Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([F:27])([F:26])C(OCC)=O>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([F:27])[F:26])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(Br)ccc1OC(F)F
Temperature: 80 °C
Yield: 33.2 %

Procedure:
step 1—To a mixture of 4-bromo-2-tert-butyl-phenol (640 mg, 2.795 mmol) and potassium carbonate (1.20 g, 8.682 mmol) in DMF (8 mL) was added ethyl chlorodifluoroacetate (1.1 mL, 8.687 mmol). The reaction was heated to 80° C. overnight then cooled to RT, and diluted with EtOAc and water. The organic layer was washed with water, with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 column eluting with hexane to afford 259 mg (33%) of 4-bromo-2-tert-butyl-difluoromethoxy-benzene (20) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:47])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:47][C:12]([F:11])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH2:27][CH:28]=[O:29])[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17]
Reactant: Cc1ccc(C[C@@H]2CN(CCOCCO)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CCOCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
To a stirred solution of oxalyl chloride (151 mg) in dichloromethane (3 ml) was added dropwise a solution of dimethylsulfoxide (123 mg) in dichloromethane (0.25 ml) at −78° C. under nitrogen atmosphere. After 15 minutes, (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-hydroxyethoxy)ethyl]piperazine (317 mg) was added at the same temperature. After 15 minutes, the resulting mixture was stirred at −45° C. for 1 hour. Triethylamine (446 mg) was added at −45° C., and the whole was stirred at 0° C. for 20 minutes and then treated with aqueous solution of ammonium chloride (2 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using ethyl acetate as eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(formylmethoxy)ethyl]piperazine (171 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:20][CH2:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[N:23]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 2,6-dichloropurine (0.062 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (5 mL). 2-Chloro-N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ C50=615 nM] was obtained after purification as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (1H, s), 8.15 (1H, s), 8.04 (1H, dd, J=8.5, 1.2 Hz), 7.96 (1H, d, J=6.7 Hz), 7.60 (1H, d, J=7.3 Hz), 7.61 (1H, t, J=7.9 Hz), 7.54 (1H, d, J=6.7 Hz), 7.50 (1H, t, J=6.7 Hz), 7.44 (1H, t, J=7.3 Hz), 4.62 (2H, d, J=26.9 Hz) Mass Spectrum (ESI) m/e=455.0 and 457.0 (M+1)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13](N)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:26].[Na+].[I:28]I>O.C(Cl)Cl>[I:26][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([I:28])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc(SSc2ccc(N)cc2)cc1
Reactant: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Ic1ccc(SSc2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 4-aminophenyl disulfide (7.452 g, 30.0 mmol, technical grade) in water (250 mL) was added sulfuric acid (60 mL) slowly at 0° C., followed by the addition of a solution of sodium nitrite (4.5 g) in water (15 mL). The resulting yellow solution was stirred at 0° C. for 15 minutes and then added to a solution of sodium iodide (20 g) and iodine (20 g) in water (30 mL) slowly at 0° C. During the addition methylene chloride (about 50 mL) was added to keep the products in solution. After stirring at room temperature overnight, the mixture was diluted with methylene chloride (400 mL) and the two phases were partitioned. The organic phase was washed with concentrated sodium bisulfite solution, sodium bicarbonate solution and water, respectively. After drying over anhydrous sodium sulfate, the solvent was removed under vacuum. Purification of the residual yellow solid from ethanol afforded 4-iodophenyl disulfide as a yellow amorphous solid: 8.25 g (58.5%); mp 122°-123° C. (Lit. mp 124.5°-125.5° C.).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(#N)C.O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(N2CCNCC2)nc1
Temperature: 60 °C

Procedure:
6-Chloronicotinonitrile (500 mg, 3.61 mmole) and piperazine (930 mg, 10.8 mmole) were dissolved in 20 ml of acetonitrile and heated at 60° C. under N2 for 5 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=1.70 Hz, 1H) 7.60 (dd, J=8.81, 2.37 Hz, 1H) 6.59 (d, J=8.48 Hz, 1H) 3.57-3.75 (m, 4H) 2.91-3.05 (m, 4H); MS (M+H)+=189.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:47][CH:48]([F:50])[F:49])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]N4CCC([C:42]([O:44]CC)=[O:43])CC4)[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:52][C:53]1([C:59]([O:61][CH3:62])=[O:60])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>>[CH:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:47][CH:48]([F:50])[F:49])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:56]4[CH2:57][CH2:58][C:53]([CH3:52])([C:59]([O:61][CH3:62])=[O:60])[CH2:54][CH2:55]4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C1CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Reactant: COC(=O)C1(C)CCNCC1
Agent: Cl
Product: COC(=O)C1(C)CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Product: O=CO

Procedure:
Using synthetic method analoguous to that of ethyl 1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate, the title compound was prepared from methyl 4-methylpiperidine-4-carboxylate hydrochloride. LCMS (Method 24) [M+H]+=714.2, RT=1.94 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.65-7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.6 Hz), 5.22 (s, 2H), 3.62 (s, 3H), 3.48-3.45 (m, 4H), 2.57-2.51 (m, 2H), 2.49-2.39 (m, 8H), 2.01-1.93 (m, 4H), 1.41-1.35 (m, 2H), 1.10 (s, 3H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OCC)C>C1COCC1>[N:22]1([CH2:6][C@@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CN1CCOCC1)c1ccccc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
The mixture of 25 g (0.0792 mol) of (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate and morpholine (69.37 mL, 0.792 mol) in 250 mL of dry THF under inert atmosphere was refluxed for 8 hours. The reaction was then cooled to room temperature, treated with diethylether and the solid filtered. The solution was evaporated affording the crude as a yellow oil that was purified through silica gel chromatography (eluant hexane/ethylacetate 6/4). 11.59 g of the title product were isolated (48% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[C:5]1[CH2:8][CH:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:6][CH:7]([NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8]1
Reactant: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of (3-tert-butoxycarbonylamino-cyclobutylidene)-acetic acid methyl ester (7 g, 29 mmol) in methanol (100 mL) was added Pd/C (5 g) and stirred at room temperature under H2 balloon overnight. After TLC showed the reaction was completed, the mixture was filtered over Celite. The filtrate was concentrated under reduced pressure to give the title compound (7 g, yield 99%) as a white solid, which was used for the next step directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:13])([F:15])[F:14])[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Agent: Cl
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 2.72 g; 11.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (2.46 g; 13.8 mmol; 1.2 eq.) as a greenish solid (1.42 g; 36%). HPLC, Rt: 2.16 min. (purity 100%). LC/MS, M+(ESI): 342.2, M−(ESI): 340.2.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([I:12])[C:4]=12.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1>>[CH:17]([OH:31])=[O:16].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH2:26][CH2:27][N:28]([C:39]([CH:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[O:40])[CH2:29][CH:30]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([I:12])[C:4]=12
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(I)c2c(N)ncnc21
Agent: Cl
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CCN(C)CC2)CC1)n1nc(I)c2c(N)ncnc21
Product: O=CO
Yield: 79.9 %

Procedure:
Title compound was prepared following the procedure used for the synthesis of Intermediate D25, from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one hydrochloride (Intermediate D23, 0.200 g, 0.363 mmol), and 1-methylpiperidine-4-carboxylic acid (0.062 g, 0.436 mmol) to give the title compound (99.4 mg, 0.145 mmol, 39.9% yield) as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (375 mg, 1.04 mmol) in dichloromethane (15 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (164 mg, 1.06 mmol) and 1-hydroxybenzotriazole (150 mg, 2.00 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 178 mg, 1.15 mmol). The reaction mixture was then stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (200 mg, 40%) as an off-white solid: LR-ES-MS m/z calculated for C27H36N4O5 [M]+ 496, observed [M+H]+ 497; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.69-1.35 (m, 6H) 1.05 (br. s., 3H) 1.06 (br. s, 3H) 1.49-1.89 (m, 7H) 3.81 (s, 3H) 3.89 (s, 2H) 4.10 (d, J=18.4 Hz, 1H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.71 (s, 1H) 4.82-4.96 (m, 1H) 6.44 (d, J=2.2 Hz, 1H) 6.94-7.07 (m, 1H) 7.18-7.24 (m, 1H) 7.30 (m, 2H) 7.54 (d, J=2.2 Hz, 1H) 10.77 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][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.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][CH:57]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:57]=[CH:58][C:59]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:60][CH:61]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(Br)cc2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg) and 4-[2-(4-bromo-phenyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (132 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-{2-[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)-phenyl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-172) as a colorless powder (5 mg, 3%).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.O>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH:17]=[CH:16][C:14]=1[O:15][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:8]=[O:7]
Reactant: C[Si](C)(C)CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
Chloromethyltrimethylsilane (36.7 g, 0.3 mol) is added dropwise over 10 minutes to a mixture of vanillin (45.6 g, 0.3 mol) and potassium carbonate (41.4 g, 0.3 mol) in 300 ml of dry DMF maintained at 100° C., and while sparging with nitrogen. The mixture is left at 100° C. for 2 hours. The reaction mixture is filtered and the solvent is removed from the filtrate by distillation under vacuum. The final traces of DMF are removed via a stage at 60° C. under a vacuum of 2 mmHg. 70 g of a pink syrup, which crystallizes, are obtained. After recrystallization from an 80/20 ethanol/water mixture, 35.5 g (yield: 50%) of 3-methoxy-4-trimethylsilanylmethoxybenzaldehyde are obtained in the form of white crystals (m.p. 45° C.), which are used without purification in the next step.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([CH:34]2[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.C[Si](N[Si](C)(C)C)(C)C.[Li].CO>C1COCC1.C(Cl)Cl>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([C:7]2[C:2]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([CH:34]4[CH2:35][CH2:36]4)=[O:33])=[CH:29][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1
Reactant: Nc1ccc(NC(=O)C2CC2)cc1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (100 mg, 0.319 mmol) and N-(4-aminophenyl)cyclopropanecarboxamide (56.2 mg, 0.319 mmol, Enamine Ltd, Ukraine) in THF (5 mL), argon was bubbled through for 2 min, and the tube was sealed. The reaction mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amine (1 N in THF, 1 mL, 1 mmol) was added dropwise. The red solution was stirred at 0° C. for 1 h and then warmed to room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (25 g) eluting with a gradient of 2% to 5% 2 M NH3.MeOH in DCM to give N-(4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (90 mg, 0.192 mmol, 60% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.69 (s, 1H); 10.12 (s, 1H); 9.73 (dd, J=7.92, 1.86 Hz, 1H); 8.87 (s, 1H); 8.35 (dd, J=4.70, 1.76 Hz, 1H); 7.76 (d, J=9.00 Hz, 2H); 7.57 (d, J=8.80 Hz, 2H); 6.99 (dd, J=7.82, 4.69 Hz, 1H); 5.84 (dd, J=10.95, 1.76 Hz, 1H); 4.04 (d, J=12.63 Hz, 1H); 3.71-3.81 (m, 1H); 2.91 (s, 3H); 2.27-2.38 (m, 1H); 1.97-2.07 (m, 2H); 1.73-1.85 (m, 2H); 1.56-1.67 (m, 2H); 0.72-0.82 (m, 4H). m/z (ESI, +ve ion) 470 (M+H)+.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][NH2:15].[OH-].[K+].Cl>C(O)C>[C:2]1([C:1]2[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:15][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)C=CC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CC(c2ccccc2)=NN1

Procedure:
A mixture of 10.0 g of 3-benzoylacrylic acid, 1.8 g of hydrazine, and 3.7 g of potassium hydroxide in 30 ml. of aqueous ethanol (1:1) is stirred and heated at reflux for 2 hours. The cooled solution is treated with 5 ml of concentrated hydrochloric acid to pH 4.0 to precipitate 7.1 g of solid, melting point 180°-182° C. This material is dissolved in 40 ml of warm dimethylformamide and treated with 140 ml of methanol to crystallize 3.9 g of the title compound, melting point 199°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[C:20](=O)[CH2:19]1)=[O:17].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:19]1)=[O:17]
Reactant: C1CCNC1
Reactant: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Product: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1N1CCCC1)c1ccc(Cl)s1

Procedure:
In analogy to example 24B 5-chloro-thiophene-2-carboxylic acid {(1RS,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentylmethyl}-amide was reacted with pyrrolidine to give 5-chloro-thiophene-2-carboxylic acid {(1RS,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-pyrrolidin-1-yl-cyclopentylmethyl}-amide. Off-white crystalline solid. 543.3 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH3:20][O:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: COCc1cccc(B(O)O)c1
Product: COCc1cccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)c1

Procedure:
3-(3′-Methoxymethyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using the procedure described above for the preparation of Example 12 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-methoxymethylphenylboronic acid (available from Digital Specialty Chemicals, Inc., Dublin, N.H.). Mass spectrum MH+=349.