Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:9]1[C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([O:32]CC[Si](C)(C)C)=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:9]1[C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([OH:32])=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2c[nH]c3ccccc23)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2c[nH]c3ccccc23)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 71.9 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 0.2 g of 2-trimethylsilylethyl (2S,5R)-3-{3-{2-[2-tert-butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoate and 1.0 cm3 of a 1M solution of tetrabutylammonium fluoride. The crude product is dissolved in 25 cm3 of ethyl acetate and extracted with 2 times 5 cm3 of a 0.1N aqueous sodium hydroxide solution. The aqueous phases are brought to a pH of 2 by addition of a 1N aqueous hydrochloric acid solution. The product precipitated is separated by filtration, washed with 2 times 5 cm3 of distilled water and dried in air. 0.12 g of (2S,5R)-3-{3-{2-[2-tert-butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoic acid is thus obtained in the form of a solid melting at 160° C., [α]D20 =+10.7°±1.1° (C=0.43%; CH3OH), [proton NMR (300 MHz, DMSO D6, δ in ppm, J in Hz): 1.5 (s, 9H, --C(CH3)3 ; 1.8 to 2.5 (m, 4H, --CH2 =--CH2 --); 3.6 and 4.1 (2dd, J=17.5 and 5.1, 2H, N--CO--CH2 --N); 4.26 (dd, J=9 and 8, 1H, N--CH--COO--); 5.52 (d, J=8.5, 1H, N--CH--Ar); 6.38 (t, J=5, 1H, --NH--CO--); 7.0 to 7.7 (m, 7H, aromatic); 7.68 (s, 1H, N--CH=); 8 (bs, 1H in position 2 on NH--Ph--COO); 9.03 (broad, 1H, Ph--NH--CO--); 11.05 (broad, 1H, --NH--), an NOE effect has been observed between the N--CH= of indole and the proton in position 5 of pyrrolidine], [infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2980, 2935, 2700 to 2250 (broad band), 1720 to 1695 (broad band), 1635, 1595, 1560, 1490, 1460, 1370, 1155, 745, 685].
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2[C:15]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[N:18][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[CH2:22]([N:19]([CH2:20][CH3:21])[C:17]1[N:16]=[C:15]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][C:10]=2[N:18]=1)[CH3:23]
Reactant: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCCNC2
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 2-diethylamino-4-(4-fluoro-phenyl)-5,6,7,9-tetrahydro-pyrimido[4,5-c]azepine-8-carboxylic acid tert-butyl ester (0.058 g, 0.14 mmol) in EtOAc (1 mL) was added 4 M HCl in dioxane (2 mL). After 16 h, the mixture was concentrated, diluted with saturated (satd.) aqueous (aq.) NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried and concentrated. Purification by FCC (2 M NH3 in MeOH/CH2Cl2) provided the title compound (>90%). HPLC: Rt=9.7 min. MS (ESI): mass calcd. for C18H23FN4, 314.4; m/z found, 315.4 [M+H]+. 1H NMR (CDCl3): 7.47 (dd, J=8.7, 5.5, 2H), 7.11 (t, J=8.7, 2H), 3.96 (5, 2H), 3.64 (q, J=7.0, 4H), 3.21-3.18 (m, 1H), 2.80-2.76 (m, 2H), 1.93-1.86 (m, 2H), 1.71-1.67 (m, 1H), 1.17 (t, J=7.0, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[CH:33]=[CH:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:38][CH2:37][N:35]2[C:36]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:26])[CH:32]=[CH:33][C:34]2=[O:40])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc2ccc(=O)n(CC=O)c12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To 2 mL of a chloroform solution containing 0.24 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (8-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 20 μL of acetic acid and 0.22 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; hexane:ethyl acetate=1:1], to give 0.13 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(8-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCC(CC(=O)OCc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and benzyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:28])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([Cl:28])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
5-Bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)-benzoic acid (3.27 g, 7.4 mmol) was suspended in thionyl chloride (30 mL). The mixture was heated to reflux for 4 hours. The solvent was removed to dryness. The residue was dissolved in anhydrous ethyl acetate and solvent removed (2×20 mL). The solid was dried at 40° C. in vacuum oven overnight.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1.BrC1C=C(C)C=C2C=1C(O)=CC=N2.O=P(Cl)(Cl)[Cl:29]>C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:29])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Br)cc2nccc(O)c12
Agent: Cc1cc(Br)c2c(O)ccnc2c1
Solvent: CC#N
Product: Cc1cc(Br)cc2nccc(Cl)c12
Temperature: 90 °C
Yield: 49.5 %

Procedure:
To a vial charged with a mixture of 7-bromo-5-methylquinolin-4-ol and 5-bromo-7-methylquinolin-4-ol (0.09 g, 0.378 mmol) was added acetonitrile (1.890 ml) followed by the addition of POCl3 (0.035 ml, 0.378 mmol). The mixture was heated to 90° C. for 1.5 hr. The mixture was dried under reduced pressure and the crude residue purified with a 25 g Interchim HP spherical silica column (15 μm spherical) (0 to 50%, 10% DCM throughout) providing adequate separation of regioisomers. The major, first eluting isomer was isolated cleanly to yield 7-bromo-4-chloro-5-methylquinoline (48 mg, 0.187 mmol, 49.5% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.02 (s, 4H) 7.46 (d, J=4.69 Hz, 1H) 7.50 (dd, J=2.01, 0.93 Hz, 1H) 8.15-8.19 (m, 1H) 8.67 (d, J=4.70 Hz, 1H). m/z (ESI) 256.1 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[CH3:19]>CN1C(=O)CCC1.C([O-])([O-])=O.[Na+].[Na+].[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>[CH3:19][C:11]1[CH:12]=[C:13]([C:2]2[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=2)[CH:14]=[CH:15][N:10]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: Cc1cc(B(O)O)ccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2ncc(C(=O)O)s2)ccn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Bubble argon through a suspension of 2-bromothiazole-5-carboxylic acid (75 mg, 0.36 mmol), 2-picoline-4-boronic acid (59 mg, 0.43 mmol), and tetrakis-(triphenylphosphine)-palladium(0) (42 mg) in NMP (1 mL) and 2M Na2CO3 (0.25 mL). Stir the sealed vial at 100° C. for 4 h. Quench the reaction with aq. NH4Cl and concentrate in vacuo. Triturate the residue in 30% MeOH/DCM, filter, and concentrate the filtrate in vacuo to an oil. Addition of H2O gives a precipitate. Filter the solid, wash with H2O and ether, and dry to give a residue containing impure product. Extract the aqueous filtrate with 1:1 EtOAc/n-butanol (4×), wash with H2O (4×), and concentrate in vacuo to get more impure product. Purify both crops by prep-TLC developing with 10% MeOH/DCM with 1% HOAc. Further purify the desired band by the same method developing with 50% MeOH/DCM to give desired product 2-(2-methyl-pyridin-4-yl)-thiazole-5-carboxylic acid as a resin (8 mg, 0.036 mmol). MS, electrospray (M+H) 221.5, rt 0.51 min.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])[CH:11]=[N:12][CH:13]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]([C:10]2[CH:11]=[N:12][CH:13]=[C:8]([CH2:7][OH:6])[CH:9]=2)=[O:15])=[CH:21][CH:20]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncc(C(=O)c2ccc(F)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1cncc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of [5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-(4-fluoro-phenyl)-methanone (1H) (1.7 g, 4.9 mmol) in 20 mL of tetrahydrofuran (THF) at 0° C., is added tetra-butyl-ammonium-fluoride (9.8 mL, 9.9 mmol, 1M in THF) slowly. After being stirred at room temperature for 1 hour, the reaction solution is quenched by addition of 5 mL of water and extracted with 3×10 mL of EtOAc. After concentration, the crude product is purified by chromatography (heptane 80%, EtOAc 20%) to give (4-fluoro-phenyl)-(5-hydroxymethyl-pyridin-3-yl)-methanone (1I) (0.97 g, yield 86%) as white solid. MS (ESI) m/e 232 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A mixture of 1,1-dimethylethyl [(1S)-1-(4-bromophenyl)-ethyl]carbamate (14.4 g, 48 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.6 g, 4.8 mmol), N-methylpiperazine (22 mL, 200 mmol), BINAP (1.4 g, 4.8 mmol) and tribasic potassium phosphate in ethylene glycol dimethylether (120 mL) was refluxed for 15 hours. On cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL). The organic mixture was extracted using 1N aqueous hydrochloric acid (3×100 mL). The pH of the combined aqueous portions was adjusted to 10 and was then extracted using ethyl acetate (3×100 mL). The combined organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue which was purified by silica gel column chromatography. Eluting with 0-20% methanol in ethyl acetate, purified fractions were pooled and concentrated to afford 12.9 g, 40.5 mmol (84%) of 1,1-dimethylethyl {(1S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate. 1H NMR (400 MHz, d6-DMSO): 7.16 (d, 2H), 6.84 (d, 2H), 4.54 (m, 1H), 3.07 (m, 4H), 2.42 (m, 4H) 2.21 (s, 3H), 1.38 (s, 9H), 1.25 (d, 3H). MS (EI) for C18H29N3O2: 320 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH:23]5[CH2:25][CH2:24]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH:23]1([C:20]2[CH:19]=[N:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4([CH3:10])[CH2:7][C:6]5[CH:26]=[C:2]([C:35]6[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=6)[CH:3]=[CH:4][C:5]=5[O:9]4)[CH2:12][CH2:13]3)=[N:22][CH:21]=2)[CH2:25][CH2:24]1
Reactant: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(Br)ccc2O1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a degassed solution of 2-(4-(5-bromo-2-methyl-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-cyclopropylpyrimidine (424 mg, 1.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol), and K2CO3 (424 mg, 3.07 mmol) in dioxane (6 mL) and water (2 mL) was added Pd(Ph3P)4 (59.1 mg, 0.051 mmol). Upon completion of addition, the reaction mixture was heated in 100° C. oil bath for 3 hours. After this time, the reaction mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 50% EtOAc) to afford Compound 11F as a white solid (360 mg, 0.697 mmol, 68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (s, 2 H), 7.15 (s, 1 H), 7.13 (d, J=8.5 Hz, 1 H), 6.65-6.71 (m, 1 H), 5.88 (br. s., 1 H), 4.75-4.87 (m, 2 H), 4.05 (br. s., 2 H), 3.73 (t, J=6.2 Hz, 1 H), 3.62 (t, J=5.5 Hz, 2 H), 3.16 (d, J=15.7 Hz, 1 H), 2.74-2.87 (m, 2 H), 2.39-2.54 (m, 2 H), 1.86-1.96 (m, 2 H), 1.76-1.84 (m, 1 H), 1.67-1.74 (m, 1 H), 1.61 (m, 1 H), 1.49 (s, 9 H), 1.37-1.41 (m, 3 H), 1.23-1.36 (m, 1 H), 0.84-0.92 (m, 2 H), 0.54-0.60 (m, 2 H). LC/MS (m/z)=517 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][C@H:25]2[C@@H:29]([OH:30])[CH2:28][O:27][CH2:26]2)=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>CN(C=O)C>[Si:31]([O:30][C@H:29]1[CH2:28][O:27][CH2:26][C@H:25]1[O:24][C:3]1[C:2]([F:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:4]=1[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1O[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To 27E (171 mg, 0.407 mmol) in DMF (3 mL) was added TBS-Cl (307 mg, 2.034 mmol) and imidazole (138 mg, 2.034 mmol). The reaction was stirred at rt for 16 h, then quenched with H2O and extracted with EtOAc (2×). The solvent was removed and the residue was purified by flash column chromatography (0-60% EtOAc/hexanes) to give 27F (215 mg, 0.402 mmol, 99% yield). MS (ESI) m/z: 535.4 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:19]3[C:26]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:28])=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:13]=[C:14]([Cl:16])[CH:15]=1.C(N)(=O)C1C=CC=CC=1>>[C:1]([NH:4][CH2:5][C:6]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([NH:17][C:18]2[C:19]3[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:11]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: Nc1cc(Cl)cc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Agent: NC(=O)c1ccccc1
Product: CC(=O)NCC(=O)Nc1cc(Cl)cc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1

Procedure:
2-Acetamido-N-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-chlorophenyl)acetamide was synthesized using 2-acetamidoacetic acid and (4-((3-amino-5-chlorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone according to the procedure for the synthesis of N-3-((5-benzoyl-7H-pyrrolo[2,3-d]pyridine-4-yl)amino)phenyl)benzamide. A white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.53 (s, 1H), 10.24 (s, 1H), 8.53 (s, 1H), 8.25-8.22 (m, 1H), 8.11-8.10 (m, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.86-7.85 (m, 1H), 7.81-7.81 (m, 1H), 7.69-7.67 (m, 1H), 7.61-7.57 (m, 2H), 7.51-7.50 (m, 1H), 3.87 (d, J=6.0 Hz, 2H), 1.90 (s, 3H); LCMS [M+H] 463.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>>[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH:11][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH3:4]
Reactant: CCOC(=O)[C@H](C)NCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)[C@H](C)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
N-(2-Aminoethyl)-alanine ethyl ester 2HCl (1.165 g, 5.0 mmol), prepared as described by Puschl (A. Puschl et al., Tetrahedron, 1998, 39, 4707–4710.), was reacted with 2-nitro-benzenesulfonyl chloride (1.11 g 5.0 mmol) as per the procedure of example 13 to give the title compound (1.64 g, 95%). 1H-NMR (500 MHz; DMSO-d6) δ 8.02˜7.96 (m, 2H), 7.86 (m, 2H), 4.05 (q, 2H), 3.16 (q, 1H), 2.94 (t, 2H), 2.58 (m, 1H), 2.43 (m, 1H), 1.17 (t, 3H), 1.09 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Mg+2:10].[Cl-].Cl[O-].[Al+3].Cl[O-].Cl[O-]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Mg+2:10].[NH2:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: NCC(=O)[O-]
Temperature: 75 °C

Procedure:
Magnesium glycinate was prepared by reacting 4 grams of glycine with 2.5 grams of basic magnesium carbonate (26.3% Mg) in 30 grams of water while agitating at 75° C. for one half hour. The cooled mixture was then added to 77 grams of zirconyl chloride (13.6% Zr) with stirring. To the above solution 100 grams of 50% aluminum chlorhydroxide (12.5% Al) was added with agitation. The mixture was heated at 85° C. for 20 minutes. The product was then evaporated at 53° C. under a vacuum of 200 mm of Hg and contained 15.8% Al, 13.6% Mg. 5.3% glycine and 22.1% Cl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(4-methoxybenzyloxy)benzoate (12.2 g, 44.8 mmole) in 50 ml 1,4-dioxane was added a solution of lithium hydroxide (2.15 g, 89.6 mmole) and the mixture was stirred overnight at 60° C. The mixture was evaporated under reduced pressure and 5% acetic acid was added. The product was filtered, washed with water and dried. Yield: 10.1 g=87%
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:25](=[O:26])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)nc1)OCc1ccccc1
Temperature: 0 °C
Yield: 102 %

Procedure:
To an ice water cooled solution of 6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-amine (3.08 g, 13.15 mmol), prepared as above, in THF (50 mL) was added pyridine (3.19 mL, 39.44 mmol) followed by benzyl chloroformate (1.9 mL, 13.15 mmol). The resulting suspension was allowed to stir at 0° C., then after 2 hrs a further 0.5 mL of benzyl chloroformate was added and reaction mixture was allowed to stir at ambient temperature overnight. It was partitioned between EtOAc (100 mL) and water (50 mL), the organic phase was separated and the aqueous phase re extracted into EtOAc (200 mL). The organic extracts were combined, dried and concentrated to leave crude product. This was purified on a 120 g silica SiliCycle cartridge, eluting with 30-50% EtOAc/isohexane using an Isco Companion, to provide the title compound (4.94 g, 100%); 1H NMR (CDCl3) δ 1.66-1.97 (m, 8H), 2.70-2.77 (m, 1H), 3.97 (s, 4H), 5.21 (s, 2H), 6.71 (s, 1H), 7.16 (d, 1H), 7.35-7.41 (m, 5H), 7.91 (s, 1H), 8.37 (s, 1H); MS m/e MH+ 369.