Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([NH2:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[Br:8][C:7]1[CH:6]=[C:5]([NH:9][C:14]2[C:15](=[O:20])[C:16](=[O:17])[C:13]=2[O:12][CH2:10][CH3:11])[CH:4]=[N:3][C:2]=1[F:1]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cnc(F)c(Br)c1
Solvent: CCO
Product: CCOc1c(Nc2cnc(F)c(Br)c2)c(=O)c1=O

Procedure:
A solution of 2-fluoro-3-bromo-5-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]([F:58])([F:57])[S:35]([O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[C:44]2OS(C(F)(F)F)(=O)=O)(=[O:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:44]3[C:45]4[C:40](=[C:39]([O:38][S:35]([C:34]([F:58])([F:33])[F:57])(=[O:36])=[O:37])[CH:48]=[CH:47][CH:46]=4)[CH:41]=[CH:42][CH:43]=3)=[CH:22][CH:23]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: O=S(=O)(Oc1cccc2c(OS(=O)(=O)C(F)(F)F)cccc12)C(F)(F)F
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: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3cccc4c(OS(=O)(=O)C(F)(F)F)cccc34)cc2)[nH]1
Temperature: 100 °C
Yield: 80.3 %

Procedure:
2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.30 g, 2.96 mmol), Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy-naphthalen-1-yl ester (982 mg, 2.31 mmol), Pd(PPh3)4 (134 mg, 0.116 mmol) and potassium carbonate (639 mg, 4.62 mmol) were suspended in toluene. After degassing with nitrogen for 28 min, the stirred suspension was heated to 100° C. for 18 hours. The reaction mixture was then cooled to RT, diluted with ethyl acetate (250 mL), washed with water, brine, dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (0% to 60% EtOAc/hexanes) to provide 2-{5-[4-(5-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.09 g, 80%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[N:11]1)(C)(C)C.[ClH:19]>C(OCC)(=O)C>[ClH:19].[N+:15]([C:13]1[CH:12]=[N:11][N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate (8.0 g) obtained in Step A of Example 348 in ethyl acetate (30 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (4.0 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (4.7 g).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][NH:8][C:7]1=[O:21])([O:3][CH2:4][CH3:5])=[O:2].F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:27][O:21][C:7]1[CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][N:8]=1
Reactant: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CNC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CN=C1OC
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of 14.9 g 3carboethoxy-5-[t-butyl(dimethyl)silyloxymethyl]-2 -piperidone in 400 ml anhydrous dichloromethane at 4° C. were added 7.7 g of trimethyloxonium tetrafluoroborate. The mixture was first stirred for 90 minutes at 4° C. and then for 1 hour at 22° C. The resulting solution was poured into a saturated solution of sodium bicarbonate and extracted with three portions of dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to give 13.8 g of the title compound: 300-MHz 1H NMR (CDCl3) δ0.04 (s, 6H), 0.88 (s, 9H), 1.25 (t, J=7 Hz, 3H), 1.51-2.18 (m, 3H), 3.11-3.32 (m, 2H), 3.48-3.56 (m, 2H), 3.60-3.76 (m, 4H), 4.19 (t, J=7 Hz, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH:7]([NH:9][C:10]([C:12]3[C:17]4[N:18]=[C:19]([NH:21]C(=O)OC(C)(C)C)[O:20][C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]12[CH2:8][C@@H:7]([NH:9][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[O:20][C:19]([NH2:21])=[N:18][C:17]=34)=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)Nc1nc2c(C(=O)NC3CN4CCC3CC4)cccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-(quinuclidine-8-yl-carbamoyl)benzoxazole-2-yl-carbamate (0.210 g, 0.54 mmol), in CH2Cl2 (5 mL) was added TFA(2 mL) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated and the crude material was treated with aqueous NaHCO3 to adjust the pH to 7 and then extracted with CH2Cl2 (5×50 mL). The combined organic phase was concentrated and purified by preparative TLC (90:9:1 CH2Cl2/CH3OH/concentrated NH4OH) to afford (S)—N-(quinuclidine-8-yl)-2-aminobenzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC#N>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)cc1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCN4CCN(C)CC4)nc3C)n2)cc1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-methoxyphenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 1-methyl-piperazine. Anal. RP-HPLC: tR=13.0 min (0-60% MeCN, purity>94%). 1H-NMR (DMSO-D6) δ: 1.17 (m, 2H, CH2), 2.11 (m, 2H, CH2), 2.48 (m, 4H, CH2), 2.57 (s, 3H, CH3), 3.28 (s, 3H, CH3), 3.30 (m, 4H, CH2), 3.72 (s, 3H, CH3), 6.85 (m, 2H, Ph-H), 6.97 (m, 1H, pyrimidinyl-H), 7.63 (m, 2H, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 468.57 [M+H]+ (C23H26N7SO2 requires 467.59).
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH3:11])[C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(Cl)[Cl:15]>>[Cl:15][CH:5]([C:4](=[O:10])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH3:11])[C:6]([O:8][CH3:9])=[O:7]
Reactant: ClCCl
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Product: COC(=O)C(Cl)C(=O)C(C)(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
SO2Cl2 (2.2 ml, 27 mmol) was added slowly to a solution of 5.0 g (26 mmol) of methyl 4,4-dimethoxy-3-oxopentanoate in 30 ml CH2Cl2 cooled in an ice water bath. The solution was warmed to room temperature and stirred for 1 h. Solvent was removed and the residue was taken up in EtOAc, which was washed with water and brine. Drying (MgSO4) and removal of solvent gave 6.1 g of an oil. NMR: (CDCl3): 1.5 (s, 3H), 3.25 (2s, 6H), 4.8 (s, 3H), 5.3 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].Cl.[CH2:11](O)[CH3:12]>>[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: O=C(O)C1COCCN1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1COCCN1

Procedure:
A solution of morpholine-3-carboxylic acid (4.035 g; 30.8 mmol) in ethanol (250 ml) was saturated with gaseous HCl, then stirred for a week. The solvent was evaporated and the residue taken up in water and made basic (pH˜10) with sodium hydrogen carbonate and sodium carbonate. The mixture was then extracted with dichloromethane (7×), the combined extracts dried (Na2SO4) and the solvent evaporated to give ethyl morpholine-3-carboxylate (746 mg). EIMS: m/z=160.4 [M+H]+. This ester derivative and lithium aluminium hydride (1 M in THF, 9.4 ml, 9.4 mmol) were carefully combined under a nitrogen atmosphere and following addition were heated to reflux. After 5 h the reaction was cooled to room temperature and carefully quenched using dropwise water addition with ice cooling, then filtered and washed with dichloromethane. The solvent was evaporated to give 3-(hydroxymethyl)morpholine (409 mg). EIMS: m/z=118.2 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH:14]([C:17]1[C:21]([O:22][C:23]2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=[C:27]([CH:30]=2)[C:28]#[N:29])=[C:20]([CH3:33])[NH:19][N:18]=1)([CH3:16])[CH3:15]>CN(C)C=O>[Si:7]([O:6][CH2:5][CH2:4][N:19]1[C:20]([CH3:33])=[C:21]([O:22][C:23]2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=[C:27]([CH:30]=2)[C:28]#[N:29])[C:17]([CH:14]([CH3:16])[CH3:15])=[N:18]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: Cc1[nH]nc(C(C)C)c1Oc1cc(C#N)cc(C#N)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)C)nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 45 mg, 1.12 mmol) was added to a stirred solution of 2-bromoethoxy-t-butyldimethylsilane (270 mg, 1.12 mmol) and the pyrazole of Example 95 (250 mg, 0.930 mmol) in N,N-dimethylformamide (5 ml) at 0° C. under nitrogen. The reaction was warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched by the addition of water (50 ml) and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting pentane:ethyl acetate (80:20, by volume) to provide the title compound (60 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]([CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[CH3:26][C:27]([S@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1.[Cl-].[Na+].O>[C:27]([S@:30](/[N:32]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)\[CH2:14][CH2:13][N:5]([C@H:3]([C:2]([CH3:25])([CH3:24])[CH3:1])[CH3:4])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:31])([CH3:29])([CH3:28])[CH3:26]
Reactant: CC(C)(C)[S@](N)=O
Reactant: C[C@H](N(CCC(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N(CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Yield: 41.2 %

Procedure:
To a solution of (S)-tert-butyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (1.50 g, 4.27 mmol) in dry THF (20 mL) was added Ti(Oi-Prl)4 (2.46 g, 8.55 mmol) and (R)-2-methylpropane-2-sulfinamide (1.03 g, 8.55 mmol) under N2, and the mixture was refluxed overnight. After the reaction was over, the solution was poured into 20 mL brine and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography to afford tert-butyl (E)-3-((R)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl((S)-3,3-dimethylbutan-2-yl)carbamate (800 mg, 42%). 1H NMR (CDCl3): 0.75 (s, 9H), 1.26 (m, 12H), 1.47 (s, 8H), 3.27 (m, 2H), 3.49 (m, 2H), 3.91 (m, 1H), 7.14 (m, 2H), 7.89 (m, 1H), 8.25 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]1([NH:30][C:28]([NH:27][C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)([C:5]2[CH:4]=[CH:3][C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:7][N:6]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(N2CCOCC2)cn1
Temperature: 100 °C
Yield: 60.9 %

Procedure:
1-(1-(5-Bromopyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-cyclopentylurea (64 mg, 0. 12 mmol), morpholine (1.3 eq), Pd2(dba)3 (0.2 eq), Xantphos (0.6 eq) and Na—O-t-Bu (3.2 eq) were stirred in toluene (0.5 mL) at room temperature. The reaction mixture was purged with N2 several times and then was heated at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature, and Et2O was added. The resulting solution was washed with H2O, brine, dried (MgSO4), filtered, and concentrated to dryness. The residue was purified by chromatography (silica gel, hexanes/EtOAc) to give 1-cyclopentyl-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-morpholinopyridin-2-yl)-2-phenylethyl)urea (39 mg, yield: 60.9%). LC-MS ESI 557.28 (M+H) (10-90% MeOH in H2O with 0.1% TFA in a 4-min run, retention time=3.63 min); 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (d, J=2.9 Hz, 1 H), 7.57 (s, 1 H), 7.40 (d, J=10.0 Hz, 1 H), 7.28 (s, 1 H), 7.24-7.17 (m, 2 H), 7.14 (d, J=7.3 Hz, 1 H), 7.09 (t, J=7.5 Hz, 2 H), 7.02 (d, J=8.8 Hz, 1 H), 6.66 (d, J=7.6 Hz, 2 H), 4.48 (d, J=12.5 Hz, 1 H), 4.34 (d, J=7.1 Hz, 1 H), 4.00-3.91 (m, 1 H), 3.90-3.87 (m, 4 H), 3.56 (d, J=12.5 Hz, 1 H), 3.18 (m, 4 H), 2.09-2.01 (m, 1 H), 1.92-1.83 (m, 1 H), 1.68-1.57(m, 4 H), 1.49-1.40 (m, 1H), 1.32-1.24 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][N:16](COCCOC)[C:13]3=[N:14][CH:15]=2)[CH:5]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1
Reactant: COCCOCn1nc(-c2ccccc2OC)c2cc(-c3cccc(C(=O)OC)c3)cnc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of 3-[1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (573 mg, 1.28 mmol) in dichloromethane (25 mL) was cooled down to 0-5° C. and boron trifluoride etherate (0.8 ml, 6.4 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 16 h. A yellow precipitate was formed was filtered off to afford 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (110 mg (0.29 mmol; 23% yield). 1H-NMR (500 MHz, d6-DMSO) δ 8.88 (d, 1H), 8.39 (d, 1H), 8.27 (t, 1H), 8.06 (td, 1H), 7.99 (td, 1H), 7.65-7.68 (m, 2H), 7.48 (ddd, 1H), 7.23 (d, 1H), 7.11 (dt, 1H), 3.90 (s, 3H), 3.87 (s, 3H). MS: m/z 360 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)CCNC(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCNC(=O)OC(C)(C)C)COCc1cc(Br)ccc1F
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-2,2-dimethylbutan-1-ol (1.5 g, 6.90 mmol) in tetrahydrofuran (49 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 7.59 ml, 7.59 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.85 g, 6.90 mmol). The resulting yellow mixture was slowly warmed to ambient temperature and stirred for about 18 hours. The cloudy reaction mixture was diluted wtih methylene chloride and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.45 grams (52%) of the title intermediate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (320 mg, 67%).
Reaction SMILES: [SiH:1]([Cl:4])([CH3:3])[CH3:2].[Si:5]([O:9][CH2:10][CH:11]=[CH2:12])([CH3:8])([CH3:7])[CH3:6]>>[CH3:6][Si:5]([CH3:8])([CH3:7])[O:9][CH2:10][CH2:11][CH2:12][Si:1]([CH3:3])([CH3:2])[Cl:4]
Reactant: C[SiH](C)Cl
Reactant: C=CCO[Si](C)(C)C
Product: C[Si](C)(Cl)CCCO[Si](C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 500 ml Schlenk flask equipped with a stir-bar, a reflux condenser and a rubber septum was charged under nitrogen with 94.6 g of HSiMe2Cl and 5 drops of a 0.1 M solution of the platinum complex Pt(0) 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane complex (a product sold by Aldrich Chemical Co) at room temperature. To this solution 131 g of Me3SiO—CH2—CH═CH2 was added during 30 minutes. After the addition the reaction mixture was gradually heated at 40° C. and mantained at this temperature under stirring for 2 hours, and finally heated at 60° C. for another 5 hours. The desired product can be isolated by distillation under vacuum (25 mbar) at 84° C. Yield 80%. 1H NMR (CDCl3): 0.125 (s, 9H, SiMe3), 0.413 (s, 6H, SiMe2), 0.798–0.890 (m, 2H, CH2), 1.595–1.720 (m, 2H, CH2), 3.585 (t, 2H, CH2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][N:2]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1)[C:23](=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC)c3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)N(C)c1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (96 mg, 0.32 mmol) in THF (3.0 mL) at room temperature was added acryloyl chloride (40 μL, 0.49 mmol), and the solution was allowed to stir at room temperature for 30 minutes. Saturated aqueous sodium carbonate (5 mL) was added and the mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(N-methylacrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C19H19N4O3 [M+H]+: 351, found 351. 1H NMR (600 MHz, DMSO-D6) δ 13.03 (bs, 1H), 8.92 (s, 1H), 8.33 (s, 1H), 7.61 (d, J=7.63 Hz, 1H), 7.55 (t, J=8.21 Hz, 1H), 7.47 (s, 1H), 7.75 (d, J=7.63 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.17 (s, 1H), 5.57 (t, J=7.04 Hz, 1H), 3.94 (q, J=7.04 Hz, 2H), 3.27 (s, 3H), 0.96 (t, J=7.04 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35]4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.050 g, 0.16 mmol), methyl 7-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.045 g, 0.16 mmol), triphenyl phosphine (0.042 g, 0.16 mmol) and diisopropyl azodicarboxylate (0.043 mL, 0.16 mmol) in dichloromethane (1.6 mL) was placed in microwave reaction tube and heated to 80° C. for 20 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.059 g, 64%). 1H NMR (DMSO-d6): 8.68 (s, 1H), 8.40 (s, 1H), 8.07-7.93 (m, 4H), 7.80 (d, J=7 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 7.28-7.24 (m, 1H), 7.14 (d, J=7 Hz, 2H), 4.99 (s, 2H), 3.91 (s, 3H), 3.32-3.20 (2m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.