Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH2:5]([CH2:7][NH2:8])[OH:6].C([O:11][C:12]([C:14]1[N:15]=[N:16][C:17]([NH:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:18][CH:19]=1)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[OH:6][CH2:5][CH2:7][NH:8][C:12]([C:14]1[N:15]=[N:16][C:17]([NH:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:18][CH:19]=1)=[O:11]
Reactant: NCCO
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NCCO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 500 μL, 1.0 mmol) was added dropwise (exothermic) to a solution of ethanolamine (61 mg, 60 μL, 1.0 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) in dioxane (3 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 h and then cooled to room temperature and then poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (19 mg, 20%) which was obtained as a light yellow foam. MS: m/e=372.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>CO>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
Isonipecotic acid (10 grams) (77.5 mmoles) and acetic anhydride (23.7 grams) (232.5 mmoles) were dissolved in MeOH (100 ml.) and the mixture was stirred at 25° C. for 24 hours. The mixture was evaporated to dryness and the residue was azeotroped with toluene to give the title compound (Yield: 12.8 grams, 97%, MH+ 172).
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1](=[N:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=C(Cl)CCC1
Reactant: Oc1cccc(N=C(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C=C(Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CCC1

Procedure:
A suspension of the 3-(benzhydrylidene-amino)-phenol (10.47 g, 38.3 mmol), 3-chloro-cyclohex-2-enone (5.00 g, 38.3 mmol) and potassium carbonate (5.82, 42.1 mmol) in 150 mL of acetone was heated at reflux overtight. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1). In this manner, 3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone was obtained as a yellow solid, (8.82 g, 63%): 1H NMR (CDCl3) δ 7.78 (d, 2H, J=7.0 Hz), 7.50 (d, 1H, J=7.1 Hz), 7.45 (d, 2H, J=7.7 Hz), 7.34-7.10 (m, 6H), 6.69 d, 1H, J=8.0 Hz), 6.61 (d, 1H, J=8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H), 2.55 (t, 2H, J=6.2 Hz), 2.34 (t, 2H, J=6.2 Hz), 2.06 (m, 2H). Anal. Calc. for C25H21NO2 O.0.2H2O: C, 80.92; H, 5.81; N, 3.78. Found: C, 81.12; H, 5.81; N, 3.72.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37]Br>O>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37][N:5]1[CH:6]=[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C:2](=[O:1])[C:3]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:13][C:4]1=2
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1c(-c2ccccc2)sc2ncc(C(=O)C(C)C)c(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
The compound obtained in Example 14 (35 g), potassium carbonate (18.6 g) and N,N-dimethylformamide (280 ml) were mixed, and 2,6-difluorobenzyl bromide (27.9 g) was added, and the mixture was stirred at room temperature for 4 hours. Water (560 ml) was added dropwise to the reaction mixture, and the mixture was stirred for 30 minutes,-cooled on ice, and then stirred further for 1 hour. The crude crystal was recovered by a filtration, washed with water, dried in air, and then suspended in a 1:1 solvent mixture (250 ml) of ethyl acetate and diisopropylether, and the suspension was stirred at 25 to 40° C. for 1 hour, and then stirred with cooling on ice for 1 hour, and the crystal precipitated out was recovered by a filtration and washed with the solvent mixture described above (125 ml) to obtain the title compound (44.6 g, 91.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=O)[C:9](=[O:22])[N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][C:4]=1[C:24]([O:26][CH3:27])=[O:25].O=P(Cl)(Cl)[Cl:30].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:8]1[C:9](=[O:22])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6]([N:7]=1)=[CH:5][C:4]([C:24]([O:26][CH3:27])=[O:25])=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Temperature: 110 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of methyl 7-methoxy-1-[(4-methoxyphenyl)methyl]-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (24 g, 64.80 mmol) in toluene (300 mL) was added POCl3 (14.8 g, 96.52 mmol) and N,N-dimethylaniline (15.7 g, 129.75 mmol). The resulting solution was stirred overnight at 110° C. and concentrated in vacuo. The product was precipitated by the addition of methanol (150 mL) and collected by filtration to afford methyl 3-chloro-7-methoxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a green solid (17 g, 65%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([C:40]([O:42]C)=[O:41])=[N:38][CH:39]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2, starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Example 1) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (Frontier Cat. No. M2012). LCMS (M+H)+: m/z=446.3.
Reaction SMILES: C([O:8]C(N1CC[C@@H](O[N+]2([O-])C3C(=CC=CC=3)C=CC2)[C@H](F)C1)=O)C1C=CC=CC=1.[F:30][C@H:31]1[C@H:36]([O:37][C:38]2[CH:39]=[CH:40][CH:41]=[C:42]3[C:47]=2[N:46]=[CH:45][CH:44]=[CH:43]3)[CH2:35][CH2:34][N:33]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[CH2:32]1.C1C=C(Cl)C=C(C(OO)=O)C=1.CC1C=C(Cl)C=CC=1OCCCC(O)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-]>C(Cl)(Cl)Cl.CO>[CH2:51]([O:50][C:48]([N:33]1[CH2:34][CH2:35][C@@H:36]([O:37][C:38]2[CH:39]=[CH:40][CH:41]=[C:42]3[C:47]=2[N+:46]([O-:8])=[CH:45][CH:44]=[CH:43]3)[C@H:31]([F:30])[CH2:32]1)=[O:49])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3cccnc23)[C@H](F)C1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O[N+]2([O-])CC=Cc3ccccc32)[C@H](F)C1
Agent: Cc1cc(Cl)ccc1OCCCC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc[n+]([O-])c23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
Preparation of 8-((trans)-1-(benzyloxycarbonyl-3-fluoropiperidin-4-yloxy)quinoline 1-oxide: To a 0° C. solution of (trans)-benzyl 3-fluoro-4-(quinolin-8-yloxy)piperidine-1-carboxylate (1.0 g, 2.63 mmol) in 20 mL CHCl3 and 2 mL MeOH was added 77% max. mCPBA in 4×250 mg portions. The reaction mixture was stirred 20 minutes, then another 2×250 mg portions of 77% max. mCPBA was added (total 77% max. mCPBA (1.51 g, 6.57 mmol)). The reaction mixture was stirred 10 minutes, warmed to ambient temperature, and stirred another 3 hours, after which it was cooled to 0° C. Another 2 equivalents of 77% max. mCPB A was added in 4 equal portions, and the reaction mixture was warmed to ambient temperature and stirred an additional 1.5 hours. The reaction mixture was cooled to 0° C., and saturated Na2S2O3 was added, followed by saturated NaHCO3. The mixture was stirred 10 minutes, then warmed to ambient temperature and stirred another 30 minutes. Solid NaCl was added, and the mixture was extracted with CHCl3. The combined extracts were dried (Na2SO4), filtered, concentrated, and dried in vacuo to give 8-((trans)-1-(benzyloxycarbonyl)-3-fluoropiperidin-4-yloxy)quinoline 1-oxide (1.0 g, 2.52 mmol, 96.0% yield), which was used without further purification in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(O)cc1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCc2ccc(-c3cc(C(N)=O)on3)cc2)cc1
Temperature: 85 °C
Yield: 34.6 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 4-methoxyphenol (24 mg, 0.22 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 85° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(4-methoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (12 mg, 35%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.90 (d, J=8.4 Hz, 2H), 7.52-7.64 (m, 3H), 6.90-7.00 (m, 1H), 6.81-6.89 (m, 1H), 5.11 (s, 1H), 3.26-3.34 (m, 3H).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:42]=[CH:43][CH:44]=1.C(N(CC)CC)C>C(#N)C.CO>[N:1]1([CH2:10][C:11]([NH:38][C:39]2[CH:40]=[C:41]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:42]=[CH:43][CH:44]=2)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cn1cnc2ccccc21
Reactant: Nc1cccc(-c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Cn1cnc2ccccc21)Nc1cccc(-c2ccccc2)c1
Yield: 19.4 %

Procedure:
(1H-Benzimidazol-1-yl)acetic acid (triethylamine salt) (315 mg, 1.1 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflurophosphate (520 mg, 1.4 mmol), 3-amino biphenyl (290 mg, 1.6 mmol) and triethylamine (0.6 mL, 4.4 mmol) in acetonitrile (10 mL) was stirred at room temperature for 24 h. Methanol (10 mL) was then added and evaporated to dryness in vacuo. The crude mixture was then passed through a silica gel column eluting with ethyl acetate:methanol (1% up to 3% methanol). The product was collected and dried, dissolved in methanol and 1 M hydrogen chloride in diethyl ether (0.5 mL) added and product crystallised, filtered and dried to give the title compound as a white solid (70 mg, 17%). 1H NMR (400 MHz, CD3OD+1 drop of DMSO-d6) δ ppm 5.55 (2H, s), 7.32-7.35 (1H, m), 7.40-7.44 (4H, m), 7.56-7.59 (3H, m), 7.67-7.72 (2H, m), 7.89-7.96 (3H, m), 9.54 (1H, s). MS (ES) m/z 327.9 [M+H]+.
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][C:11]([Cl:17])=[C:10]([CH3:18])[C:9]=1[Br:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:19][C:9]1[C:8]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=2)=[C:13]([C:14](=[O:16])[CH3:15])[CH:12]=[C:11]([Cl:17])[C:10]=1[CH3:18]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.21 g, 2.5 mmol) in water (5 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (0.50 g, 1.3 mmol) in toluene (5 mL) followed by (3-fluorophenyl)boronic acid (0.21 g, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to give the desired product (0.40 g, 93%). LCMS calculated for C15H12BrClFO (M+H)+: m/z=341.0. found: 341.0.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=O)[N:2]=1.CN(C)C=O.[CH3:21][N:22]([CH3:24])[NH2:23]>O>[CH3:21][N:22]([CH3:24])[N:23]=[CH:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Reactant: CN(C)N
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)N=Cc1cc2c(cn1)[nH]c1ccccc12
Reaction time: 3 h

Procedure:
A mixture of 1.0 g of beta-carboline-3-carboxaldehyde, 10 ml of dimethyl-formamide and 3 ml of N,N-dimethyl hydrazine is introduced into a glass autoclave. The air is replaced by nitrogen. After stirring for 3 h, the reaction mixture is allowed to stand overnight at room temperature. After adding 25 ml of water, the reaction mixture is extracted with 100 and 50 ml of chloroform. The chloroform phase is dried using magnesium sulfate, then filtered. Then, the chloroform is evaporated. After adding 10 ml of ether, the reaction product is filtered off. 0.9 g of beta-carboline-3-carboxaldehyde-dimethylhydrazone with a m.p. of 203°-206° C. is obtained.
Reaction SMILES: C(NC(NC1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][C:18](OC)=[N:19][CH:20]=3)[CH:12]=[CH:11][N:10]2C=1)=O)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:35]1[CH:40]=CC=C[CH:36]=1>C(OCC)(=O)C>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[N:19][C:18]([N:35]([CH3:40])[CH3:36])=[N:17][CH:16]=2)[CH:12]=[CH:11][N:10]=1
Reactant: c1ccncc1
Reactant: CCNC(=O)Nc1cn2ccc(-c3cnc(OC)nc3)cc2n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CN(C)c1ncc(-c2ccnc(N)c2)cn1
Temperature: 80 °C
Yield: 79 %

Procedure:
2-Amino-4-bromopyridine 4 (5.00 g, 28.9 mmol) and p-toluenesulfonyl chloride (6.10 g, 31.8 mmol) were dissolved in dry pyridine (100 mL) and heated at 80° C. for 5 h. The pyridine was removed under reduced pressure to give a solid. The solid was suspended in ethyl acetate, then collected by filtration and washed with ethyl acetate to give the tosylate 5 as a crystalline solid (yield: 7.50 g, 79%); 1H NMR [400 MHz, (CD3)2SO] δ 11.6 (v br s, 1H), 7.99 (br d, J=5.6 Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.37 (d, J=7.0 Hz, 2H), 7.27 (br s, 1H), 7.17 (br d, J=5.2 Hz, 1H), 2.36 (s, 3H).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1>[Cu]I>[C:20]1([C:17]2[S:16][C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1nnc(-c2ccccc2)s1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1nnc(-c2ccccc2)s1

Procedure:
The compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromo-5-phenyl-1,3,4-thiadiazole using 5 equivalents of copper (I) iodide. The title compound (180 mg) was obtained as a yellow solid, m/z 343 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: BrCCCCCBr
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Yield: 96 %

Procedure:
The title compound was prepared from 2-(3-(trifluoromethyl)phenyl)acetonitrile (3.463 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.40 g, 90%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.51-7.60 (m, 3H), 7.73 (s, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8,GC-MS m/z 253.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:21]=[O:22]>O1CCCC1>[F:10][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[C:4]=1[CH:21]=[O:22]
Reactant: COc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C=O
Temperature: -55 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1,2-difluoro-4-methoxy-benzene (Aldrich; 10.0 g, 69.4 mmol) in dry tetrahydrofuran (500 mL) was cooled to −78° C. under a nitrogen atmosphere. A solution of lithium diisopropylamide (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 1.8 M in tetrahydrofuran/heptane/ethylbenzene, 40 mL, 72.9 mmol) was added dropwise by syringe. The reaction mixture was warmed to −55° C. and held at this temperature for 1 h. The mixture was then cooled again to −78° C., and dry N,N-dimethylformamide (10.7 mL, 139 mmol) was added by syringe. The cooling bath was removed and the reaction was allowed to warm to −10° C. and quenched by the addition of ice flakes (˜200 mL) and a solution of saturated ammonium chloride (200 mL). Ethyl acetate (200 mL) was added, the layers were separated and the aqueous later was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, eluting with 0-30% ethyl acetate/hexanes to give 2,3-difluoro-6-methoxy-benzaldehyde (7.0 g, 59% yield) as an oil that solidified upon standing.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](I)[N:11]=1)=[O:5])[CH3:2].[CH:24]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Sn](C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1nc(I)c2snc(-c3ccc(F)cc3)c2c1O
Agent: [Cu]I
Agent: [Pd]
Agent: C[Sn](C)(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C)c2snc(-c3ccc(F)cc3)c2c1O
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 533.4 %

Procedure:
A mixture of 3-(4-fluoro-phenyl)-4-hydroxy-7-iodo-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (295 mg, 0.66 mmol), Pd2(dba)3 (60.8 mg, 0.066 mmol), PPh3 (17.4 mg, 0.066 mmol), and NMP (3.3 mL) was stirred at 70° C. for 10 min. After cooling to r. t. CuI (12.6 mg, 0.066 mmol) was added and the reaction mixture was stirred at 70° C. for another 10 min. After cooling to r. t. Me4Sn (0.37 mL, 2.65 mmol) was added and the mixture was stirred at 70° C. for 15 h. After cooling to r. t. the mixture was partitioned between 1 M HCl (28 mL) and EtOAc (60 mL). The organic layer was washed with brine, water, dried over MgSO4, and was then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title compound as a white solid (117 mg): MS (m/z) 333.2 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[C:27](=[O:31])[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[CH:27]([OH:31])[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2=O)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2O)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
A solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one (2.16 g, 5 mmol) in 30 mL of dry MeOH was treated with NaBH4 (189 mg, 5 mmol). After 5 min, the reaction was quenched with 5 mL of sat. NH4Cl solution. The MeOH was evaporated and the residue was extracted with DCM, dried over Na2SO4 and evaporated. Flash chomatography (SiO2, DCM to EtOAc) gave the desired product as a white solid.