Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1O)(=[O:3])[CH3:2].[CH3:13][S:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>C(Cl)(Cl)Cl>[N:26]1([C:9]2[CH:8]=[C:7]([CH3:11])[O:6][C:5](=[O:12])[C:4]=2[C:1](=[O:3])[CH:2]=[CH:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([O:17][CH2:16][CH2:15][S:14][CH3:13])[CH:19]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: CSCCOc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSCCOc1cccc(C=CC(=O)c2c(N3CCCCC3)cc(C)oc2=O)c1
Temperature: 25 °C
Yield: 6.9 %

Procedure:
In 8 ml of chloroform were dissolved 85.7 mg of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 100 mg of 3-(2-methylthioethoxy)benzaldehyde and 30.3 mg of piperidine, and the solution was heated under refluxing for 13 hours while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction mixture washed successively with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. Precipitated crystals were filtered, and this was subjected to silica gel column chromatography to obtain 10.1 mg of 4-piperidino-3-[3-[3-(2-methylthioethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (14b)] as a pale yellow crystal.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[C:8](Cl)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=1>C1COCC1>[N+:11]([C:7]1[C:8]([NH2:1])=[CH:9][C:4]([C:3]([F:15])([F:14])[F:2])=[N:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Reactant: N
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ncc1[N+](=O)[O-]
Yield: 96 %

Procedure:
Ammonia gas is bubbled through a solution of 2-trifluoromethyl-4-chloro-5-nitro-pyridine (4.12 g, 18.23 mmol) in anhydrous THF at room temperature for 3 h. Removal of solvent under reduced pressure affords 5-nitro-2-trifluoromethyl-pyridin-4-ylamine (3.6 g, 96%); 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1H), 9.15 (s,1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30])C>CS(C)=O>[CH2:27]([C:26]1[N:15]2[CH2:14][C@@H:13]([CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)[O:17][C:16]2=[N:18][C:24](=[O:23])[CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCC#CC(=O)OCC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: CS(C)=O
Product: CCCCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and hept-2-ynoic acid ethyl ester employing the procedure described in Example 99. [α]D25 +8.40 (c 0.5, DMSO)
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][OH:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:9]([O:8][P:1]([O:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]([OH:22])=[O:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(CCO)COP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CC(=O)O
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a solution of the product from Example 10C (0.235 g, 0.76 mmol) in DMF (7.6 mL) at room temperature was added pyridinium dichromate (1.71 g), and the mixture was stirred for 16 hours. 10% citric acid was added and the reaction mixture was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with chloroform and ending with 5% methanol in chloroform, to give the title compound (0.144 g, 60%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]1[CH2:26][O:25]CC1.C[Si](Cl)(C)C.BrN1C(=[O:38])CCC1=O>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C(OCC)(=O)C>[C:26]([O:38][CH2:2][C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12)=[O:3])(=[O:25])[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: C1CCOC1
Reactant: CC(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Acetylimidazo[5,1-b]thiazole (2.49 g) was dissolved in a solution of 150 ml of THF and 30 ml of HMPA. A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (18 ml) was added dropwise to the solution in an argon atmosphere at −70° C. The mixture was stirred at the same temperature for 30 min. Trimethylsilyl chloride (2.28 ml) was added dropwise thereto. The mixture was stirred at the same temperature for 30 min. A solution of 3.21 g of N-bromosuccinimide in 90 ml of THF was added dropwise thereto. The mixture was stirred for 2 hr while raising the temperature to room temperature. Ethyl acetate (400 ml) was added to the reaction solution. The mixture was washed twice with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in 120 ml of DMF. Sodium acetate (1.48 g) was added to the solution. The mixture was stirred at room temperature for 14 hr and then at 60° C. for 4 hr. The reaction solution was concentrated under the reduced pressure until the amount of the solution became half. Brine (290 ml) was added to the concentrate, followed by extraction twice with 300 ml of ethyl acetate. The organic layers were combined together, washed three times with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (eluting with dichloromethane:ethyl acetate=1:1 and then with ethyl acetate) to give 2.11 g of 7-acetoxyacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][N:6]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:37])[F:38])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCN5CCNCC5)cc4)CC3)nn12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
A solution of methanesulfonyl chloride (0.034 mL, 0.44 mmol) in DCM (0.5 mL) was added dropwise to 6-[4-[4-(2-piperazin-1-ylethoxy)phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 727) (175 mg, 0.37 mmol) and triethylamine (0.103 mL, 0.74 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge then the organic layer evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[4-[2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (122 mg, 60%).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Yield: 92 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 92% of theory, C27H27N9O (493.6); EKA mass spectrum: (M+H)+=494; (M+Na)+=516; (M+2H)++=258.7.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49]>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:2][CH3:3])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2OC)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a white solid, m.p. 120–121° C. (uncorrected). IR (diffuse reflectance) 2965, 2935, 1615, 1566, 1480, 1390, 1305, 1256, 1215, 1209, 1183, 1165, 1040, 825, 747 cm−1; OAMS supporting ions at: ESI+ 448.1; MS (EI) m/z 447 (M+); HRMS (FAB) calcd for C27H33N3O3+H1 448.2600, found 448.2600. Anal. Calcd for C27H33N3O3: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.46; H, 7.59; N, 9.39.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1c(Br)cnn1C
Yield: 63.6 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-(trifluoromethoxy)phenyl isocyanate (0.025 g, 18.4 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 19 (0.032 g, 0.07 mmol, 58%) as a white solid. LCMS m/z (%)=485 (M+H79Br, 92), 487 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.19 (s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.51 (s, 1H), 7.45 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][C:8](=[O:25])[C@@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][O:4][CH2:3]1.B(F)(F)F.CCOCC.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][CH:9]([C:8]12[O:7][CH2:6][C:2]([CH3:3])([CH2:5][O:4]1)[CH2:1][O:25]2)[CH2:10][CH:11]([CH3:12])[CH3:13])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:9]([C:8]([OH:25])=[O:7])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(2S)-2-Benzyloxycarbonylamino-4-methyl-pentanoic acid 3-methyloxetan-3-ylmethyl ester (Cbz-Leu oxetane ester) (2 g, 5.7 mmol) was dissolved in dry CH2Cl2 (10 mL) under nitrogen. BF3.Et2O (40 μl, 0.3 mmol, 0.054 eq.) was diluted in dry CH2Cl2 (1 mL) and added to the reaction flask. The reaction was allowed to warm up to room temperature and stirred for 12 h. Triethylamine (335 μl, 3.3 mmol, 0.58 eq) was added and the reaction was stirred for an additional 30 min., before being concentrated to thick oil. The crude product was redissolved on EtOAc (15 mL), washed with 3% NH4Cl (10 mL), and saturated NaCl (10 mL), dried (MgSO4), and evaporated to dryness. The reaction yielded a colorless thick oil, which crystallized on standing to give [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-carbamic acid benzyl ester, (Cbz-Leu-OBO ester).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].CCN(CC)CC>ClCCl>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31](=[O:34])[CH2:32][CH3:33])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionyl chloride (8.7 μL, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed to stir at 25° C. for 3 hours. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propionamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide (13 mg, 28%). ESI-MS m/z calc. 456.5. found 457.5 (M+1)+; retention time 3.22 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[N:40]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([N:43]2[CH2:42][CH2:41][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (200 mg, 0.34 mmoL), tert-butyl piperazine-1-carboxylate (224 mg, 1.20 mmoL) and NaHCO3 (116 mg, 1.38 mmoL) in NMP (5 mL) was heated at 130° C. overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate: LCMS tR=3.04 Min (5 min run, UV254nm). Mass calculated for, M+ 731.4, observed LC/MS m/z 732.4 (M+H).
Reaction SMILES: [Mg].[C:2]1([SiH:8](Cl)Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1.C=CC=C>CCOCC.C(O)CO>[C:2]1([SiH:8]2[CH2:13][CH:12]=[CH:11][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cl[SiH](Cl)c1ccccc1
Agent: C=CC=C
Agent: [Mg]
Solvent: CCOCC
Solvent: OCCO
Product: C1=CC[SiH](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed magnesium powder (9.6 g, 0.4 mol), phenyldichlorosilane (35.4 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Ethylene glycol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. There were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. A fraction, bp 87° C./5 mm, 6.0 g, 19% yield, was collected.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][C:28]([CH3:55])([CH3:54])[CH:29]([OH:53])[CH2:30][O:31]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][C:28]([CH3:54])([CH3:55])[CH:29]([O:53][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:30][OH:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(C)(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(C)(C)C(CO)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a suspension of 3.28 g of 50% sodium hydride in 40 ml of dimethylformamide containing 13.49 g of benzyl bromide was added dropwise a solution of 31.8 g of 3-(hexadecyloxy)-1-[(4-methoxyphenyl)diphenylmethoxy]-3-methyl-2-butanol in 50 ml of dimethylformamide over 45 minutes. The mixture was stirred overnight, then water was added and the mixture extracted with ether. The ether extract was dried and the solvent removed. The residue was stirred with 125 ml of methanol, 25 ml of tetrahydrofuran and 10 g of a strongly acidic ion exchange resin for 1.5 hours with warming, then filtered and the solvent removed. The residue was purified by HPLC, using hexane:ether (9:1), giving 12.14 g of the desired compound as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=1>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:31][C:32]=1[C:37]([F:38])([F:39])[F:40]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(Cl)c(C(F)(F)F)c3)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.053 g, 0.183 mmol) in DMF (1 mL) was added Cs2CO3 (0.0.071 g, 0.219 mmol) followed by 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (0.050 g, 0.183 mmol). The reaction was stirred at 60° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a white solid (0.048 g). LCMS m/z=480.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H), 2.21-2.34 (On, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.32 Hz, 1H), 2.81-2.93 (m, 1H), 3.64-3.77 (m, 1H), 3.94-4.05 (m, 1H), 4.06-4.17 (On, 1H), 5.10 (s, 2H), 6.84 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.47-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([NH:33][CH2:34][CH2:35]Br)=[O:32])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.BrCCN=C=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([NH:33][CH2:34][CH2:35][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:32])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC(=O)NCCBr)C1
Agent: O=C=NCCBr
Solvent: CCO
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC(=O)NCCN2CCOCC2)C1

Procedure:
To a solution of 41 mg (0.075 mmol) of trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-bromo-ethyl)-urea, which is prepared as described in Example 26 using 2-bromoethyl isocyanate (Aldrich, Buchs, Switzerland), in 5 ml of ethanol is added 33 μl (0.375 mmol) of morpholine. The mixture is refluxed for 3 h and the crude mixture is purified by medium-pressure liquid chromatography to provide trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-morpholin-4-yl-ethyl)-urea. Analytical HPLC: tR=6.12 min (Grad 2); ES-MS: m/eo=555.9.