Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[Li]CCCC.[CH3:17][Si:18]([CH3:29])([CH3:28])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[Cu]I>[O:26]=[C:25]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)[CH2:24][CH2:23][CH2:22][CH2:21][C:20]#[C:19][Si:18]([CH3:29])([CH3:17])[CH3:28]
Reactant: c1ccc(-c2cnco2)nc1
Reactant: C[Si](C)(C)C#CCCCCC(=O)Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A solution of 5-(2-pyridyl)oxazole (Saikachi, H.; Kitagawa, T.; et al. Chem. Pharm. Bull. 1969, 27, 793-796) (600 mg, 4.11 mmol) in anhydrous THF (15 mL) at −78° C. was treated dropwise with a solution of n-BuLi (2.2 M in hexanes, 2.4 mL, 4.52 mmol,) under N2 and the resulting solution was stirred at −78° C. for 20 min. A solution of ZnCl2 (0.5 M in THF, 18 mL, 8.22 mmol,) was added, and the mixture was warmed to 0° C. After stirring at 0° C. for 45 min, CuI (850 mg, 4.46 mmol) was added to the mixture. After the mixture was stirred at 0° C. for 10 min, a solution of 7-(trimethylsilyl)hept-6-ynoyl chloride (1.2 equiv; prepared from 7-(trimethylsilyl)hept-6-ynoic acid and oxalyl chloride) in anhydrous THF (9 mL) was added dropwise, and the mixture was stirred at 0° C. for an additional 1 h. The reaction mixture was diluted with a 1:1 mixture of hexanes and EtOAc (60 mL) and washed with 15% aqueous NH4OH (2×30 mL), water (30 mL) and saturated aqueous NaCl (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated. Column chromatography (SiO2, 4×6 cm, 30% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(trimethylsilyl)hept-6-yne (3a, 875 mg, 2.68 mmol, 74%) as a tan oil: 1H NMR (CDCl3, 400 MHz) 8.68 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.6, 1.8 Hz), 7.34-7.31 (m, 1H), 3.15 (t, 2H, J=7.3 Hz), 2.30 (t, 2H, J=7.2 Hz), 1.94-1.86 (m, 2H), 1.68-1.60 (m, 2H), 0.14 (s, 3H); 13C NMR (CDCl3, 100 MHz) 187.9, 157.2, 153.2, 150.0, 146.1, 137.0, 126.8, 124.1, 120.3, 106.6, 84.8, 38.4, 27.9, 22.9, 19.6, 0.0; IR (film) νmax 2955, 2867, 2173, 1699, 1603, 1576, 1504, 1469, 1426, 1383, 1249, 1152, 1118, 1083, 1024, 929, 842, 784, 760 cm−1; ESI-TOF m/z 327.1530 (C18H22N2O2Si+H+ requires 327.1523).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([C:46](=[O:54])[CH2:47][NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:42][CH2:41][N:40]([C:46](=[O:54])[CH2:47][NH:48][C:49]4[S:50][CH:51]=[CH:52][N:53]=4)[CH2:45][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CNc1nccs1)N1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CNc2nccs2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-piperazin-1-yl-2-(thiazol-2-ylamino)-ethanone dihydrochloride (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H44Cl2N7O3S [(M+H)+] 748.2598, observed 748.2602.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[N:12]([CH3:13])[C@H:11]([CH3:14])[C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9]1.C([Li:25])CCC>O1CCNC1.C1COCC1>[CH3:13][N:12]1[C@H:11]([CH3:14])[C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9][C@@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Li:25]
Reactant: C[C@@H]1[C@@H](c2ccccc2)O[C@H](c2ccccc2Br)N1C
Reactant: [Li]CCCC
Agent: C1COCN1
Solvent: C1CCOC1
Product: [Li]c1ccccc1[C@H]1O[C@H](c2ccccc2)[C@@H](C)N1C
Reaction time: 2 h

Procedure:
In a separate flask, the oxazolidine in the form of the mixture of Example 1 (17.43 g, 52.62 mmol, 1 eq) was dissolved in 25 mL of THF under an argon atmosphere. The solution was cooled to -70° C. (internal temperature) and n-C4H9Li (n-BuLi) (21 mL, 52.5 mmol, 1 eq) was added dropwise over 10 min such that the internal temperature did not rise above -50° C. The reaction was brought back to -70° C., and stirred for 2 h.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2Br)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCC1)Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: O=C(CC1CCCC1)Nc1c(-c2cccnc2)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 130 °C
Yield: 18.1 %

Procedure:
2-Cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide (1b, 15 mg), 3-pyridylboronic acid (21 mg), aqueous potassium carbonate (5 M, 90 μL) and palladium(II) acetate (1 mg) were mixed in acetone (2 mL) and heated to 130° C. for 20 minutes in a sealed microwave process vial. The reaction mixture was filtered through silica (500 mg), concentrated in vacuo, redissolved in dimethyl sulfoxide (0.5 mL) and subjected to preparative LC-MS purification to furnish 2.7 mg (18% yield) of the title compound as a colorless oil. LC-MS (m/z) 434 (MH+); tR=1.89, (UV, ELSD) 99%, 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:30])[CH2:29][O:28]2)=[CH:23][CH:22]=1>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:28])([CH3:29])[CH2:30][N:11]2[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]3[CH:3]=[C:2]([CH3:1])[CH:14]=[N:13][C:12]2=3)=[CH:25][CH:26]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC1(c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN2CCCC12
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (700 mg, 3.0 mmol) was dissolved in DMF (7 mL) and sodium hydride (360 mg, 9.0 mmol) was added portionwise at 0° C. and stirred for 10 min. 2-(4-Fluoro-phenyl)-2-methyl-oxirane (720 mg, 4.8 mmol) in 3 mL DMF was added dropwise into the reaction mixture and the mixture was stirred at RT for 18 h. The reaction mixture was quenched with ice cooled water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (4×75 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by passing through a column of silica gel (100-200 mesh), using the eluent 5% MeOH in DCM to obtain 520 mg of 2-(4-fluoro-phenyl)-1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza cyclopenta[c]fluoren-6-yl)-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.02 (s, 1H), 7.54 (s, 1H), 7.43 s (OH), 7.37 (t, 2H), 6.93 (t, 2H), 4.37 (d, 1H), 4.22 (d, 1H), 4.04 (t, 1H), 3.23 (dd, 1H), 2.9 (m, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 2.42 (s, 3H), 2.3 (m, 1H), 1.84 (m, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided diastereomers II-149a-d.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]3[CH:19]=[C:18]([CH3:27])[CH:23]=[CH:22][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and m-tolylboronic acid to give (1H-pyrazol-3-yl)-(1-m-tolyl-isoquinolin-3-yl)-amine. LC-MS m/e 301(MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[OH-].[Na+].[CH3:12][N:13]([CH3:28])[C:14]([C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])=[O:15]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[CH3:28][N:13]([CH3:12])[C:14]([C:16]1[CH:17]=[C:18]([S:24]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])=[O:15]
Reactant: COC(=O)c1ccc[nH]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccn1S(=O)(=O)c1ccc(OC)c(C(=O)N(C)C)c1
Reaction time: 24 h
Yield: 65.7 %

Procedure:
To a mixture of methyl 1H-pyrrole-2-carboxylate (135 mg, 1.080 mmol), tetrabutylammonium hydrogensulfate (36.7 mg, 0.108 mmol) and sodium hydroxide (389 mg, 9.72 mmol) in water (2 ml) and DCM (4 ml) under vigorous stirring, a solution of 3-(dimethylcarbamoyl)-4-methoxybenzene-1-sulfonyl chloride (Int. 9) (300 mg, 1.080 mmol) in DCM (5 ml) was added drop-wise at RT over 10 minutes, and the reaction was stirred at the same temperature for 24 hours. The mixture was diluted with water and DCM, the organic phase was separated, washed with brine and dried over sodium sulfate. The solvent was evaporated under vacuum yielding methyl 1-(3-(dimethylcarbamoyl)-4-methoxyphenylsulfonyl)-1H-pyrrole-2-carboxylate (Int. 10) (260 mg, 0.710 mmol, MS/ESI+367.0 [MH]+) which was used as such in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:14])[CH2:8][C:9](OCC)=O)[CH2:3][CH2:2]1.[H-].[Na+].ClC1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:28])[CH:21]=[C:20]([C@@H:29]([NH:31][C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH3:30])[N:19]=1.O>C1COCC1>[Cl:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:9]([CH2:8][C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:14])=[N:19][C:20]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[CH3:30])=[CH:21]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: CCOC(=O)CC(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(CC(=O)N5CCOCC5)n4)ncnc32)cc1

Procedure:
To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol, 1.0 eq) and NaH (144 mg, 3 mmol, 1.5 eq) in THF (3 mL) at RT, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 mg, 1.6 mmol, 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoethanone 34.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CCOC1(c2ccc(I)cc2)CCOCC1
Product: CCOC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Yield: 68.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60.4 mg) was reacted with tetrahydro-4-(4-iodophenyl)-4-ethoxy-2H-pyran (66.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-ethoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (68.9 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/ethyl acetate=4/1) was used for purification.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C: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)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>ClCCl.O>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of methyl chloroglyoxylate (2.98 ml, 32.4 mmol) in dichloromethane (10 ml) was added dropwise at a slow speed to a mixture of 4-amino-4′-(trifluoromethoxy)biphenyl (5.476 g, 21.6 mmol), sodium hydrogencarbonate (3.62 g, 43.2 mmol), dichloromethane (40 ml) and water (40 ml), and stirred at 0° for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.71 g, 91.5%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH:17]1([CH:20]=O)[CH2:19][CH2:18]1>C1COCC1>[CH:17]1(/[CH:20]=[CH:7]/[C:6]([O:5][CH2:3][CH3:4])=[O:16])[CH2:19][CH2:18]1
Reactant: O=CC1CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 2.1 g, 51.5 mmol) in dry THF (50 mL) was added dropwise ethyl(diethoxyphosphoryl)acetate (10.6 g, 47.1 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 0° C. for 0.5 hr and added dropwise a solution of cyclopropanecarbaldehyde (3.0 g, 42.9 mmol) in dry THF (50 mL). After the addition, the mixture was stirred at rt for 16 hrs. Then the reaction mixture was quenched by addition of 5% NH4Cl (100 mL) at 0° C. and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=30:1) to give the title compound (5.3 g, 88.3% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:24]4[CH:25]=[CH:26][C:27]([C:30]5([NH2:34])[CH2:33][CH2:32][CH2:31]5)=[CH:28][CH:29]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 68.1 %

Procedure:
Tert-butyl (1-(4-(1-isobutyl-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.013 mmol) was dissolved in dichloromethane (1 mL); TFA (1 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (4 mg, 68% yield). LCMS (Method D): RT=0.844 min, M+1=452. 1H-NMR (500 MHz, CD3OD) δ 8.07 (1H, s), 7.52-7.45 (2H, d), 7.44-7.40 (2H, d), 7.38-7.33 (3H, m), 7.31-7.26 (2H, m), 5.66 (2H, s), 3.11 (2H, d), 2.81-2.68 (2H, m), 2.61-2.45 (2H, m), 2.32-2.17 (1H+1H, 2 m), 2.02-1.87 (1H, m), 1.10 (6H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][CH:26]1[CH:31]([CH2:32][CH2:33][OH:34])[C:30]2[CH:35]=[CH:36][C:37]([C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:38][C:29]=2[O:28][C:27]1([CH3:49])[CH3:48].C(N(CC)CC)C.[C:57](OC(=O)C)(=[O:59])[CH3:58]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:57]([O:25][CH:26]1[CH:31]([CH2:32][CH2:33][OH:34])[C:30]2[CH:35]=[CH:36][C:37]([C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:38][C:29]=2[O:28][C:27]1([CH3:48])[CH3:49])(=[O:59])[CH3:58]
Reactant: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(O)C2CCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(OC(C)=O)C2CCO
Temperature: 0 °C

Procedure:
A solution of 3.48 g (0.01 mole) dl-5-hydroxy-4-(2-hydroxyethyl)-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran in 50 ml methylene chloride and containing 1.01 g (0.01 mole) triethylamine is cooled to 0° C. while stirring in a nitrogen atmosphere. To this is added a solution of 1.22 g (0.01 mole) 4-dimethylaminopyridine in 5 ml of methylene chloride followed by 1.02 g (0.01 mole) acetic anhydride. After stirring at 0°-5° C. for one hour, the mixture is allowed to warm to room temperature, extracted with methylene chloride and the extracts washed with sodium bicarbonate. After drying over anhydrous magnesium sulfate and evaporation of solvent, the desired product is obtained. It can be purified by column chromatography on silica gel if desired.
Reaction SMILES: BrC1C2C(=NC(N)=NC=2)N(C)N=1.[CH2:13]([NH:20][C:21]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[N:28]([CH3:32])[N:29]=[C:30](Br)[C:22]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>>[CH2:13]([NH:20][C:21]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[N:28]([CH3:32])[N:29]=[C:30]([C:36]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([F:33])[CH:35]=3)[C:22]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1nc(Br)c2c(NCc3ccccc3)nc(N)nc21
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cn1nc(Br)c2cnc(N)nc21
Product: COc1ccc(-c2nn(C)c3nc(N)nc(NCc4ccccc4)c23)cc1F

Procedure:
This compound is prepared analogously to Example 88 by replacing 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) with N*4*-Benzyl-3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Intermediate 15) and by replacing 2-methoxy-5-trifluoromethylphenylboronic acid with 3-fluoro-4-methoxyphenylboronic acid to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][NH:13][C:14]2[C:15]([CH3:31])=[N:16][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:29][CH2:28][CH2:27][C@@H:26]4[CH3:30])[CH2:21]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH3:31][C:15]1[C:14]([N:13]2[CH2:12][CH2:11][C:5]3([CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)[C:3]2=[O:2])=[CH:19][CH:18]=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])[CH2:21]2)[N:16]=1
Reactant: COC(=O)C1(CCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCOCC2)C1=O
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To a solution of 4-{2-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-ethyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (0.034 g, 0.079 mmol) in THF (10 mL) was added a solution of potassium t-butoxide (1M in THF) (0.2 mL), and allowed to stir at room temperature. After 3 hours additional potassium t-butoxide (0.4 mL) was added and reaction mixture stirred at room temperature for 16 hours. More potassium t-butoxide (0.2 mL) was added and stirred at room temperature for 4 hours, then heated to 50° C. for 3 hours. Reaction mixture was cooled to room temperature then diluted with ethyl acetate (10 mL), quenched with brine (2 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). Combined organics were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification over silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.0068 g (22%) of title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:36])[CH:16]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CH2Cl2 (200 mL) was added dropwise (triphenyl-phosphanylidene)acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) at 0° C. After the addition was complete, the resulting mixture was stirred for 1 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6% yield). 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.23 (dd, J=0.8, and 8.0 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.36 (t, J=6.8 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@@H:8]([NH2:7])[CH2:13][CH2:12]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Yield: 90.5 %

Procedure:
A solution of cis-[4-(2-benzyloxycarbonylamino-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.26 g, 14 mmol) in 50% TFA in CH2Cl2 (60 mL) was stirred at ambient temperature for 1 hr. The mixture was concentrated and the residue was diluted with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (therr times). The organic layer was dried over Na2SO4 and concentrated to give cis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acid benzyl ester (3.5 g, 91%) as a colorless oil.