Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.ClCCl>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CNC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -45 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A dichloromethane solution (45.0 ml) of N-acetylglycine ethyl ester (1.50 g, 10.33 mmol) and N-methylimidazole (1.02 mg, 12.40 mmol) was cooled to −45° C., and palmitoyl chloride (2.84 g, 10.33 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, titanium tetrachloride (6.86 mg, 36.16 mmol) and triethylamine (4.18 g, 41.31 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −45° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 2.81 g of the title compound (yield: 71%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13](Br)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.[I:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](I)[N:21]=1>O1CCCC1.CN(C)C=O.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>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:22]3[CH:23]=[N:24][CH:25]=[C:20]([I:19])[N:21]=3)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Reactant: Ic1cncc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (1.0 g, 3.03 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (10 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2,6-diiodopyrazine (704 mg, 2.1 mmol, 0.7 equiv), Pd(PPh3)4 (175 mg, 0.2 mmol, 5 mol %) in tetrahydrofuran (2 mL) and dimethyl formamide (0.1 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 140° C. for 20 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 40:60, v/v] to afford 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 7%). MS (M+H)+=455.1, Rt=1.53 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Mg+2].[Cl-].[Cl-].[CH2:12]=[O:13]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]=[O:13])=[C:4]([OH:8])[CH:3]=1
Reactant: C=O
Reactant: Oc1cccc(F)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=Cc1ccc(F)cc1O
Temperature: 2.5 °C
Yield: 109 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 3-fluorophenol (400 g, 3.57 mol, 1.00 equiv) in CH3CN (5 L), followed by the addition of MgCl2 (1018 g, 3.00 equiv) in several batches at 0° C. To this was added TEA (1443 g, 14.26 mol, 4.00 equiv) dropwise with stirring at 0-5° C., followed by paraformaldehyde (640 g, 6.00 equiv). The resulting solution was stirred at 80° C. for 3 h, cooled to 20° C., quenched by the addition of 5 L of 2N HCl and extracted with 3×3 L of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 545 g (crude) of 4-fluoro-2-hydroxybenzaldehyde as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[CH:9]1([CH2:12][O:13][C:14]([C:16]2[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[N:18]=[C:19]([CH3:23])[NH:20][C:21]=2[CH3:22])=[O:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:40]([N:47]([CH2:57]CO)[CH2:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.[Cl-].[Na+]>[CH2:40]([N:47]([CH2:57][CH2:5][O:4][C:2]([N:18]1[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[C:16]([C:14]([O:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)=[O:15])=[C:21]([CH3:22])[N:20]=[C:19]1[CH3:23])=[O:3])[CH2:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1=NC(c2ccccc2[N+](=O)[O-])C(C(=O)OCC2CC2)=C(C)N1
Reactant: OCCN(CCCc1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=NC(C)=C(C(=O)OCC2CC2)C(c2ccccc2[N+](=O)[O-])N1C(=O)OCCN(CCCc1ccccc1)Cc1ccccc1
Temperature: -23 °C
Yield: 69 %

Procedure:
Trichloromethyl chloroformate (719 μl) was dissolved in 40 ml of tetrahydrofuran (THF). To the resulting solution, a mixture of 5-cyclopropylmethoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyrimidine (1.65 g) and triethylamine (3.04 g) in THF (80 ml) was added under stirring at -23° C., followed by stirring for an additional one hour at -23° C. To the resulting mixture, 2-{N-benzyl-N-(3-phenylpropyl)amino}ethan-1-ol (6.73 g) in THF (40 ml) was added at 0° C., followed by stirring for 2 hour at room temperature. The reaction mixture was diluted with a saturated aqueous solution of sodium chloride and subjected to extraction with chloroform. After drying the extract, the solvent was evaporaed and the residue (ca. 12 g) was subjected to silica gel chromatography. By elution with a 1:1 mixture of ethyl acetate and n-hexane, the end compound was obtained in an amount of 2.14 g (yield: 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([N:15]1[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][N:4]=2)=[N:14]1)=[O:25]
Reactant: FC(F)(F)c1cnc(Oc2cc(C(F)(F)F)[nH]n2)c(Cl)c1
Reactant: CN=C=O
Product: CNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Yield: 20.1 %

Procedure:
Reaction of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole with methyl isocyanate was carried out in the same manner as in Example 173, to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole-1-carboxamide (0.39 g, yield: 20.1%). mp: 61-63° C.; 1H-NMR (CDCl3, TMS, ppm): δ 3.52 (s, 3H), 5.66 (s, 1H), 8.00 (d, J=11.8 Hz, 1H), 8.61 (d, J=1.8 Hz, 1H), 10.10-10.40 (m, 1H).
Reaction SMILES: N[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[OH:27][C:28]1([C:41]([N:43]2[CH2:50][CH2:49][CH2:48][C@H:44]2[C:45](O)=[O:46])=[O:42])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.C([N:53](CC)CC)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]([Si:13]([CH3:14])([CH3:15])[O:12][CH2:11][CH:10]([C:4]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=1[CH2:2][C@@:44]1([C:45]([NH2:53])=[O:46])[CH2:48][CH2:49][CH2:50][N:43]1[C:41]([C:28]1([OH:27])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:42])[NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)S(=O)NC(CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)cc1CN
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NC(CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)cc1C[C@@]1(C(N)=O)CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of diastereomer A of N-(1-[2-(aminomethyl)-4-chlorophenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-methylpropane-2-sulfinamide (from the previous step, 67 mg, 0.16 mmol, 1.07 eq), 1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-proline (48 mg, 0.15 mmol, 1.0 eq (43 mg, 0.22 mmol, 1.5 eq), triethylamine (22 μL, 0.16 mmol, 1.07 eq) and HOAt (10 mg, 0.08 mmol, 0.5 eq) in anhydrous DMF (1 mL) was stirred at room temperature overnight. Most of the DMF was removed in vacuo and the residue was purified by silica gel chromatography (isocratic elution, 1:1 EtOAc:hexanes) to afford diastereomer A of N-(2-{2-{[tert-butyl(dimethylsilyl)oxy}-1-[(tert-butylsulfinyl)amino]ethyl}-5-chlorobenzyl)-1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-prolinamide as a white solid (66 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 7.66-7.64 (m, 2H), 7.44-7.00 (m, 9H), 5.91 (m, 1H), 4.71-4.58 (m, 3H), 4.40 (m, 1H), 4.35 (br s, 1H), 3.75 (dd, J=4.4, 10.3 Hz, 1H), 3.67 (apparent t, J=9.7 Hz, 1H), 2.38-2.28 (m, 2H), 2.02 (m, 1H), 1.81 (m, 1H), 1.65 (m, 1H), 1.45 (m, 1H), 1.23 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H). LCMS RT=3.05 min, (M+H)=724.6. Diastereomer B of the amine (17 mg from previous step) was coupled and purified under similar conditions to afford diastereomer B of N-(2-{2-{[tert-butyl(dimethylsilyl)oxy}-1-[(tert-butylsulfinyl)amino]ethyl}-5-chlorobenzyl)-1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-prolinamide a a pale yellow oil (20 mg) which still contained traces of triphenylphosphine oxide from the previous step. LCMS RT=3.01 min, (M+H)=724.6.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5](C2C=NN(C3CCN(C(OC(C)(C)C)=O)CC3)C=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.NC1C(C(O)=[O:44])=NC=CN=1.NC1C=CC(F)=CC=1O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([C:8]([NH:12][C:11]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=2[OH:9])=[O:44])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccc(F)cc5o4)n3)cn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccc(F)cc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nccnc1C(=O)Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The tert-butyl 4-[4-[5-amino-6-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 3-aminopyrazine-2-carboxylic acid (5 g) and 2-amino-5-fluoro-phenol (5.94 g) were dissolved in DMF (30 ml). Triethylamine (5.81 g) and HATU (19.13 g) were added to the solution. The resulting mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate (100 ml) and washed with brine (3×20 ml). The organic layer was dried over sodium sulfate. The precipitate was collected, recrystallized in ethanol and further purified by chromatography on silica gel (hexane/ethyl acetate/Methanol) to give 3-amino-N-(4-fluoro-2-hydroxy-phenyl)pyrazine-2-carboxamide (6 g). NMR Spectrum: (400 MHz, DMSOd6) 10.8 (s, 1H), 10.2 (s, 1H), 8.30 (m, 2H), 7.80 (s, 1H), 7.50 (br, 2H), 6.60 (m, 2H). Mass spectrum: M+H+ 249.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[CH2:11][CH3:12].C(OC(N1CCC(CC(Br)=O)CC1)=O)(C)(C)C>>[CH2:11]([C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1)[CH3:12]
Reactant: Nc1ccccn1
Reactant: CCC(=O)CBr
Agent: CC(C)(C)OC(=O)N1CCC(CC(=O)Br)CC1
Product: CCc1cn2ccccc2n1

Procedure:
The title compound was prepared from 2-aminopyridine and 1-bromo-2-butanone, employing procedures analogous to those described for Piperidine 1. 1H NMR (500 MHz, CDCl3) δ 1.34 (t, J=7.3 Hz, 3H), 2.82 (q, J=7.6 Hz, 2H), 6.70 (t, J=6.6 Hz, 1H), 7.10 (m, 1H), 7.32 (s, 3H), 7.51 (d, J=8.9 Hz, 1H), 8.03 (dd, J=6.6, 0.9 Hz, 1H).
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1>C(Cl)Cl>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:13]2[CH2:14][CH2:15][CH:10]([C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)(=[O:33])=[O:32])[N:28]=[CH:27]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N2CCC(C(=O)c3ccccc3)CC2)c1
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 4-benzoylpiperidine hydrochloride (1.50 g, 6.64 mmol) and DIPEA (2.74 mL, 15.3 mmol) in CH2Cl2 (35 mL) was added 1-methylimidazole-4-sulfonyl chloride (1.31 g, 7.31 mmol) and stirred for 18 h. The reaction was washed with 2 N NaOH (30 mL), dried over MgSO4 and concentrated under vacuum to afford 4 as a white solid (2.05 g, 93%); 1H-nmr (400 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.52-7.36 (m, 5H), 3.86-3.78 (m, 2H), 3.71 (s, 3H), 3.26-3.17 (m, 1H), 2.82 (td, J=11.0, 3.0 Hz, 2H), 1.92-1.84 (m, 4H); m/z 334.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=O.O>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cc(Cl)ncn1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cn3cnc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
6-Chloropyrimidin-4-amine (50 mg, 0.39 mmol) and 2-bromo-1-(3-nitrophenyl)ethanone (94 mg, 0.39 mmol) were dissolved in 2 mL of DMSO and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 5 mL of water and it was then extracted with ethyl acetate. The filtrate was dried (Na2SO4) and evaporated. The compound was purified by silica gel column chromatography by using hexane/ethyl acetate (3:1) as eluent (60 mg, 56% Yield). MS m/z 275.00 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-:15].[Na+]>>[NH2:6][C:7]1([C:13]([NH2:14])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [OH-]
Reactant: N#CC1(N)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1(N)CCCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 20 g concentrated sulfuric acid at 5° C is added with stirring 10 g of 1-aminocyclohexanecarbonitrile. After the addition, the mixture is heated with stirring at 100° C for 1 hour. The hot solution is then poured onto ice, the solution made strongly basic with 50% aqueous sodium hydroxide solution, and extracted three times with chloroform. The extract is washed with water, saturated NaHCO3 solution, dried, and the solvent removed in vacuo to leave the product, 1-aminocyclohexanecarboxamide, as a crystalline residue, melting point 99°-102° C. This can be recrystallized from either benzene or ether to give a pure product, melting point 101°-102° C.
Reaction SMILES: [C:1]([C:3]1[C:29]([C:30]#[N:31])=[CH:28][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=3)[NH:9][C:5]=2[CH:4]=1)#[N:2].[CH2:32]1[CH2:42]CN2C(=NCCC2)C[CH2:33]1.ICCC>CN1C(=O)CCC1>[C:1]([C:3]1[C:29]([C:30]#[N:31])=[CH:28][C:6]2[N:7]([CH2:33][CH2:32][CH3:42])[C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:19]([CH3:20])[CH3:21])[CH:22]([CH3:23])[CH3:24])=[CH:14][CH:15]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)[Si](C#Cc1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1)(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCCI
Product: CCCn1c(-c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)nc2cc(C#N)c(C#N)cc21
Temperature: 120 °C
Reaction time: 0.03 h
Yield: 60.6 %

Procedure:
A 20 mL vial was charged with 5d (763 mg, 1.79 mmol), and NMP (10 mL). The vial was capped with a septum and placed in an oil bath heated to 120° C. DBU (267 μL, 1.79 mmol) was added, and the mixture was stirred for 2 min. Then iodopropane (175 μL, 1.79 mmol) was added and the mixture was stirred for 20 min. A second dose of DBU (267 μL, 1.79 mmol), followed by iodopropane (175 μL, 1.79 mmol), was added, and 20 min later, a third identical round of DBU and iodopropane was again added. After the third round of reagents was added and the mixture was stirred for 20 min, the reaction mixture was removed from heat and added to ethyl acetate. The solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was chromatographed (silica, CHCl3), yielding a colorless solid (506 mg, 61%): mp 242-243° C.; 1H NMR (d6-acetone) δ 0.89 (t, J=7.2 Hz, 3H), 1.17-1.19 (m, 21H), 1.86-1.96 (m, 2H), 4.53 (t, J=7.6 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 8.50 (s, 1H); 13C NMR (d6-acetone) δ 10.5, 11.3, 18.4, 23.2, 47.1, 93.1, 106.6, 108.1, 108.3, 116.8, 116.9, 118.3, 125.8, 126.3, 129.6, 129.9, 132.5, 138.5, 145.4, 158.4; Anal. Calcd for C29H34N4Si: C, 74.63; H, 7.34; N, 12.01. Found: C, 74.75; H, 7.32; N, 12.01.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][Cl:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Example 67(a), but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 5-chlorovaleryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 93% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[O:20][C:21]2[C:22](=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:26][CH:27]=2)[N:23]=1>COCCOC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:26][CH:27]=3)[N:23]=2)[C@@H:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC[C@H]1CN(Cc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@H]1CN(Cc2ccccc2)CCN1c1nc2c(C(=O)OC)cccc2o1
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
To a solution of (S)-1-benzyl-3-ethylpiperazine (650 mg, 3.22 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 144 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-ethylpiperazine-1-yl)benzoxazole-4-carboxylate (0.87 g, 71%) as an oily solid. 1H NMR and MS consistent.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:32]1[N:40]=[C:39]([CH3:41])[N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1.[NH2:48][C:49]1[CH:50]=[N:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1.O1CCCC1>>[CH3:56][O:55][C:52]1[N:51]=[CH:50][C:49]([NH:48][C:12]2[N:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:14][C:13]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[CH:54][CH:53]=1
Reactant: Cc1nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 75 %

Procedure:
LiHMDS (1.0 M in THF, 3.75 mL, 3.75 mmol) was slowly added to a stirred mixture of tert-butyl 4-((6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.6397 g, 1.250 mmol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, Mo.; 186 mg, 1.50 mmol) in tetrahydrofuran (10 mL, 1.250 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h before being quenched with NH4Cl(aq) (10 mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatograph (hexanes to 50% ethyl acetate/hexanes) to give tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.577 g, 0.937 mmol, 74.9% yield) as a yellow foam. LCMS (API-ES) m/z 616 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1C=CC=C[CH:3]=1.[H][H].C([OH:24])C>[Pd]>[O:24]1[CH2:3][C@H:2]1[CH2:1][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCO
Reactant: CS(=O)(=O)Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1

Procedure:
N-[4-(Benzyloxy)phenyl]methanesulfonamide (3.0 g, 10.8 mmol) was dissolved in ethanol (150 mL). 10% Palladium on carbon (0.3 g) was added and the mixture shaken overnight under 50 psi hydrogen on a Parr apparatus. The solution was filtered through a Celite pad and the solvent removed to yield the title compound (1.32 g, 7.4 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]1[O:15][CH:1]2[C:10]3[C:5]([CH:4]=[CH:3][N:2]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]1=2)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2cnccc2c1
Reactant: O=Cc1ccccc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccccc1C1OC2c3ccccc3C=CN2c2ccccc21
Yield: 64 %

Procedure:
Following the general procedure, treatment of isoquinoline (00.064 g, 59 μL, 0.50 mmol) and 2-fluorobenzaldehyde (0.095 g, 79 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=93/07) of the crude reaction mixture afforded 6-(2-fluorophenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.105 g, 64% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:1).