Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:44]2[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:43])[N:23]([C@H:33]2[CH2:36][C@H:35]([O:37][CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:43])[N:23]([C@H:33]2[CH2:36][C@H:35]([O:37][CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])[CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogen carbonate (0.21 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.066 g) was added, and the mixture was stirred at 90° C. for 14 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.025 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.023 mL) were added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.054 g, 73%).
Reaction SMILES: NC1C=CC(N2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1.F[C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1>>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:26][CH2:27]2)=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
tert-Butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G39) can be prepared by nucleophilic aromatic substitution of commercially available tert-butyl piperidin-4-ylcarbamate (G36) and 1-fluoro-4-nitrobenzene (G37) under thermal conditions to give tert-butyl (1-(4-nitrophenyl)piperidin-4-yl)carbamate (G38). Reduction of G38 with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal, gives tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G39).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23]O)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: [Pd]
Agent: C#C
Solvent: ClCCl
Solvent: CO
Product: CCCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Yield: 3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 134 (500 mg) and Pd/C (10%, 100 mg) is dissolved in 80 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 30 psi and monitored by mass spectroscopy for complete reduction of the acetylene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction is taken off the Parr. The reaction mixture is filtered over celite to remove the palladium. The filtrate is condensed. The crude solid is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 16.3 mg (3%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:25]1[CH2:29]OC[CH2:26]1>>[CH:26]1([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:10])[CH2:25][CH2:29]1
Reactant: COc1cccc(C(=O)c2cccnc2)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)(c2cccnc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-methoxyphenyl)-(3-pyridinyl)methanone (500 mg) in THF (10 ml) was added 1.1 M cyclopropylmagnesium bromide THF solution (2 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give cyclopropyl-(3-methoxyphenyl)-(3-pyridinyl)methanol (470 mg).
Reaction SMILES: CO[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:27])=[CH:21]3)[CH:14]=[CH:13][N:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:49][C:31]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][O:49][C:11]1[N:16]=[C:15]([N:17]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:27])=[CH:21]3)[C:3]2[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COc1nccc(N)n1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: Cc1cc2cc(Nc3ccnc(Cl)n3)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1nccc(N(c2ccc3[nH]c(C)cc3c2)c2nccc(N)n2)n1
Temperature: 200 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a solution of 2-methoxypyrimidin-4-amine (0.1 mmol) and N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1 mmol) in 3 ml dioxide, CsCO3 (0.2 mmol), Pd(OAc)2(10 mmol %) and Xantphos (10 mmol %) were added. The mixture was stirred under microwave irradiation at 200° C. for 40 mins. After cooling the solution was filtered and the filtrate was concentrated in vacuo, the residue was purified by column chromatography(C-18) to give N-(2-methoxypyrimidin-4-yl)-N-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine (yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([NH:10][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)c2ccccc2)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.92 grams (55 mmol) of methyl-2-methoxy-5-aminobenzoate was taken up in 250 ml methylene chloride, treated with 8.4 mL (61 mmol) triethylamine and cooled to 0° C. The reaction mixture was then treated with 8.1 grams (57 mmol) benzoyl chloride in a dropwise fashion. The reaction mixture was stirred for 30 minutes while warming to room temperature. The reaction mixture was diluted with 500 mL of methylene chloride, washed with 200 mL saturated bicarbonate solution and then rewashed with water and brine. The organic phase was dried and evaporated to a flaky white solid (15.7 grams). This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][N:8]1[CH2:29][CH2:28][C:11]2[N:12]([CH:19]([C:22]3C=CC=CC=3)[O:20]C)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[C:9]1=[O:30].[OH-:31].[Na+].[C:33]([OH:36])(=[O:35])[CH3:34]>C(O)C.[Pd]=O>[C:19]([OH:31])(=[O:20])/[CH:22]=[CH:34]\[C:33]([OH:36])=[O:35].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][N:8]1[CH2:29][CH2:28][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[C:9]1=[O:30]
Reactant: COC(c1ccccc1)n1c2c(c3ccccc31)C(=O)N(Cc1nc[nH]c1C)CC2
Reactant: [OH-]
Reactant: CC(=O)O
Agent: O=[Pd]
Agent: [Na+]
Solvent: CCO
Product: Cc1[nH]cnc1CN1CCc2[nH]c3ccccc3c2C1=O
Product: O=C(O)/C=C\C(=O)O
Reaction time: 8 h

Procedure:
A suspension of 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-5-[phenyl(methoxymethyl)]-1H-pyrido[4,3-b]indol-1-one (400 mg) in ethanol (20 ml) and glacial acetic acid (5 ml) was hydrogenated overnight at room temperature and atmospheric pressure over a pre-reduced 10% palladium oxide on carbon catalyst (50% aqueous paste; 100 mg). The reaction mixture was filtered and the residue was washed with ethanol (100 ml). The filtrate was concentrated in vacuo to give an oil, to which was added 2N sodium hydroxide (50 ml). The resulting suspension was extracted with dichloromethane (2×50 ml) and the combined, dried organic extracts were evaporated to give a solid. This was purified by FCC eluting with System A (75:8:1) to give the free base of the title compound as a solid (240 mg) which was then dissolved in dry methanol (50 ml). Maleate formation gave the title compound (261 mg), t.l.c. (System A, 75:8:1) Rf 0.2
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:24][CH2:23][CH2:22][O:21]2)[C@@:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([OH:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:21][CH2:22][CH2:23][O:24]2)[C@@:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
A solution of pyridine (70.3 g, 0.89 mol) and chromium trioxide (44.5 g, 0.445 mol) in methylene chloride (1.8 l) in a nitrogen atmosphere is stirred for 45 minutes. Celite (180 g) is added followed by (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane (25.8 g, 0.074 mol) in methylene chloride (100 ml). The mixture is stirred for 90 minutes at 23° C. The mixture is then filtered and the celite cake is washed with methylene chloride (10×200 ml). The filtrate and washings are combined and the solvents are removed under reduced pressure to give a dark oil, which is diluted with ether (750 ml) and filtered. The ether phase is dried (MgSO4) and the solvents are removed at reduced pressure. The crude product (21 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 6% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexane as a clear colorless oil (15.7 g, 61%): ir (neat) 1712 cm-1 (CO); nmr (CDCl3)δ1.106 (s, 3H, -CH3), 2.04 ##STR30## 2.30 (m, 2H, -CH2 -CO), 3.50 ##STR31## 3.98 (s, 4H, ketal), 4.55 (d of d, J=10 Hz, 2H, -O-CH2Ph), 7.20 (s, 5H, aromatic).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.[C:31]([C:33]1[CH:41]=[CH:40][C:36](C(Cl)=O)=[CH:35][CH:34]=1)#[N:32].C(N(CC)CC)C.C(OCC)(=O)C>Cl.O1CCOCC1>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:7])=[CH:35][CH:34]=1)#[N:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)CC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N[C@@H](COc2cccc(C#N)c2)CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.8 g (4.38 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-(3-cyanophenoxy)butyrate was dissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at 0° C. for 6 hours. The solvent was evaporated, and the oily residue was dissolved in 5 ml of dichloromethane. 1.09 g (6.58 mmol) of 4-cyanobenzoyl chloride and 1.22 ml (8.76 mmol) of triethylamine were added to the solution under cooling with ice, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11](/[CH:19]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(/C=C/c2ccccc2)=Nc2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a solution of 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one (3.0 g, 11.4 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (content 60%, 0.51 g, 12.8 mmol), and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added benzaldehyde (1.45 g, 13.7 mmol), which was stirred for further 30 minutes at the same temperature. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and dried, followed by concentration. The concentrate was crystallized from ethylacetate-hexane to give 1.9 g of the titled compound. Yield 75%. m.p. 150°-151° C.
Reaction SMILES: Br[C:2]1(Br)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>CC#N>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc2c(=O)c(N3CCC(O)(c4ccccc4)CC3)coc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
3,3-Dibromo-7-(triisopropylsilyloxy)-4-chromanone (5.0 g, 10.5 mmol) was dissolved in CH3CN (150 ml) and 4-hydroxy-4-phenylpiperidine (2.2 g, 12.5 mmol) and triethylamine (2.9 ml, 20.8 mmol) were added. The mixture was stirred overnight at ambient temperature, then concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with water (2×50 ml) and brine, dried over CaSO4, concentrated, and the residue chromatographed on silica gel, using gradient elution with ethyl acetate/hexane to yield title product as a white solid (2.3 g, 54%). A portion was recrystallized from ethanol/ether; mp 163°-163.5° C.; IR (KBr) 3437, 2950, 2870, 1635, 1615, 1600, 1447, 1285, 1247, 1200, 1185, 703, 690. Anal. Calcd. for C29H39NO4Si: C, 70.55; H, 7.96; N, 2.84. Found: C., 70.44; H, 7.76; N, 2.84.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[CH3:26])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:23]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:6]1.O.C(=O)([O-])O.[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>COC(C)(C)C>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[CH2:8][CH2:9][O:10][C@@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH2:27][Cl:26])[CH2:6]1
Reactant: O=C(Cl)CCl
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2S)-2-Aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (120 g) was dissolved in tert-butyl methyl ether (450 ml), water (450 ml) was added and the mixture was cooled on an ice bath. Sodium hydrogen carbonate (95.56 g) was gradually added and, after the addition, chloroacetyl chloride (29 ml) was added dropwise over about 10 min while maintaining the inside temperature at 15° C. or below. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hr. After 1.5 hr, sodium hydrogen carbonate (3 g) and chloroacetyl chloride (2.7 ml) were successively added to the reaction mixture at room temperature, and the mixture was further stirred for 1.5 hr. The reaction mixture was stood still and partitioned, and the organic layer was obtained as a solution of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}chloroacetamide in tert-butyl methyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:12][Mg]Br>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)Cc1ccc(Br)cc1
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 4-bromophenylacteone (6.85 g, 32 mmol) in diethyl-ether (100 ml) was cooled to 0° C. and treated with methylmagnesium bromide (23.5 ml of a 3M solution in diethyl-ether, 70 mmol). The reaction mixture was allowed to warm gradually to room temperature. After 2 hours the reaction was quenched by addition of saturated aqueous ammonium chloride (200 ml). The organic phase was separated and washed with saturated sodium chloride (100 ml), dried (sodium sulfate) and reduced in vacuo. Purification by flash column chromatography on silica gel eluting with pentane:dichloromethane (60:40 changing to 0:100, by volume) gave the title compound as a colourless oil (6.23 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:22]#[N:23].[ClH:24]>O1CCOCC1>[ClH:24].[NH2:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][CH:5]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)c(N)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NC2CCCNC2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (6.3 mmol) of tert-butyl 3-[(6-amino-5-cyanopyridin-2-yl)amino]piperidine-1-carboxylate (Example 37A) were dissolved in 40 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 2 h. After the reaction had gone to completion the solvent was concentrated to half of its original volume and 20 ml of diethyl ether were added. The precipitate was filtered off and dried. This gave 1.80 g (100% of theory) of the product as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:32][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[N:17]=[CH:16][N:15]=[C:14]3[C:19]=2[N:20]=[CH:21][N:13]3[C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=2[CH3:12])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:30])=[CH:23][CH:24]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(CO)cc3)ncnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(CBr)cc3)ncnc21
Temperature: 25 °C

Procedure:
To a mixture of N-cyclopropyl-3-[6-(4-hydroxymethyl-phenyl)-purin-9-yl]-4-methyl-benzamide (58 mg, 0.145 mmol, see example 4C-3 1) in dichloromethane (0.5 ml) was added carbon tetrabromide (58 mg, 0.175 mmol) then triphenylphosphine (47 mg, 0.179 mmol). The mixture was stirred at RT for an hour, then purified by a column eluting with EtOAc/Hex. (1:1) to give the desired product as a crude (88 mg, 0.19 mmol, 63%).
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)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>N1C=CC=CC=1>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:26]3[CH2:27][C@@H:28]([CH2:30][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH2:29]3)[C:9]=2[CH3:25])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCN(C)CC2)C1

Procedure:
The title compound is prepared in a one pot reaction in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 3.5 ml (31.2 mmol) 1-methyl piperazine. Analytical HPLC: tR=8.14 min (Grad 1); ES-MS: m/eo=497.3; NMR (DMSO-d6; not all data reported): 8.08/s (1H), 7.25-7.45/several m's (6H), 7.02/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.4-6.0/b (NH2); 5.13/s (2H); 4.77/m (1H); 2.22/s (3H); 2.12/s (3H).