boc).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:14]2CCCC2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:22]=[C:23]([C:29](=O)[C:30]([F:33])([F:32])[F:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])C.C([O-])(=O)C.[NH4+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
A solution of the crude enamine (2.67 g, 10.6 mmol) from Step A above in 30 mL of dry 1,4-dioxane was cooled to approximately 10° C. and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (2.3 mL, 11.7 mmol) was added dropwise. The resultant orange solution was allowed to warm to room temperature overnight. Ammonium acetate (1.78 g) was added to the blood-red solution, and the mixture was heated at reflux for 2 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ether and water, and the ether layer was washed with saturated brine, dried over magnesium sulfate and concentrated to a red oil. Purification by flash chromatography (silica gel; 12% ethyl acetate/hexanes as eluant) followed by preparative TLC (silica gel; 15% ethyl acetate/hexanes as eluant) afforded the title compound as a light yellow oil. LC/MS 365.2 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[C:13]([C:20]2[C:21](F)=[N:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=3)[CH:25]=2)=[C:14]([NH2:19])[CH:15]=[N:16][C:17]=1[Cl:18]>C1COCC1.O>[Br:11][C:12]1[C:13]2[C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:23]=[N:22][C:21]=3[NH:19][C:14]=2[CH:15]=[N:16][C:17]=1[Cl:18]
Reactant: Nc1cnc(Cl)c(Br)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c2c1Br
Yield: 16.9 %

Procedure:
Sodium bis(trimethylsilyl)amide (3.9 mL, 3.90 mmol) was added to a solution of 5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (187 mg, 0.39 mmol) in anhydrous THF (7.0 mL) and the resultant solution stirred at ambient temperature for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with DCM: MeOH (4:1, 3×20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 4 g column, ISCO, 0-15% MeOH in DCM) to afford the title compound as a beige powder (30 mg, 17%). 1H NMR (CDCl3, 400 MHz): 9.17 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.67 (s, 1H), 7.65 (d, J=7.5 Hz, 2H), 7.49 (d, J=7.5 Hz, 2H), 3.59 (s, 2H), 2.51-2.47 (m, 4H), 1.68-1.59 (m, 4H), 1.51-1.45 (m, 2H). LCMS (Method A): RT=7.10 min, M+H+=455/457.