Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][C@H:4]([O:8]/[CH:9]=[C:10]2\[C@H:11]3[CH2:18][CH:17]=[CH:16][C@H:12]3[NH:13][C:14]\2=[O:15])[CH:3]=1.[O:19]1CCOCC1>>[OH:19][C@H:18]1[C@H:11]2[C@H:12]([NH:13][C:14](=[O:15])/[C:10]/2=[CH:9]/[O:8][C@@H:4]2[CH:3]=[C:2]([CH3:1])[C:6](=[O:7])[O:5]2)[CH:16]=[CH:17]1
Reactant: C1COCCO1
Reactant: CC1=C[C@@H](O/C=C2/C(=O)N[C@@H]3C=CC[C@H]23)OC1=O
Product: CC1=C[C@@H](O/C=C2/C(=O)N[C@@H]3C=C[C@@H](O)[C@H]23)OC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of (3E,3aR,6aR)-3-[[(2S)-4-methyl-5-oxo-2H-furan-2-yl]oxymethylene]-1,3a,4,6a-tetrahydrocyclopenta[b]pyrrol-2-one Ia-1″ (125 mg, 0.50 mmol) in 1,4-dioxane (2.5 mL) was added SeO2 (67.1 mg, 0.60 mmol) The suspension was stirred at 100° C. for 4 h then the dark suspension was then allowed to cool to room temperature followed by filtration and concentration under reduced pressure. Purification using flash chromatography (CH2Cl2/MeOH, gradient) afforded the desired compound as a dark oil (58 mg, 44%); 1H NMR (400 MHz, MeOH-d4) 7.35 (1H, d), 7.16 (1H, m), 6.38 (1H, m), 5.95 (1H, dd), 5.91 (1H, m), 4.76 (1H, m), 4.72 (1H, m), 3.39 (1H, m), 1.97 (3H, m): LCMS (Method D): 0.24 min; ES+264 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[Zn][CH2:23][CH:24]([CH3:26])[CH3:25]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:23][CH:24]([CH3:26])[CH3:25])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC(C)C[Zn]Br
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Yield: 22.1 %

Procedure:
To methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D25) (1.5 g, 4.85 mmol) was added bromo(2-methylpropyl)zinc (48.5 ml, 24.25 mmol) in tetrahydrofuran (50 ml) under argon. To the solution was then added 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.355 g, 0.485 mmol) and the reaction heated to reflux for 6 h. The mixture was quenched with water (2 mL) and then filtered through celite, washing with ethyl acetate. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL) and the organic phase dried (phase separator) and the solvent removed in vacuo. The residue was purified by silica chromatography, eluting 0-15% EtOAc in iso-hexane over 40 min. Two batches were collected, one of which was the title compound as a colourless oil (233 mg, 1.072 mmol). δH (CDCl3, 400 MHz): 8.28 (1H, d), 8.15 (1H, dd), 7.38 (1H, d), 3.94, 3H, s), 2.78 (2H, d), 2.02 (1H, m), 0.96 (6H, d).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:21]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:23])[CH3:22]
Reactant: OCCn1ccc2cc(OCc3ccccc3)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCn1ccc2cc(OCc3ccccc3)ccc21

Procedure:
Crude N-(2-hydroxyethyl)-5-benzyloxyindole (11.09 g, 42.1 mmol), acetic anhydride (4.36 mL, 46.3 mmol), triethylamine (6.50 mL,46.3 mmol), and DMAP (100 mg) were stirred together in THF for 1 hour before standard aqueous workup provided N-(2-acetoxyethyl)-5-benzyloxyindole in yield as a clear oil (13.0 g, 99%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8.1 Hz, 2H), 7.42 (t, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.01 (dd, J=2.4, 8.1 HZ, 1H), 6.47 (dd, J=0.8, 3.1 Hz, 1H), 5.14 (s, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31 (t, J=5.0 Hz, 2H), 2.02 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 170.6, 153.3, 137.7, 131.6, 128.9, 128.5 (2 C's), 128.4, 127.7, 127.5 (2 C's), 112.8, 109.8, 104.,3 101.4, 70.9, 63.0, 45.0, 20.7. MS (EI, m/z) M+=309.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].C(O)(=O)C.[F:16][C:17]([F:25])([F:24])[C:18](=O)[CH2:19][C:20](=O)[CH3:21]>COCCO>[CH3:21][C:20]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[OH:3])[N:11]=[C:18]([C:17]([F:25])([F:24])[F:16])[CH:19]=1
Reactant: COc1ccccc1NN
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1-c1ccccc1O

Procedure:
300 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 1.3 ml of 2-methoxyethanol, and 2.5 ml of acetic acid and 208 μl of 1,1,1-trifluoro-2,4-pentanedione were added and heated at reflux for 1 hour and 40 minutes. The solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate was added, and the organic layer was washed with 50 ml of a saturated sodium bicarbonate solution and 50 ml of saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to yield 485.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1.C[Si](C)(C)[O:34][C:35]1[CH2:38][CH2:37][C:36]=1O[Si](C)(C)C>CO>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:36]3[CH2:37][CH2:38][C:35]3=[O:34])[CH2:12][CH2:13]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:25][CH2:26]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Solvent: CO
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CCC3=O)CC2)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To the stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208) (20 mg, 0.046 mmol) in TIIF (1 ml) was added drop wise a solution of 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (12.75 mg, 0.055 mmol) in MeOH (0.4 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 5 days (converted to clear solution). Solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 18 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[N:20](CC3C=CC=CC=3)[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[CH:23]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[NH:21][N:20]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)nn2Cc2ccccc2)cc1OC
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Yield: 95.8 %

Procedure:
2 g of 3-{3-[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-N-methylamino]-propyloxy}-5-(3,4-dimethoxyphenyl)-2-benzylpyrazole prepared according to Example 13 were dissolved in 10 ml of methanol and added to 2 g of palladium black under nitrogen. 5.5 ml of 98% strength formic acid were added to the solution, which was stirred under nitrogen. After the mixture had been stirred for 3 hours under nitrogen the catalyst was filtered out, and the filtrate was concentrated by evaporation. The oily residue was taken up in saturated sodium carbonate solution and extracted repeatedly with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated by evaporation. 1.6 g of 3-{3-[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-N-methylamino]-propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained as an oily base. This base was converted analogously to Example 1 E) into the hydrochloride having a melting point of 189° to 192° C.
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([C:36](=[O:44])[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([C:36](=[O:44])[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CCN(CC)CCC(=O)N(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NOC(C)OCC(C)C)cn3)CC21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)CCC(=O)N(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NO)cn3)CC21
Yield: 56.7 %

Procedure:
N-(1-Isobutoxyethoxy) 2-{6-[(3-diethylaminopropionyl)naphthalen-2-ylmethyl-amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide (199 mg, 0.33 mmol) was dissolved in DCM (3 ml) and treated with a solution of 4M HCl in dioxane (0.5 ml, 2 mmol). The resulting precipitate was filtered and dried to give the title compound as a white solid (94 mg, 57%). LCMS purity 98%, m/z 475 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 1.39 (6H, t, J=7.2 Hz), 2.26 (2H, br s), 2.77 (1H, s), 3.37 (4H, m), 3.55 (2H, d, J=10.5 Hz), 3.81 (4H, br s), 3.93 (2H, d, J=10.5 Hz), 4.71 (2H, br s), 7.61 (2H, m), 7.76 (1H, d, J=8.4 Hz), 7.95-8.04 (3H, m), 8.20 (1H, s), 8.71 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc2c(Cl)nc(Cl)nc2s1
Solvent: CO
Product: Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 5,7-dichloro-2-methyl-thiazolo[5,4-d]pyrimidine (4.1 g, 18.72 mmol) in MeOH (100 mL) was added morpholine (3.26 mL, 37.44 mmol) at 0° C. and the mixture stirred at 0° C. for 30 minutes. The resultant precipitate was collected by filtration and dried in vacuo at 40° C. to give the title compound as a cream solid (4.42 g, 89%).
Reaction SMILES: [C:1]([S:4][C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[CH2:11][S:12][C:13](=[O:15])[CH3:14])(=O)[CH3:2].C[O-].[Na+].ICC[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CO>[C:13]([S:12][CH2:11][C:6]1[N:7]=[C:8]([CH3:10])[S:9][C:5]=1[S:4][CH2:1][CH2:2][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:15])[CH3:14]
Reactant: CC(=O)SCc1nc(C)sc1SC(C)=O
Reactant: O=S(=O)(CCI)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)SCc1nc(C)sc1SCCS(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of 5-acetylthio-4-acetylthiomethyl-2-methyl-1,3-thiazole (600 mg, 2.3 mmol) in methanol (10 mL) was dropwise added 0.5 M sodium methoxide in methanol (4.6 mL) at 0° C. and stirred at the same temperature for 30 min. 2-Iodoethyl phenylsulfone (620 mg, 2.1 mmol) was added and stirred for an additional 30 min. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the residue was chromatographed (silica gel, dichloromethane), affording 800 mg of the title compound. 1H NMR (CDCl3) δ 2.30 (s, 3H), 2.64 (s, 3H), 3.00 (t, 2H), 3.30 (t, 2H), 4.23 (s, 2H), 7.58 (2H), 7.69 (1H), 7.89 (2H).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[OH:27].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOCC>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH:5]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[O:27][C@@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([O:24][CH3:23])=[O:32])=[CH:18][CH:17]=1
Reactant: N=C(OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](O)CC(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](CC(C)C)OC(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the (4-bromophenyl)(4-fluorophenyl)methyl 2,2,2-trichloroethanimidoate of step 2 (1.18 mmol, 500 mg) in CH2Cl2 (5 mL) was added L-leucic acid methyl ester 2 (1.18 mmol, 146 mg) and then camphor sulfonic acid (0.12 mmol, 27 mg). The mixture was stirred at r.t. for 18 h. A few drops of saturated NaHCO3 was added, The mixture was diluted with ether and filtered. The filtrate was concentrated under reduced pressure and the crude product was chromatographed to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1>C(O)C.C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Reaction time: 18 h
Yield: 109.3 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-nitroindole (0.550 g, 1.39 mmol) in a mixture of ethanol (120 mL) and THF (40 mL) was added 10% palladium-on-charcoal (0.30 g) and the mixture was hydrogenated on a Parr shaker at 40 psi for 18 h. The mixture was then filtered through Celite and the catalyst was washed with additional ethanol-THF. Evaporation of the filtrate gave the essentially pure title compound (0.557 g, 100%) as a brown foam. A sample of this material (0.143 g) was treated with excess methanolic HCl and the resulting solution was diluted with acetone to give a precipitate. The precipitate was filtered and then crystallized from ethanol to give 0.100 g of a purplish solid, mp 192° C. (dec): IR (KBr) 3410, 3200, 1630, 1540 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.22(br s, 1H), 10.20 (br s, 2H), 8.60 (m, 1H), 8.20 (s, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.6, 1.9 Hz, 1H), 4.89-4.82 (m, 2H), 3.91 (s, 3H), 3.8-3.0 (br m, 8H), 2.76 (m, 2H). Anal Calcd. for C20H26N6O. 4 HCl. H2O: C, 45.29; H, 6.08; N, 15.85. Found: C. 45.32; H, 5.97; N, 15.59.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.[C:26](O)(=[O:28])C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:26]=[O:28])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Yield: 60 %

Procedure:
It has now been found that reaction of 2,4-di-tert-butylphenol with hexamethylenetetramine in glacial acetic acid followed by quenching with water or aqueous acid, extraction with a water insoluble non-polar solvent and filtration through silica gel provides 3,5-di-tert-butylsalicylaldehyde in more than 60% yield and of a purity suitable for the production of chiral Mn-Salen catalysts. Alternatively, reaction of 2,4-di-tert-butylphenol with HMT in glacial acetic acid followed by quenching with an aqueous acid, separating the aqueous phase from the organic phase and recrystallizing the organic phase in methanol provides 3,5-di-tert-butylsalicylaldehyde in more than 40% isolated yield and a purity suitable (>95%) for the production of the catalyst.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1

Procedure:
2,4-Dichloro-5-fluoropyrimidine (800 mg, 4.8 mmoL), tert-butyl (3-aminophenyl)carbamate (996 mg, 4.8 mmoL) and Hunig's base (948 uL, 5.75 mmoL) were dissolved in THF (20 mL). The reaction mixture was heated at reflux overnight. After cooling, partitioned between water/brine (10 mL), agitated and separated the layers. Dried organic phase over sodium sulfate, and the solvent was removed via rotary evaporation. Titration with EtOAc and Heptane gave after filtration a white solid, 1 g. LC/MS (RT=2.03/(M+1)) 339.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([B:10]2[O:14]C(C)(C)C(C)(C)[O:11]2)[CH:7]=[C:6]([F:19])[C:3]=1[C:4]#[N:5]>CC(C)=O.O>[C:4]([C:3]1[C:2]([F:1])=[CH:9][C:8]([B:10]([OH:14])[OH:11])=[CH:7][C:6]=1[F:19])#[N:5]
Reactant: CC1(C)OB(c2cc(F)c(C#N)c(F)c2)OC1(C)C
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c(F)cc(B(O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (55 g) was dissolved in acetone (1 L) and water (1 L). T this stirred mixture was added NaIO4 (160 g) and NH4OAc (50 g). The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was evaporated under vacuum at 40° C. until most of acetone was removed. The residue was cooled to 0° C. and 2N NaOH (1 L) solution was added with stirring over 30 minutes. The mixture was filtered, and the filtrate was washed with CH2Cl2 (1 L). To the aqueous layer was added 5N hydrochloric acid at 0° C. until pH=2. The resulting solid was filtered and then dissolved in EtOAc (1.5 L), dried over Na2SO4, filtered and evaporated under vacuum to provide 30 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[C:8]([CH2:11][N:12]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:13]1)([OH:10])=[O:9].[OH-].[K+]>O1CCOCC1.O>[OH:5][CH:3]([C:2]([F:7])([F:6])[F:1])[CH2:4][N:21]1[CH2:22][CH2:23][N:12]([CH2:11][C:8]([OH:10])=[O:9])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:20]1
Reactant: FC(F)(F)C1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(F)(F)F)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
12.94 g (115.44 mmol) of (1,1,1-trifluoro-2,3-epoxypropane) and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. with exclusion of pressure. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.81 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][C:22]2[S:23][CH:24]=[N:25][N:26]=2)=[O:20])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[S:23]1[CH:24]=[N:25][N:26]=[C:22]1[NH:21][C:19]([C:18]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:4][CH:3]=2)[C:15]([CH3:14])=[CH:28][CH:27]=1)=[O:20]
Reactant: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(C(=O)Nc4nncs4)ccc3C)cc2)n1

Procedure:
Example 27 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and 4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-([1,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23) using DMF as the solvent.
Reaction SMILES: [C:1]1([CH:11](O)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[C:1]1([CH:11]([Cl:16])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccc2ccccc12
Solvent: Cc1ccccc1
Product: CC(Cl)c1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthalyl)ethanol (6.34 g, 38.8 mmol) and thionyl chloride (5.37 ml, 73.6 mmol) in 65 ml of toluene was refluxed for 4 hours. The reaction mixture was evaporated to give the residue as an oil. The residue was dissolved in 150 ml of ethyl acetate, washed successively with 50 ml of water, 50 ml of saturated sodium bicarbonate and 50 ml of brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 3(6.83 g, 97%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12].[H][H].C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12]
Reactant: [H][H]
Reactant: CC(O)c1cc([N+](=O)[O-])ccc1N
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1cc(N)ccc1N
Yield: 100 %

Procedure:
Catalytic hydrogenation of 6 (27.0 g, 150 mmole) under 60 psi hydrogen pressure with 10% Pd/C (2.7 g) in anhydrous MeOH (150 mL)/ethyl acetate (150 mL) was completed in 2.5 h. The catalyst was removed by filtration over Celite. The filtrate was evaporated under vacuum to afford 1-(2,5-diamino-phenyl)-ethanol 1 (22.83 g, 100 % yield). Mp 124° C.; 1HNMR (400 MHz, DMSO-d6) δ1.26 (d, 3H, J=6.4 Hz), 4.15 (d, 4H, J=10.7 Hz), 4.61-4.65 (m, 1H), 4.94 (d, 1H, J=3.6 Hz), 6.24 (dd, 1H, J=2.5, 8.2 Hz), 6.36 (d, 1H, J=8.2 Hz), 6.45 (d, 1H, J=2.5 Hz); MS m/z 152 (M+); Anal. Calcd. for C8H12N2O: C, 63.13. H, 7.95. N, 18.41.O, 10.51. Found: C, 62.83. H, 7.90. N, 18.46. O, 10.17.