Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([CH3:3])[CH3:2].[Li]CCCC.Cl[C:22]([O:24][CH3:25])=[O:23].CCOC(C)=O>C1COCC1.CCCCCC>[CH:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:10][CH2:11][O:12][CH3:13])=[C:8]([CH:9]=1)[C:22]([O:24][CH3:25])=[O:23])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COCOc1ccc(C(C)C)cc1OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1c(OC)cc(C(C)C)cc1C(=O)OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-isopropyl-2-methoxy-1-methoxymethoxy-benzene (2.0 g, 9.51 mmol) in 35 mL dry THF cooled to 0° C., BuLi (9 mL of a 1.6 m solution in hexane, 1.5 eq.) was added dropwise via a syringe and the reaction mixture was stirred 2.5 h at 0° C. This solution was then slowly added to a solution of methyl chloroformate (9 g, 95.1 mmol, 10 eq.) in 10 mL dry THF at 0° C. The mixture was stirred 12 h at r.t. Saturated KHCO3 solution and EtOAc were then added to the solution and the phases were separated. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane EtOAc 9:1→6:1) to yield the title compound as a yellowish oil.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: C[C@@H](O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of (R)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added and a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (249(a)) (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), washed with brine (1×), and the organic layers were dried with sodium sulfate. The solution was concentrated and the product was purified by reverse phase HPLC to afford (R)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (364) (0.129 g, 21% yield) as a light brown solid. 1H-NMR (400 MHz, DMSO)-d6: 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:37])[C:11]([CH2:32][C:33]([O:35]C)=[O:34])=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:10](=[O:37])[C:11]([CH2:32][C:33]([OH:35])=[O:34])=[CH:12][N:13]([CH2:26][CH:27]([O:28][CH3:29])[O:30][CH3:31])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(Cn1cc(CC(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of methyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate (150 mg) obtained in Example 187, Step 1 in tetrahydrofuran (1.5 ml)-methanol (1.5 ml) was added 4N aqueous sodium hydroxide solution (0.11 ml), and the mixture was stirred at 70° C. for 30 min. The reaction mixture was warmed to room temperature, 1N aqueous hydrochloric acid (0.5 ml) and water (15 ml) were added, and the mixture was extracted twice with ethyl acetate (30 ml each). The ethyl acetate layer was washed with water, dried, concentrated, and crystallized from ethyl acetate-diisopropyl ether to give [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetic acid (116 mg).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[Cl:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[Cl:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl
Reactant: C#CCCO
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 422 (0.21 mmol) and but-3-yn-1-ol (0.21 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 100:0 as the eluent to afford the title compound as light yellow foam.
Reaction SMILES: C([O-])(=O)C.[K+].O[CH:7]([CH:12]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:13][CH:14]=[CH2:15])[CH2:8][C:9]([OH:11])=O>C(OC(=O)C)(=O)C>[CH:16]1([C:12]2[CH2:13][CH:14]3[CH:8]([CH:7]=2)[C:9](=[O:11])[CH2:15]3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CCC(C(O)CC(=O)O)C1CCCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2CC(C3CCCC3)=CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium acetate (4.16 g, 42.4 mmol) was added to an acetic anhydride (20 mL) solution of 3-hydroxy-4-cyclopentylhept-6-enoic acid (4.00 g, 17.7 mmol at the maximum), and the mixture was stirred at room temperature for 1 hour and then stirred at 120° C. for 3.5 hours. The mixture was treated with ice water, followed by extraction with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (2.30 g, 74%).
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1>O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:12]=[O:2])=[O:13])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 79 %

Procedure:
Thus, 18.5 g of selenium dioxide was dissolved in 100 mL of dioxane by warming to 50° C. and stirring until all was in solution. To this solution was added. 23 g of 4′-fluoroacetophenone and the reaction was refluxed for 4 h. The hot solution was decanted from the solid selenium and the dioxane and water were removed by distillation through a short column at atmospheric pressure. Distillation of the residue at reduced pressure afforded 20 g of 4-fluorophenylglyoxal as a thick yellow oil which was contaminated by some starting 4′-fluoroacetophenone. This can be used directly or, more preferably, it can be converted to pure hydrate (see the last paragraph of the reference and note 5). A portion was boiled in water for 0.5 h and the aqueous layer was decanted from an oily residue and then allowed to cool. The hydrate is obtained as a white solid after filtration and air drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][CH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:52][C:53]6[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: NCc1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4ccncc4)cc3F)cn2)cc1
Yield: 147.9 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 4-(aminomethyl)pyridine (24.0 μl, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-pyridin-4-ylmethyl-benzamide as a yellow solid (134 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-271) as a yellow powder (49.4 mg, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@H:10]([CH:37]([CH3:39])[CH3:38])[NH:11][C:12](=[O:36])[C@@H:13]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH:14][C:15](=[O:31])[CH:16]([OH:30])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:41].O1CCOCC1>ClCCl>[ClH:41].[CH2:1]([O:8][C:9](=[O:40])[C@H:10]([CH:37]([CH3:39])[CH3:38])[NH:11][C:12](=[O:36])[C@@H:13]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:14][C:15](=[O:31])[CH:16]([OH:30])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](NC(=O)C(O)C1CCCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@@H](NC(=O)C(O)C1CCCCN1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
[2-Hydroxy-2-(N-t-butyloxycarbonylpiperidin-2-yl)acetyl]-D-leucylvaline benzyl ester (85 mg) was dissolved in dichloromethane (1 ml) and a 4N hydrochloric acid/dioxane solution (1 ml) was added to the solution under cooling with ice to conduct a reaction at room temperature for 2 h. The reaction liquid was concentrated under reduced pressure and the residue was washed with n-hexane several times and dried to give [2-hydroxy-2-(piperidin-2-yl)acetyl]-D-leucylvaline benzyl ester hydrochloride.
Reaction SMILES: [C:1](=O)([CH3:20])[CH2:2][N:3]1[CH2:8][C@H:7]2[CH2:9][C@@H:4]1[CH2:5][N:6]2S(C1C=CC(C)=CC=1)(=O)=O.[H][H]>CC1OCCC1.[Pd]>[CH:4]([N:6]1[CH2:5][C@H:4]2[CH2:9][C@@H:7]1[CH2:8][N:3]2[C:2]1[CH:1]=[CH:20][C:2]([NH2:3])=[CH:1][CH:20]=1)([CH3:9])[CH3:5]
Reactant: CC(=O)CN1C[C@H]2C[C@@H]1CN2S(=O)(=O)c1ccc(C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC1CCCO1
Product: CC(C)N1C[C@H]2C[C@@H]1CN2c1ccc(N)cc1

Procedure:
A solution of 3 (1.6 g; 6 1 mmol) in 2-MeTHF (25 mL) is stirred under a 1 bar hydrogen atmosphere in the presence of Pd/C catalyst (10% Degussa type E101 NE/W; 0.1 g) at 30° C. for a period of 3 h. The catalyst is filtered off over a bed of Dicalite 478 and the filter cake washed with 2-MeTHF (2×10 mL). The filtrate is concentrated in vacuo to a volume of 25 mL and the resulting solution is used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:13][C:14]([O:16]CC)=O)([CH3:12])[C:5](=[O:11])[NH:6]2>CC(O)=O>[CH3:12][C:4]12[C:5](=[O:11])[NH:6][C:7]3[C:3]1=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1][C:14](=[O:16])[CH2:13]2
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc(N)c21
Solvent: CC(=O)O
Product: CC12CC(=O)Nc3cccc(c31)NC2=O

Procedure:
A mixture of (±)-ethyl (4-amino-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step C (2.37 g, 9.56 mmol) and AcOH (1 mL) was heated in xylenes (10 mL) at reflux for 24 h, then concentrated to dryness under reduced pressure. The crude product was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4H—100:0:0 to 90:9:1, to give a crude sample of the title compound. Further purification by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, gave the racemic title compound. The enantiomers were resolved by HPLC, utilizing a ChiralPak AS column and eluting with hexane:EtOH—70:30. The first major peak to elute was 2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione, enantiomer A, and the second major peak to elute was 2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione, enantiomer B, the title compound. MS: m/z=203 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH2:13](N)[CH2:14][CH2:15]C#C>ClCCl>[CH2:12]([NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2])[CH2:11][CH2:15][C:14]#[CH:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#CCCCN
Solvent: ClCCl
Product: C#CCCCNC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Add 1,1′-carbonyldiimidazole (0.539 mg 1.05 equiv; 3.26 mmoles) slowly portion wise to a −78° C. solution of 4-pentyn-1-amine (0.258 mL; 1.0 equiv; 3.10 mmoles) in dichloromethane (10 mL). Allow the reaction to warm to ambient temperature and stir for 72 hours. Use the solution directly for subsequent chemistry: MS (m/z): 178(M+1).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:52]=[CH:51][C:13]([C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C@@H:27]([CH2:40][S:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:28][CH2:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[C:22]([N+:48]([O-:50])=[O:49])[CH:21]=2)(=[O:19])=[O:18])=[O:15])=[CH:12][CH:11]=1.Cl>O1CCOCC1>[NH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([N:2]3[CH2:3][CH2:4][C:5]4([CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:1]3)=[CH:52][CH:51]=2)(=[O:19])=[O:18])=[CH:21][C:22]=1[N+:48]([O-:50])=[O:49])[CH2:40][S:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)C3)cc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)C3)cc2)cc1[N+](=O)[O-]

Procedure:
A solution of Example 120D (24 mg, 0.03 mmol) and 4N HCl (0.5 mL) in dioxane at room temperature was stirred for 4 hours, partially concentrated, and treated with diethyl ether. The precipitate was filtered, washed with diethyl ether, and was dried under vacuum to provide the desired product. MS(ESI(+)) m/e 652 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.52 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.74 (d, 2H), 7.70 (s, 2H), 7.24-7.07 (m, 6H), 6.51 (d, 2H), 4.10 (m, 1H), 3.57 (s, 4H), 3.35 (m, 4H), 3.18 (s, 2H), 2.74 (m, 2H), 1.86 (t, 2H), 1.76 (m, 2H), 1.65 (m, 4H), 1.55 (t, 4H).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:16][CH:17]([C:25]([F:28])([F:27])[F:26])[C:18]([F:24])([F:23])[S:19]([O-:22])(=[O:21])=[O:20].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:24][C:18]([F:23])([S:19]([O-:22])(=[O:21])=[O:20])[CH:17]([O:16][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:14]=1)[C:25]([F:28])([F:26])[F:27].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=C(C)C(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2.4 g (11 mmol) of the resulting 4-methacryloyloxybenzoic chloride were added 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 1.1 g (11 mmol) of triethylamine and 0.2 g (2 mmol) of N,N-dimethylaminopyridiene in 5 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 3 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. The residue was washed with diisopropyl ether and purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(4-methacryloyloxy-benzoyloxy)-propane-1-sulfonate was obtained as colorless oil (6.0 g, yield 88%). The compound has the following structure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:17]=[C:18]([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[C:39]1([CH2:38][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:36])([F:37])[F:13])[CH:17]=2)[C:23]#[N:24])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of diisopropyl amine (2.48 mL, 17.5 mmol) in THF (60 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexane, 11.5 mL, 18.3 mmol) and the reaction mixture was stirred for 5 min. A solution of (2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (5.51 g, 15.3 mmol), prepared as described in Procedure 14, in THF (5 mL) was added dropwise to the reaction mixture and stirred for 1h. Benzyl bromide (2.17 mL, 18.3 mmol) was added dropwise, then the cooling bath was removed and the reaction mixture was stirred at rt for 45 min. The reaction mixture was poured into H2O (75 mL) and extracted with diethyl ether (2×75 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 5 to 15% Et2O/hexane to give 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propanenitrile (6.75 g, 98% yield) as a clear yellow oil. LCMS: RT=2.18 min [M-CN] 425.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 3.63 (s, 2 H), 6.87 (d, J=7.03 Hz, 2 H), 7.15-7.26 (m, 9 H), 7.40 (t, J=8.13 Hz, 2 H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]5[CH:29]=[N:30][N:31]([CH2:33][C@H:34]6[O:39][CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]6)[CH:32]=5)[N:22]=4)[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH:36]1[CH2:37][CH2:38][O:39][C@H:34]([CH2:33][N:31]2[CH:32]=[C:28]([NH:27][C:23]3[N:22]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([C:12]5[N:11]=[CH:10][C:9]([CH:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH3:8])=[CH:14][N:13]=5)[CH2:20][CH2:19]4)[N:26]=[CH:25][N:24]=3)[CH:29]=[N:30]2)[CH2:35]1
Reactant: CC(c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CN(C(=O)OC(C)(C)C)CCO5)c4)n3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CNCCO5)c4)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-tert-butyl 2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (130 mg, crude) in dichloromethane (6 mL) was dropwise added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 0.5 hour and then concentrated. The residue was purified by Prep-HPLC to provide N-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amine as a white solid, which was then separated by Chiral-HPLC to afford N-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-((R)-1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amine as a white solid (15.4 mg, 17%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][N:6]=1.P([O-])(O)(O)=O.[K+]>C(#N)C>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][N:6]=1)[C:11]#[N:12]
Reactant: C[O-]
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C#N)ccn1
Temperature: 0 °C
Reaction time: 23 h
Yield: 70.5 %

Procedure:
A stirred suspension of 17.86 g NaOMe (330.7 mmol, 1.22 eq) in 95 mL acetonitrile was cooled to 0° C. and a solution of 37.56 g 2-chloro-4-cyano pyridine (8, 271.1 mmol) in 225 mL acetonitrile was added over 45 min. Stirring was continued at room temperature for 23 h until less than 4% (area) starting material were detected by HPLC. 11.1 g potassium dihydrogen phosphate (81.56 mmol, 0.30 eq) were added at 0° C. and stirring was continued for 3 h at room temperature. The reaction mixture was then evaporated to dryness in a rotary evaporator (40° C./10 mbar) yielding the crude product (64.94 g, 179% by weight) as a brown solid. 64.94 g crude product were extracted with 900 mL toluene for 18 h at reflux temperature using a soxhlet extraction apparatus yielding the title product (25.65 g, 71% by weight) as an orange solid.