Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3([C:23]4[N:27]5[CH:28]=[C:29]([C:32]6[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=6)[CH:30]=[N:31][C:26]5=[N:25][CH:24]=4)[CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl.[NH2:42][C@@H:43]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:44]([O:46]C(C)(C)C)=[O:45].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[ClH:8].[ClH:8].[CH3:54][C:51]([CH3:52])([CH3:53])[C@H:43]([NH:42][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:32]([C:29]2[CH:30]=[N:31][C:26]3[N:27]([C:23]([C:20]4([C:16]5[CH:15]=[C:14]6[C:19](=[CH:18][CH:17]=5)[N:10]=[CH:11][CH:12]=[CH:13]6)[CH2:22][CH2:21]4)=[CH:24][N:25]=3)[CH:28]=2)=[CH:33][CH:34]=1)[C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (230 μL) was added to a mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid dihydrochloride (162 mg, 0.339 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (75.8 mg, 0.339 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (165 mg, 0.373 mmol) in methylene chloride (10 mL). The mixture was stirred at RT for 3 h, washed with NaHCO3 (7.5%) and brine, dried over Na2SO4, filtered, and concentrated. The residue [LCMS: (M+H)=576.2] was treated with HCl in 1,4-dioxane (4M, 1.0 mL) at RT for 3 h. The solvent was evaporated. The residue was washed with ether and dried to give the desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=O.O.NN>C(O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:18]3[C:22]([CH3:23])=[N:21][N:20]=[C:19]3[CH2:24][N:25]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]=2[CH:17]=1
Reactant: CSc1ccc(-n2c(C)nnc2CN2C(=O)c3ccccc3C2=O)c(C(=O)c2ccccc2Cl)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CSc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C)n1-2

Procedure:
In the manner given in Example 5, 5-methylthio-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 8-methylthio-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(O)=O.[CH:4]([NH2:6])=[O:5].[C:7]1([CH2:13][C:14](=O)[CH2:15][CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:13]([CH:14]([NH:6][CH:4]=[O:5])[CH2:15][CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC=O
Reactant: CCC(=O)Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: CCC(Cc1ccccc1)NC=O
Temperature: 167.5 °C
Yield: 80 %

Procedure:
To a stirred solution of formic acid (250 ml) and formamide (500 ml) was added 1-phenyl-2-butanone (25 g, 0.168 mols); the reaction was then heated to 165-170° C. for four hours. The reaction was then cooled and poured into water (1 l). The aqueous phase was then extracted with ethyl acetate (3×300 ml). The organic phase was washed with saturated sodium bicarbonate (2×200 ml) and dried over magnesium sulfate. Evaporation of the solvent yielded an oil (24.1 g, 80%).
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1F>CN(C=O)C>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:30]2[CH:29]=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][C:25]=2[F:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Temperature: 0 °C
Yield: 83.7 %

Procedure:
Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (5.0 g, 17.5 mmol) [prepared as in Example 1, Step (a)], was dissolved in DMF (50 ml) and the solution was cooled in an ice bath to 0 ° C. under an argon atmosphere. Sodium hydride, 50% /mineral oil, (1.3 g, 27.1 mmol) was added, and after 5 min 3,4-difluoronitrobenzene (3.36 g, 21.1 mmol) was added to the reaction mixture. After 1 h the reaction mixture was poured into 10% HCl/ice and the product was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and evaporated to dryness. Purification on a Florisil® column (hexane-ethyl acetate, 9:1) gave ethyl 2-(5-benzoyl-1,4-di-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (6.22 g, 84%) as a solid. ##STR20##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)CC2C=CC(OC)=CC=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N:36]2[CH2:39][CH:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:37]2)[C:34]=1[F:35])[C:30]#[N:31].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:30]([C:29]1[CH:32]=[C:33]([N:36]2[CH2:37][CH:38]([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)[CH2:39]2)[C:34]([F:35])=[C:27]([NH:26][C:2]2[N:7]=[C:6]([NH:8][CH:18]3[CH2:19][CH2:20]3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)[CH:28]=1)#[N:31]
Reactant: CN1CCN(C2CN(c3cc(C#N)cc(N)c3F)C2)CC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CN1CCN(C2CN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3F)C2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(60 mg, 0.169 mmol), 3-amino-4-fluoro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile (48 mg, 0.166 mmol), DPPF (6.44 mg, 0.012 mmol), Cs2CO3 (92 mg, 0.282 mmol), Xantphos (9.60 mg, 0.017 mmol), Palladium(II)Acetate (11.17 mg, 0.050 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture was cooled to 25° C., diluted with EtOAc, washed with brine and dried (Na2SO4). The solvents were removed and DCE (1 mL)/TFA (0.5 mL) was added. The reaction stirred 3 h and solvents were removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 50-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((5-cyano-2-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (16.9 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[C:15]([F:16])([F:17])[F:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1
Yield: 77 %

Procedure:
A mixture of 395 mg (1.50 mmol) of ethyl 3-nitro-4-(trifluoromethyl)benzoate (from Step C), 20 mg of platinum oxide, and 6 mL of ethanol was shaken with hydrogen at 3-4 atm. for a few hours, by which time the reaction was essentially complete. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel (elution with 25:1 hexane-EtOAc) to afford a 77% yield of the title compound as a pale yellow, gummy foam; TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 233 (M+). 200 MHz 1H NMR (CD3OD) δ1.36 (t, J=7.1 Hz, 3H), 4.33 (q, J=7.1 Hz, 2H), 7.26 (d, J=8 Hz, 1H), 7.44 (d, J=8 Hz, 1H) overlapping 7.47 (s, 1H).
Reaction SMILES: [OH-].[K+].C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]3[C:25]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[N:24][C:23]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])=[N:22][C:21]=3[N:40]=2)[CH:14]=[CH:13][C:12]=1[O:41][CH3:42])(=O)C(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>C1COCC1.CO>[CH3:39][C@H:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:23]1[N:24]=[C:25]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH3:32])[C:20]2[CH:19]=[CH:18][C:17]([C:15]3[CH:14]=[CH:13][C:12]([O:41][CH3:42])=[C:11]([CH2:10][OH:9])[CH:16]=3)=[N:40][C:21]=2[N:22]=1
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COC(=O)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Potassium hydroxide solution (1.7 mL, 3.10 mmol) was added to a solution of 5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxybenzyl pivalate (172 mg, 0.30 mmol) in THF (6.9 mL) and methanol (1.7 mL) at RT under an atmosphere of nitrogen. After 240 minutes, HPLC analysis showed complete disappearance of the starting material. The reaction was maintained at RT overnight (for convenience) and aqueous citric acid (20% w/v, 2 mL) was added followed by methylene chloride (15 mL). The upper aqueous layer was extracted with two further extractions of methylene chloride (2×15 mL) and the organic layers combined. Evaporation of the methylene chloride afforded (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (6) as a yellow solid (133 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][O:8][C:9]2[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=[C:11]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](B5OC(C)(C)C(C)(C)O5)[CH:26]=4)[N:21]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:20]=3)[CH:10]=2)=[CH:5][CH:4]=1.Br[C:47]1[CH:52]=[N:51][CH:50]=[C:49]([CH:53]2[CH2:55][CH2:54]2)[N:48]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[CH:53]1([C:49]2[N:48]=[C:47]([C:25]3[CH:26]=[C:27]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH:20]=[C:19]4[C:11]3[CH:10]=[C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=4)[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=3)[CH:52]=[N:51][CH:50]=2)[CH2:55][CH2:54]1
Reactant: COc1ccc(COc2cc(-c3cn(C(=O)OC(C)(C)C)c4ccc(B5OC(C)(C)C(C)(C)O5)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: Brc1cncc(C2CC2)n1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(COc2cc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5cncc(C6CC6)n5)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 28.4 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (150 mg, 0.236 mmol) and 2-bromo-6-cyclopropylpyrazine (70.5 mg, 0.354 mmol, CombiPhos) in p-dioxane/H2O (4:1, 2.0 mL) followed by potassium phosphate (100 mg, 0.472 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (8.36 mg, 0.012 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 20 min. The mixture was diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-60% EtOAc in hexanes) to give tert-butyl 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole-1-carboxylate (42 mg, 0.067 mmol, 28.3% yield) as a solid: MS (ESI, pos. ion) m/z: 628.0 (M+1), and 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole (28 mg, 0.053 mmol, 22.49% yield) as a solid. MS (ESI, pos. ion) m/z: 528.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:39](O)=[O:40])=[CH:25][C:24]=3[CH:42]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)[CH2:28][CH2:27][C:26]([C:39]([NH:29][C:23]4[CH:24]=[CH:42][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:40])=[CH:25][C:24]=3[CH:42]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (140 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (100 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (74 mg) and triethylamine (344 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(4-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 56) (89 mg) as yellow crystals.
Reaction SMILES: C1(O[C:8](=O)[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33]CN[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([N:9]2[CH2:8][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)[CH2:29][CH2:30]2)[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Oc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1N1CCN(c2cccc(O)c2)CC1
Yield: 78 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#CCO)CCOCC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(/C=C/CO)CCOCC1
Temperature: 0 °C
Yield: 48 %

Procedure:
A solution of 4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran (10.8 g, 44.9 mmol), prepared as in step 3, in dry THF (100 mL) was cooled to -75° C., and RED-AL (sodium bis(2-methoxyethoxy)aluminum hydride, Aldrich Chemical Co., 20 mL of 3.4M solution in toluene, 68 mmol) was added under a dry argon atmosphere. The cooling bath was removed and the reaction was warmed to 0° C. and quenched by addition of crushed ice and saturated aqueous NH4Cl. The resulting two-phase mixture was extracted with ethyl acetate (4×90 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100 g, 10% ethyl acetate: hexanes) provided 4-methoxy-4-(3-hydroxy -trans-prop-1-enyl)tetrahydropyran(3.71 g, 34 %) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:12]2[CH2:13][CH2:14][CH:9]([C:2]([OH:15])([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][CH2:11]2)=[CH:21][CH:22]=1
Reactant: CC(O)(c1ccccc1)C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: CC(O)(c1ccccc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
The mixture of 2 g of α-methyl-α-(4-piperidyl)-benzyl alcohol, 1.95 g of 4'-fluoro-4-chlorobutyrophenone, 2 g of sodium carbonate (anhydrous), a crystal of sodium iodide and 150 ml of 4-methyl-2-pentanoneare stirred and refluxed for 72 hours. The reaction mixture is filtered to remove the inorganic salts and the filtrate evaporated under reduced pressure. Diethyl ether is added to the residue and the resulting solutionextracted with 5% aqueous hydrochloric acid. The aqueous solution is made basic with ammonia and extracted with diethyl ether. The extract is then dried and evaporated under reduced pressure to afford the 4'-fluoro-4-[4-(α-hydroxy-α-methylbenzyl)-piperidino]-butyrophenone of the formula ##SPC5##
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[C:12]([SiH2:16][O:17][C:18]([CH3:33])([CH3:32])[C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[C:19]([C:18]([CH3:33])([CH3:32])[O:17][SiH2:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:20]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)ccc1N1CCOCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Nc2ncc(Br)n3ncnc23)ccc1N1CCOCC1
Yield: 45.7 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.391 g, 1.41 mmol), 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-morpholin-4-yl-phenylamine (0.5 g, 1.55 mmol) and N-ethyldiisopropyl-amine (0.27 mL, 1.55 mmol) is heated at 90° C. in 2-propanol (10 mL) for 8 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and water. The aqueous phase is extracted twice with dichloromethane. The organic layers are combined, washed with brine, dried over MgSO4, filtrated and concentrated in vacuo to afford the title compound (335 mg, 46%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][C:33]([Cl:37])=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][C:33]([Cl:37])=[N:34][C:35]([O:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(Cl)nc32)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)nc(Cl)nc32)CC1
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
A solution of 4-(methylsulfonyl)phenol (available from Matrix Scientific, Columbia, S.C., USA; 52 mg, 0.3 mmol) in tetrahydrofuran (3 mL) was cooled to 0° C. under argon. Sodium hydride (60% dispersion; 13.2 mg, 0.33 mmol) was added and the mixture was stirred for 10 min. 4-(4,6-Dichloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 24; 100 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 4 h and then poured into saturated aqueous ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered, evaporated and purified by column chromatography, eluting with 25-50% ethyl acetate/hexanes to give 4-[6-chloro-4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (91 mg, 66%) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17]>C1(C)C=CC=CC=1>[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:22]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])=[O:23])([O-:18])=[O:17]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C1CCCCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CCCCCN1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
All glassware is dried thoroughly, and the reaction is kept under an inert atmosphere (argon) at all times. With stirring, 2.33 g (20.6 mmol) of caprolactam (Aldrich) and 2.30 g (22.7 mmol) of triethylamine (Aldrich, d=0.726 g/mol) are added to 100 mL toluene (Aldrich) in a 3-neck round bottom flask equipped with a reflux condenser, addition funnel, and mechanical stirrer, to give a clear, pale yellow solution. Addition of a solution of 4.75 g (20.6 mmol) of 3,5-dinitrobenzoyl chloride (Aldrich) in 100 mL toluene proceeds dropwise over a period of 30 min. The resulting reaction mixture is heated to reflux and stirred for 16 h. Upon cooling to room temperature, the reaction is filtered to remove the triethylamine hydrochloride, and poured into a separatory funnel. After dilution with 300 mL of chloroform, the organic solution is extracted with 5% aq HCl, 5% aq NaOH, and finally D.I. water. The organic layer is dried over Na2SO4, filtered, and the solvent removed by evaporation under reduced pressure. Recrystallization of the crude product from toluene followed by drying under vacuum yields N-(3,5-dinitrobenzoyl)caprolactam as a light yellow, crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)CC1C=CC=CC=1>[Pd].C(O)C>[CH3:1][NH:2][CH:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1
Reactant: CN(Cc1ccccc1)C1CN2CCC1CC2
Agent: [Pd]
Solvent: CCO
Product: CNC1CN2CCC1CC2
Temperature: 80 °C
Yield: 43 %

Procedure:
A mixture of 33.3 g of 3-(N-methyl N-benzylamino)quinuclidine and 16 g of palladium on charcoal at 10% (50% humidity) in 500 ml of ethanol is heated in an autoclave at 80° C. for 6 hours 30 minutes and under a hydrogen pressure of 6 bars. Then it is filtered, the solvent is evaporated (under a good vacuum and when cold) and the residue is distilled (Boiling point [24 mm/Hg]=110° C.). Thus the expected product is obtained with a yield of 43%.