Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][O:60][C:61]([C:63]1[CH:68]=[CH:67][C:66]([CH2:69][CH2:70][C:71](O)=[O:72])=[CH:65][CH:64]=1)=[O:62].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:71](=[O:72])[CH2:70][CH2:69][C:66]1[CH:67]=[CH:68][C:63]([C:61]([O:60][CH3:59])=[O:62])=[CH:64][CH:65]=1
Reactant: COC(=O)c1ccc(CCC(=O)O)cc1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.45 g, 0.9 mmol) in anhydrous NMP (12 ml) was treated with HBTU (0.48 g, 1.2 mmol), 3-(4-(methoxycarbonyl)phenyl)propanoic acid (0.22 g, 1.08 mmol) and diisopropylethyl amine (0.47 mL, 2.7 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (100 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to a yellow residue, 0.59 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford methyl 4-(3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-3-oxopropyl)benzoate (37) as a white solid, 0.18 g (29%), LC/MS (+APCI) m/z 690 (M++1) and 704 (M++1), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.92 (m, 2 H), 7.60 (m, 1H), 7.49 (m, 1H), 7.29 (m, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.91 (m, 1H), 6.82 (m, 2H), 6.35 (m, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.89 (s, 3H), 4.1 to 2.5 (many multiplets, 10H). 13CNMR (100 MHz, CDCl3) δ 171.4, 168.2, 156.1, 149.6, 149.0, 146.2, 138.4, 138.1, 137.0, 135.8, 135.3, 130.2, 129.9, 128.4, 128.2, 122.6, 121.7, 120.8, 107.3, 103.0, 67.0, 57.5, 51.9, 47.7, 41.9, 37.4, 35.9, 31.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[C:11]=3[C:10]([CH2:21][NH:22][C@@H:23]3[CH:28]4[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]4)[CH2:24]3)=[N:9]2)=[CH:4][CH:3]=1.O.O.[OH-].[Li+:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O-:19])=[O:18])[C:11]=3[C:10]([CH2:21][NH:22][C@@H:23]3[CH:28]4[CH2:27][CH2:26][N:25]([CH2:30][CH2:29]4)[CH2:24]3)=[N:9]2)=[CH:4][CH:3]=1.[Li+:34]
Reactant: COC(=O)c1cccc2c1c(CN[C@H]1CN3CCC1CC3)nn2-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2c1c(CN[C@H]1CN3CCC1CC3)nn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 1-(4-fluorophenyl)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate (492 mg, 1.2 mmol) from Step B above in THF (2.5 mL) and H2O (2.5 ml) was added lithium hydroxide monohydrate (152 mg, 3.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (R)-1-(4-fluorophenyl)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate which was used in the next step without further purification; MS (ESI+) m/s 394 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12]([O:14]CC)=[O:13])[C:4]([CH3:17])=[CH:3]1.[OH-].[K+].[OH-].[Na+]>C(O)C>[OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:12]([OH:14])=[O:13])[C:4]([CH3:17])=[CH:3]1
Reactant: CCOC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C[C@H](O)CC2(CCCC2)[C@H]1C(=O)O
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A 33:67 cis-/trans-ethyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (38 g, 0.16 mol, prepared as described in Example 16) was added to a solution of KOH (52.6 g, 0.8 mol) in ethanol (300 ml). The resulting mixture was stirred for 2 h at reflux, poured into cold 2N aqueous NaOH (100 ml), and extracted twice with MTBE (100 ml). The combined organic phases were washed with 2N aqueous NaOH (50 ml), the combined aqueous phases were acidified with conc. HCl, extracted twice with MTBE (150 ml), and the combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (100 ml), dried (MgSO4), and concentrated, giving crude trans-9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylic acid (22.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([NH2:16])[C:13]([N+:17]([O-])=O)=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[C:20](OCC)(=[O:26])[C:21](OCC)=[O:22]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3=[CH:15][C:14]4[NH:16][C:20](=[O:26])[C:21](=[O:22])[NH:17][C:13]=4[CH:12]=[C:10]3[N:11]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc2[nH]c(-c3ccncc3)nc2cc1[N+](=O)[O-]
Product: O=c1[nH]c2cc3nc(-c4ccncc4)[nH]c3cc2[nH]c1=O
Yield: 45 %

Procedure:
Analogously to Example 3, from 2-(4-pyridyl)-5-amino-6-nitrobenzimidazole, by hydrogenation and reaction with diethyl oxalate, there was obtained, in a yield of 45% of theory, the title compound; m.p. above 300° C.
Reaction SMILES: [C:1](=[C:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[CH:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)=C1CCOC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1CCOC1=O

Procedure:
A mixture of 8.3 g (66 mmol) of α-isopropylidene-γ-butyrolactone and 0.5 g of 10% Pd-C in 200 mL of EtOAc was hydrogenated at 40 p.s.i. in a Parr shaker until H2 uptake ceased (ca. 1 h). The catalyst was removed by filtration through Celite, the solvent removed, and the product distilled to yield 7.8 (93%) of α-isopropyl-γ-butyrolactone as a colorless liquid: bp 53°-54° C./0.2-0.3 torr. The 1H-nmr and IR were identical to those reported by Kendall and Wells, Aust. J. Chem. 27(10), 2293-2295 (1974).
Reaction SMILES: C1(C)C=CC=CC=1.FC(F)(F)S(O[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH:22]=2)[CH:17]=[N:16][CH:15]=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:58]=[CH:57][C:46]([O:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:54]1[CH2:53][CH2:52][CH:51]([O:50][CH2:49][CH2:48][O:47][C:46]2[CH:57]=[CH:58][C:43]([C:17]3[C:18]4[C:23](=[CH:22][C:21]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])=[CH:20][CH:19]=4)[CH:14]=[CH:15][N:16]=3)=[CH:44][CH:45]=2)[CH2:56][CH2:55]1
Reactant: CC1(C)OB(c2ccc(OCCOC3CCOCC3)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(-c3ccc(OCCOC4CCOCC4)cc3)nccc2c1
Yield: 51.8 %

Procedure:
Into toluene (10 ml), 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (500 mg, 1.2 mmol) was dissolved, to which 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy}tetrahydro-2H-pyran (630 mg, 1.8 mmol) synthesized in Reference Example 2, 4,5-bis(diphenylphosphino)-9-dimethylxanthene (210 mg, 0.36 mmol), tris(dibenzylideneacetone)palladium (160 mg, 0.17 mmol), and potassium carbonate (500 mg, 3.6 mmol) were added. The resulting mixture was stirred at 100° C. for four hours, to which ethyl acetate was added. The resulting mixture was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (307 mg, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 78.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(4-cyanobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 4-cyanophenylboronic acid (0.033 g; 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.047 g; 0.449 mmol), sodium iodide (0.067 g; 0.449 mmol), in dimethoxyethane (3 mL) and water (1 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.0705 g (78%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:28])[NH:26][CH3:27])[CH3:23].[H-].[Na+].Cl.O>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:28])[N:26]([CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1)[CH3:27])[CH3:23]
Reactant: CCOC(=O)NC
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(C)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
1.00 g (3.2 mmol) of 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) was dissolved in 20 ml of DMF. Then, the reaction mixture was cooled down to 0° C. 0.36 ml=0.366 g (3.52 mmol) of methyl-carbamic acid ethyl ester was added to the stirred solution, followed by 0.14 g (3.2 mmol) of sodium hydride (55%). After 18 hours, the reaction mixture was poured into crashed ice, the pH was adjusted to <3 with HCl/H2O and it was then extracted twice with Et2O. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of EtOAc, n-heptane) to give 0.87 g of the title compound as light yellow solid.
Reaction SMILES: [N+:1]([CH:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[O:7]1)[CH3:5])([O-:3])=[O:2].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][O:7][C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH:6]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C1OC(=O)c2ccccc21)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1C=C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,3-dihydro-3-(1-nitroethyl)-isobenzofuran-1-one [2.0 g, described by J. J. Stehle et al., J. Org. Chem., 10, 429 (1945)], dimethyl sulfate (1.6 ml) and potassium carbonate (2.4 g) in acetone (50 ml) is stirred at 25° C. for 18 hr under dry conditions. The mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel using benzene and the eluates are evaporated to give the title compound (1.672 g), nmr (CDCl3) δ2.25(s), 3.91(s), 7.40(s), 7.60(m), 8.18(s) and 8.50(s).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.9 %

Procedure:
In 30 ml of dichloromethane was suspended 6.0 g (69.0 mmol) of active manganese dioxide. Next, 1.17 g (3.45 mmol) of 4-[2-[4-(dibutylamino)phenyl]vinyl]benzyl alcohol was dissolved in dichloromethane and added to the suspension. After stirred at room temperature for 20 hours, the suspension was filtrated and the solvent was evaporated off. The residue was purified by silica gel column, chromatography to give 0.74 g of a yellow crystal (yield: 64.1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)(=[O:10])=[O:9])=[C:4]([Cl:27])[CH:3]=1.Cl[C:29]1[CH:30]=[CH:31][C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:37]=2[N:38]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:29]3[CH:30]=[CH:31][C:32]4[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)[C:37]=4[N:38]=3)[CH:17]=2)(=[O:9])=[O:10])=[C:4]([Cl:27])[CH:3]=1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccc(Br)cc3Cl)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 19.9 %

Procedure:
A mixture of 4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (Intermediate 10) (0.0740 g, 0.279 mmol), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.145 g, 0.306 mmol), 1N aq. sodium bicarbonate (0.557 ml, 0.557 mmol) and PdCl2(dppf)-CH2Cl2 (0.0230 g, 0.0280 mmol) in dioxane (1.40 ml) was subjected to microwave irradiation for 1 hour at 110° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with DCM. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 4-bromo-2-chloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.032 g, 20%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.04-2.12 (2H, m), 2.23-2.27 (2H, m), 3.68-3.74 (2H, m), 4.10-4.15 (2H, m), 5.63-5.69 (1H, m), 7.83 (1H, t, J=2.2 Hz), 7.92 (1H, brs), 8.13-8.16 (1H, m), 8.22 (1H, d, J=8.0 Hz), 8.34-8.42 (4H, m), 8.84 (1H, s). m/z=577.9 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16](C)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:20].[H][H]>C(O)C.[Pd]>[ClH:20].[ClH:20].[CH3:1][N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CN1CCC2(CC1)CCN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC2(CCNCC2)CC1

Procedure:
3-Benzyl-9-methyl-3,9-diaza-spiro[5.5]undecane (Rice, L. M. et al. J Heterocyclic Chem. 1964, 1, 3, 125.) (1.2 g, 4.65 mmol) was dissolved in ethanol (20 mL). To this solution was added hydrochloric acid (4 N in dioxane, 3 mL) and palladium (10% on charcoal, 500 mg). The reaction was shaken on a Parr shaker overnight under 60 psi of hydrogen. The reaction mixture was filtered through a pad of celite, concentrated, and the residue treated with a mixture of ethyl acetate and hexanes, to yield 670 mg (60%) as a white powder. 1H-NMR (CD3OD) δ 1.68-1.72 (m, 4H), 2.88 (s, 3H), 3.16-3.22 (m, 6H), 3.38 (m, 2H). Mass spec.: 169.12 (MH)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][P:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])[O:11]CC)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:7][CH2:8][CH2:9][P:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:11])[OH:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CCCN1CCOCC1)c1ccccc1
Agent: Cl
Product: O=P(O)(CCCN1CCOCC1)c1ccccc1
Yield: 115.1 %

Procedure:
A solution of ethyl [3-(morpholin-4-yl)propyl](phenyl)phosphinate (300 mg, 1.0 mmol) in 4N HCl (5 ml) was refluxed for 18 hours. Lyophilization afforded 310 mg (100%) of the title compound as an amorphous hygroscopic solid; MS: 270 m/z (M+H)+.
Reaction SMILES: C([NH:11][C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.[C:38]([NH:48][CH2:49][C:50]([OH:52])=O)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>>[C:38]([NH:48][CH2:49][C:50]([NH:11][C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:52])([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)O

Procedure:
Carbobenzoxy-glycyl-phenylalanyl-glycyl-arginine is prepared by the method similar to that described for the preparation of carbobenzoxy-phenylalanyl-glycyl-arginine on the basis of 2.71 g (5.28 mM) of the latter and 1.93 g (5.83 mM) of p-nitrophenyl ester of carbobenzoxy-glycin.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(C)ccc1I
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Temperature: 100 °C
Yield: 87.5 %

Procedure:
A stirred solution of 2-iodo-5-methylbenzoic acid (17.3 g, 66.0 mmol) and concentrated H2SO4 (3 mL) in MeOH (200 mL) was heated at reflux for 18 h. After this time, the reaction mixture was cooled to rt, concentrated to one third volume, diluted with EtOAc (300 mL), washed with saturated NaHCO3 (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dried under high vacuum to afford methyl 2-iodo-5-methylbenzoate as a colorless oil (18.2 g, quant.). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 6.99-6.96 (m, 1H), 3.92 (s, 3H), 2.33 (s, 3H). A stirred suspension of methyl 2-iodo-5-methylbenzoate (18.2 g, 66.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.2 g, 73.3 mmol), K2CO3 (27.5 g, 200 mmol), and Pd(PPh3)4 (11.5 g, 9.99 mmol) in 1,4-dioxane (150 mL) and H2O (50 mL) was heated at 100° C. for 18 h under nitrogen. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (400 mL), washed with saturated NaHCO3 (2×300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 80% EtOAc/hexanes to afford methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate as a colorless oil (13.3 g, 87%). 1H NMR (300 MHz, CDCl3) δ 7.55-7.25 (m, 5H), 3.94 (s, 3H), 3.80 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C([O-])(O)=O.[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.O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CC(C)n1cc(Br)c2c(N)ncnc21
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: C1COCCO1
Product: CC(C)n1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 100 °C
Yield: 43.3 %

Procedure:
To 5-bromo-7-(1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.392 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (188 mg, 0.470 mmol) was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vial. The mixture was then bubbled with N2 for 10 minutes then Pd(Ph3P)4 (45.3 mg, 0.039 mmol) was added and bubbled for an additional 5 minutes. It was then capped and heated at 100° C. overnight. The reaction was then checked with LCMS and 10% of the bromide starting material remained. 50 mg of the boronic ester was added, and the reaction was capped and heated at 100° C. for an additional 5 hr. The reaction was diluted with water (5 ml) then extracted with EtOAc (3×10 ml). The organics wer combined, washed with brine and dried over MgSO4, filtered and concentrated. The residual oil was then diluted with DMSO (3 mL) then purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 28% ACN/H2O, 0.1% TFA to 53% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred into a 40 mL vial with MeCN then added water and freeze-dried to isolate 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mgt, 43.3% yield) as a white solid. LC-MS (ES) m/z=448.4 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.09 (d, J=8.08 Hz, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 7.14-7.30 (m, 4H), 6.08 (br. s., 2H), 4.97 (quin, J=6.76 Hz, 1H), 4.29 (t, J=8.46 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J=8.46 Hz, 2H), 1.46 (d, J=6.82 Hz, 6H).