Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([CH2:14][C:15]#[N:16])[CH2:3][CH2:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: N#CCBr
Product: N#CCN1CCN(c2ncccn2)CC1

Procedure:
The title compound is synthesized by coupling of 2-piperazin-1-yl-pyrimidine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=204.2: 1HNMR(DMSO-d6) 8.35 (d, 2H), 6.60 (t, 1H), 3.80-3.70 (m, 6H), 2.45-2.40 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (52 mg), which decomposed in the melting apparatus above 140° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:20][C:21](=[CH2:23])[CH3:22].OS(O)(=O)=O>O1CCOCC1>[CH:1]1([C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[CH2:9][C@@H:10]([C:12]([O:14][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:13])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](Cc1ccccc1C1CCCCC1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1C1CCCCC1
Yield: 80 %

Procedure:
According to example 54, 0.73 g of 2-cyclohexyl-L-phenylalanine.HCl was treated with 25 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.4 mL of conc. H2SO4. Work-up followed by acidification of the free amine with ethereal HCl afforded 0.70 g (80%) of tert-butyl 2-cyclohexyl-L-phenylalaninate.HCl as a yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[N:18][CH:17]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 110 °C

Procedure:
The mixture of 1-chloro-2-methyl-4-nitrobenzene (17.2 g), 6-methylpyridin-3-ol (12 g) and Cs2CO3 (39 g) in DMF (150 mL) was heated at 110° C. for 4 h. The solid was filtered and water (100 mL) and EtOAc (200 mL) were added. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained yellow solid was used for the next step directly.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.[BH3-]C#N.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:20]2[CH2:22][CH2:21]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 14.0 g (0.0699 mol) piperidin-4-yl-carbamic acid tert-butyl ester in 500 mL abs. MeOH 250 g of dried molecular sieves 3 Å were added. Under argon 39.9 mL (0.699 mol) acetic acid and 52.5 mL (0.262 mol) (1-ethoxy-cyclopropoxy)-trimethyl-silane were added. Finally 314.5 mL (0.3145 mol) of a 1 M NaCNBH3-solution in THF were added dropwise. After 20 min at room temperature the reaction mixture was stirred for 6 h at 60° C. The mixture was filtered over “Celite”. The filtrate was concentrated under reduced pressure. The resulting residue was taken up in 700 mL ethyl acetate and washed with 250 mL of a 1 M NaOH-solution. The aqueous layer was extracted with 300 mL ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under vacuo to give crude (1-cyclopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:14])=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8][CH3:9])=[O:7].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:14][C:4]1[C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:12]([F:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)c(CN)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(F)c(CNC(=O)C(C)(C)C)c1Cl
Yield: 81.7 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 3-(aminomethyl)-2-chloro-4-fluorobenzoate (340 mg, 1.42 mmol), DIPEA (550 mg, 4.27 mmol) and pivaloyl chloride (204 mg, 1.7 mmol) in CH2Cl2 (5 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.81-7.74 (m, 2H), 7.36-7.30 (t, J=9.0 Hz, 1H), 4.39-4.37 (d, J=4.5 Hz, 2H), 3.85 (s, 3H), 1.06 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:26][CH2:27]1
Reactant: NC1CCN(Cc2ccc(F)c(Cl)c2)CC1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCN(Cc2ccc(F)c(Cl)c2)CC1
Reaction time: 24 h

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.218 g) and N,N′-carbonyldiimidazole (0.194 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(3-Chloro-4-fluorobenzyl)-4-piperidinamine (JP 59101483; 0.242 g) was then added and left to stir for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with ethyl acetate/ethanol and filtered to leave N-[1-(3-chloro-4-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide. m.p. 150° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:23][C:24](=O)[CH3:25])(=[O:22])=[O:21]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:24]([CH3:25])[CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:14])[CH3:2]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.9 %

Procedure:
To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfonyl-2-propanone (7-2-1) (0.30 g) were added under a nitrogen atmosphere and stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:acetone=3:1) to give 0.25 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39).
Reaction SMILES: N[C@@H](C([N:6]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:7][C:8](=[O:35])[C@@H:9]([CH:14]([C:25](=[O:34])[NH:26][O:27]C1CCCCO1)[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)C.O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[CH:19]1([CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8]([NH:7][NH:6][CH2:36][CH:37]([CH3:38])[CH3:39])=[O:35])[C:25](=[O:34])[NH:26][OH:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(CCCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)CNNC(=O)[C@H](CC(C)C)C(CCCCC1CCCCC1)C(=O)NO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.210 g of 2′-(D-alanyl)-2(R)-[5-cyclohexyl-1(RS)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]pentyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.080 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 6 hours and evaporated. The residue was triturated with diethyl ether to give 0.151 g of 2′-D-alanyl)-2(R)-[5-cyclohexyl-1(RS)-(hydroxycarbamoyl)pentyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]#[N:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(Cl)cc23)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (660 mg, 1.77 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL) and the resulting mixture was heated to reflux for 2 hours. The solvent was subsequently removed to give the title compound as a yellow solid, which was used without further purification (710 mg). ESI-MS m/z [M+H]+ 405.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:5][C@@:6]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH:41](I)([CH3:43])[CH3:42]>CN(C=O)C>[CH:41]([N:23]1[C:24](=[O:27])[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@@H:13]([N:9]3[CH2:8][CH2:7][C@:6]([CH2:5][C:2]([CH3:1])([CH3:34])[C:3]#[N:4])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:11][C:10]3=[O:12])[CH3:14])=[CH:16][CH:17]=2)=[CH:22]1)([CH3:43])[CH3:42]
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccccc4)OC3=O)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (6 mg, 0.013 mmol) was dissolved in DMF (2.5 mL). Cs2CO3 (c.a. 15 mg, excess) and i-PrI (100 μL, excess) were added. The mixture was stirred for 3 h at rt. LC-MS found the reaction was complete. The mixture was purified by prep HPLC to afford 3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (1.99 mg, 30%). LC-MS Method 1 tR=2.03 min, m/z=498; 1H NMR (CDCl3) 8.35(d, 1H), 7.80(dd, 1H), 7.37(m, 5H), 7.22(d, 2H), 6.92(d, 2H), 6.83(d, 1H), 5.66(q, 1H), 5.22(m, 1H), 2.93(m, 1H), 2.16(s, 2H), 1.55(d, 3H), 1.46(s, 3H), 1.40(d, 6H), 1.33(s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH:28]1([CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][NH:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]([N:35]2[CH2:36][CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])([OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccccc2C1C1CCCCC1)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.6 %

Procedure:
1-benzyl-4-hydroxypiperidine-4-carboxylic acid (951 mg) was dissolved in DMF (25 mL), and N,N′-carbonyldiimidazole (720 mg) was added thereto, followed by stirring at room temperature for 18 hours. Thereafter, N,N-diisopropylethylamine (784 mg) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.22 g) were added to the reaction liquid, followed by stirring at 60° C. for 18 hours. The solvent was evaporated, and water and EtOAc were added to the reaction liquid. The resulting insoluble materials were separated through celite, extracted with EtOAc and dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and dissolved in 1,4-dioxane (12 mL), and di-tert-butyl dicarbonate (1.3 g) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc and then chloroform-MeOH) to obtain 1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-4-ol (115 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:16][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[F:15])[N:5]([CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20][CH2:19]1)[C:6](=[O:17])[CH2:7][CH2:8]2
Reactant: CC(C)(C)C(=O)OCC1CCNCC1
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCC1CCN(CCCN2C(=O)CCc3cc(F)c(F)cc32)CC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethylpropionic acid piperidin-4-ylmethyl ester (45 mg, 0.21 mmol) (40 mg, 0.20 mmol), and Cs2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (26 mg, 62 μmol, 31%). 1H NMR (CDCl3) δ 7.07 (dd, J=1.8, 3.1 Hz, 1H), 6.98-6.91 (m, 1H), 3.94-3.87 (m, 4H), 2.94-2.86 (m, 2H), 2.82 (br t, J=6.8 Hz, 2H), 2.02 (dd, J=5.2, 7.6 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.94 (dt, J=2.0, 11.6 Hz, 2H), 1.74-1.58 (m, 3H), 1.42-1.28 (m, 2H), 1.91 (s, 9H); 13C NMR (CDCl3) δ178.7, 169.7, 149.3 (dd, J=13, 230 Hz), 145.6 (dd, J=243, 13 Hz), 136.7 (br), 122.7 (br), 116.6 (d, J=18 Hz), 105.3 (d, J=22 Hz), 68.8, 55.8, 53.7, 42.3, 39.1, 35.7, 31.1, 29.1, 25.2, 24.9; HPLC-MS (ammonium acetate) [M+H]+=423.20.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:18]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:18][CH:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(NC(=O)OC(C)(C)C)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Yield: 93.6 %

Procedure:
Cis-tert-butyl N-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]carbamate (2.05 g, 0.00344 mol) was triturated in anhydrous dichloromethane (50 mL) and the reaction mixture was cooled to 0° C. Trifluoroacetic acid (10 mL) was added dropwise and the resulting solution was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for one and a half hour. The solvents were removed under reduced pressure, the residue suspended in water (50 mL) and basified with saturated aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3×150 mL), the combined organic extracts were dried with magnesium sulfate and the solvent was removed under reduced pressure to yield cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.60 g, 0.00322 mol) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cccc(F)c4)cn3)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.10 g, 0.3 mmol, 1.0 equiv) and 3-fluorophenyl boronic acid (0.086 g, 0.61 mmol, 2.0 equiv) in 5 Ml dichloromethane was added pyridine (0.05 Ml, 0.61 mmol, 2.0 equiv), copper (II) acetate (0.084 g, 0.46 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous mixture was allowed to stir open to atmosphere for 18 h. Purification by silica gel chromatography (20-45% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 2 H) 1.47 (br. S., 1 H) 1.53 (dd, J=12.51, 2.65 Hz, 1 H) 1.67 (br. S., 1 H) 1.85 (d, J=12.38 Hz, 4 H) 2.29 (d, J=6.57 Hz, 2 H) 3.34 (s, 2 H) 3.64 (s, 3 H) 6.69 (td, J=8.46, 2.53 Hz, 1 H) 6.89 (dt, J=11.62, 2.15 Hz, 1 H) 6.96 (dd, J=7.83, 1.77 Hz, 1 H) 7.33 (d, J=8.34 Hz, 2H) 7.63 (dd, J=8.59, 2.78 Hz, 1 H) 7.84 (d, J=8.59 Hz, 1 H) 7.95 (d, J=8.34 Hz, 2 H) 8.47 (s, 1 H) 8.71 (s, 1H); (M+H)+ 419.3.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>O1CCCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:32])[N:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepi n-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 271°-273° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:34]=[CH:33][C:12]([O:13][C:14]3[C:15]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28]C(C)(C)C)=O)[CH2:22][CH2:21]4)=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.F[C:36](F)(F)C(O)=O.C(OC(=O)C)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:34]=[CH:33][C:12]([O:13][C:14]3[C:15]([CH:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:36])[CH2:22][CH2:21]4)=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(Cl)cn3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(3-(4-(5-chloropyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate (0.14 g, 0.29 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.22 mL, 2.9 mmol) and stirred at room temperature for 2 h. The reaction was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a golden yellow oil. A solution of the crude golden yellow oil in CH2Cl2 (1 mL) was cooled to 0° C. and added acetic anhydride (0.041 mL, 0.43 mmol). The reaction was gradually allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 70% EtOAc/Hexanes) provided a crude crop of the desired product. Further purification via reverse phase HPLC afforded 1-(4-(3-(4-(5-chloropyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 424.9 (M+1). IC50 (uM) 0.001.