Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:12]1([C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: Cl[Mg]c1ccccc1
Agent: CCCCCCCCCCCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
1.32 mL (10.0 mmol) 2-tetralone in 5 mL of THF was added to a solution of 5.77 mL (12.0 mmol) 2.08 M phenylmagnesium chloride in THF at 0° C. The mixture was allowed to warm to room temperature, and was then stirred for an additional 1 hour. Tridecane (1.22 mL; 5.00 mmol; internal GC standard) was added, the mixture was cooled to 0°, 10 mL of 6N HCl was added. The mixture was heated to 65° and vigorously stirred for 4 hours. The mixture was then cooled to room temperature and diluted with toluene. GC analysis of the organic phase showed the presence of 2.9 mmol 2-phenyl-3,4-dihydronaphthalene (29% yield on 2-tetralone) and 4.6 mmol 2-tetralone (46% recovery). No benzylic alcohol intermediate from addition of the arylmagnesium reagent to the ketone was detected, indicating that its dehydration to the vinylaromatic had been completed by the warm acid treatment.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c2ccccc2c1O
Reaction time: 1 h

Procedure:
4-Chloro-1-naphthol, 9 g, in 100 ml acetic acid was cooled to 15° C. and 3.25 ml concentrated nitric acid in 20 ml acetic acid was added dropwise over 15 minutes. After 1 hour, the reaction mixture was poured into 600 ml chilled water. The precipitate was filtered off, washed with water and dried to give a crude product. The product was partially purified by extracting with boiling hexane to obtain 3.5 g. Further purification was accomplished by dissolving in 10 ml chloroform, absorbing on 15 g silica and loading on a column of 90 g silica gel, equilibrated with hexane. The product was eluted with 5% ethyl acetate in hexane to give 0.8 g of 4-chloro-2-nitro-1-naphthol after evaporation, m.p. 142°-3° (d).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][Mg]Br)[CH3:2].C(OCC)C.[C:16](=S)([O:27]C1C=CC=CN=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>C1COCC1>[CH2:1]([CH:3]([CH2:4][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: C=CCCCCCCCCC(=S)Oc1ccccn1
Reactant: CCCCC(CC)C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(=O)CC(CC)CCCC
Reaction time: 0.5 h

Procedure:
A Grignard solution of 2-ethylhexylmagnesium-bromide in diethylether (1.0 M, 1.96 mL, 1.96 mmol) was slowly added via syringe to a stirred mixture of pyridin-2-yl undec-10-enethioate (0.54 g, 1.96 mmol) in THF (50 mL) at 0° C. under N2 atmosphere. After vigorously stirring for another 30 minutes, the reaction was completed by adding (2.0 M, 50 mL). The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with a saturated bicarbonate solution and brine, dried over MgSO4 and evaporated under reduced pressure to give a yellow oil. The resulting oil was purified by vacuum distillation at 90-100° C. at 10−2 mbar. 1H-NMR (CDCl3): δ=5.85-5.67 (m, 1H), 5.00-4.83 (m, 2H), 2.37-2.22 (m, 4H), 1.99 (q, J=14.0 Hz, J=6.9 Hz, 2H), 1.89-1.76 (m, 1H), 1.61-1.44 (m; 4H), 1.39-1.09 (m, 16H), 0.90-0.74 (m, 6H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1)=[O:2].[CH3:28][Mg]Br.C(OCC)C>C1COCC1>[OH:2][CH:1]([C:3]1[C:4]([C:24]([F:27])([F:25])[F:26])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1)[CH3:28]
Reactant: NC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To 2-(2-(4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.6 g, 4.00 mmol) in THF (10 mL) at −50° C. under an argon atmosphere was added 3M methylmagnesium bromide in diethyl ether (1.249 mL, 3.75 mmol) in a dropwise manner over 10 min. The reaction was stirred at −50° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl before partitioning between EtOAc/water (×2), and washing with EtOAc (×1) and brine (×1). The organics were dried over MgSO4 before removing the solvent in vacuo. The residue was purified by silica gel flash chromatography (1:2 heptane/EtOAc) and the solvent removed in vacuo to give the title compound as a yellow solid (0.8 g, 1.921 mmol, 48%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (193 mg, 0.74 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-yl-3,3-difluoropyrrolidine as a white solid (122 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 3.63 (m, 4H), 3.48 (m, 1H), 2.87 (t, J=13.1 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H) and 2.29 (m, 2H)
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[CH:16]=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:34]C.OO.Cl>C1COCC1.CO>[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[C:16]([OH:34])=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1CCC(C2)N1C(=O)OC(C)(C)C
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
Tert-butyllithium (1.7M, 2.3 mL, 4.0 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (450 mg, 1.2 mmol) in THF (5 mL) at −78° C. The solution was then allowed to warm slowly to −20° C. and stir at that temperature for 1 h before cooling again to −78° C. and adding trimethyl borate (0.37 mL, 3.2 mmol) via syringe. The reaction was allowed to warm to room temperature slowly and stir overnight. The reaction was quenched with methanol (1 mL) and hydrogen peroxide (30% solution, 0.37 mL, 3.6 mmol) was added to the reaction and allowed to stir at room temperature for 2 h. The mixture was then adjusted to neutral pH with 1 N HCl, extracted with CH2Cl2 (3×10 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a brown foam (260 mg, 55%). 1HNMR (400 MHz, CDCl3) δ 7.7 (m, 1H), 7.5 (s, 1H), 7.1 (d, 1H, J=8.1 Hz), 6.9 (m, 1H), 4.5 (d, 1H, J=7.8 Hz), 4.1 (m, 1H), 3.1 (dd, 1H, J=14.4, 4.9 Hz), 2.9 (dd, 1H, J=14.4, 4.9 Hz), 2.7 (dd, 1H, J=18.2, 8.1 Hz), 2.6 (dd, 1H, J=18.2, 10.6 Hz), 2.2-2.1 (m, 1H), 1.5-1.3 (m, 19H); 1H-1H COSY interactions between peak at 7.7 and 7.1 ppm; MS (m/e) 391 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)C.C(O)CCC>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCCCO
Product: c1ccc(Cn2ccnc2)nc1

Procedure:
A solution of 2-chloromethylpyridine hydrochloride (16.4 g, 0.1 mol) in ethanol (50 ml) was added dropwise to a stirred, boiling solution of potassium tert-butoxide (22.4 g, 0.2 mol) and imidazole (6.8 g, 0.1 mol) in dry butan-1-ol (100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 5 h. After removal of the solvents under reduced pressure, the resulting oil was dissolved in hydrochloric acid (150 ml, 2M), and the acid solution was washed with ether (100 ml). The acid solution was then basified with sodium hydroxide solution (10M), and the basic solution was extracted with chloroform (3×100 ml). The chloroform solutions were combined, dried (MgSO4), and the chloroform was then removed under reduced pressure. The residue was purified by using a silica-gel column and by elution with chloroform/methanol (9:1). The resulting solid was recrystallised from ethanol/light petroleum affording 1-(2-pyridylmethyl)imidazole as white cubes m.p. 79°-80°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl:37][C:38]1[CH:39]=C(O)C=[CH:42][CH:43]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>CC#N>[Cl:37][C:38]1[CH:39]=[C:15]([CH:19]=[CH:42][CH:43]=1)[O:16][CH2:17][C:18]1[CH:47]=[CH:45][O:46][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1cccc(OCc2ccoc2C2CCNCC2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)furan-3-yl]piperidine-1-carboxylic acid t-butyl ester (65 mg, 0.15 mmol was dissolved in MeCN (770 μL) and added to a mixture of potassium carbonate (32 mg, 230 mmol, 1.6 eq.) and 3-chlorophenol (28.8 mg, 224 μmol, 1.5 eq.). The resulting mixture was shaken at 50° C. overnight. The mixture was then cooled and the solids removed. The supernatant was combined with TFA (12 μL, 160 mmol, 1.0 eq.) and the resulting mixture was shaken overnight at room temperature. The solution was concentrated using an evaporator, then dissolved in 1:1 AcOH:H2O (5.0 mL) then an additional 2.0 ml AcOH, filtered, and purified by preparative HPLC to yield the title compound as a TFA salt (4.3 mg, 98% purity). MS m/z: [M+H]+ calcd for C16H18ClNO2, 292.10. found 292.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:8]([Mg]Br)=[CH2:9]>C(OCC)C>[CH:8]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH2:9]
Reactant: O=C1CCOCC1
Reactant: C=C[Mg]Br
Solvent: CCOCC
Product: C=CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dihydro-2H-pyran-4(3H)-one (8.01 g) in anhydrous ethyl ether (50 mL) was treated with 1.0 M vinylmagnesium bromide (104 mL) over 20 minutes at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl, and the organic layer was separated. The aqueous layer was extracted with additional ethyl ether three times. The combined organic layers were washed with brine, dried, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: CC[C:3]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][N:4]=1.[O-][CH2:17][CH3:18].[Na+]>CCO.O>[CH2:17]([O:15][C:13]([C:12]1[NH:11][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:8]=2[C:9]=1[NH2:10])=[O:14])[CH3:18]
Reactant: CCc1nccc(NCC(=O)O)c1C#N
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccncc2c1N
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of ethyl-4-(3-cyanopyridine)glycinate (2.47 g, 12.1 mmol) under nitrogen in EtOH (60 mL) was added sodium ethoxide (0.90 g, 13.3 mmol) and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool to ambient temperature then quenched by the addition of water (3 mL) and saturated ammonium chloride solution (5 mL). The solvent was concentrated in vacuo, to provide a residue that was diluted with water (30 mL), and extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound as a brown solid (1.35 g, 55%). LCMS (method B): RT=0.61 min, M+H+=206.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>C1(C)C=CC=CC=1>[CH:17]1([NH:23][C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2[nH]c1=O
Temperature: 115 °C
Yield: 34.6 %

Procedure:
Methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 70) (2.70 g, 12.3 mmol) was suspended in toluene (27 mL), and cyclohexylamine (1.40 g, 14.1 mmol) was added. The reaction was heated at 115° C. for 5 hours, then cooled to room temperature. Diethyl ether (50 mL) was added, and the resultant precipitate was collected by filtration to give N-cyclohexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide (1.22 g, 35%) as an off white solid. M.p.: 221° C. 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.88 (m, 2H), 3.86 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 10.35 (d, J=7.6 Hz, 1H), 11.83 (bs, 1H). MS 287 (MH+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH2:11]([Si:16](OC)([O:19][CH3:20])[O:17][CH3:18])[CH2:12][CH:13]([CH3:15])[CH3:14].C([Mg]Br)CC(C)C.CO[Si](OC)(OC)OC>O.CCOCC>[CH2:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Si:16]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([O:19][CH3:20])[O:17][CH3:18])[CH3:10]
Reactant: CCc1ccccc1Br
Reactant: CO[Si](CCC(C)C)(OC)OC
Agent: CC(C)CC[Mg]Br
Agent: CO[Si](OC)(OC)OC
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCc1ccccc1[Si](CCC(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A 1000 mL round bottomed flask was charged with magnesium turnings (1.97 g, 81.0 mmol, Aldrich) and ether (500 mL, Aldrich). Bromo-2-ethylbenzene (14.0 mL, 101 mmol, Aldrich) was added over 30 minutes. The reaction stirred for three hours at room temperature and became dark brown in color. The contents were refluxed for one hour. The contents were cooled to 0° C. and isoamyl-trimethoxysilane (15.9 g, 82.8 mmol, previously prepared by reaction between isoamyl magnesiumbromide and tetramethylortho-silicate) was added over 25 minutes. The reaction was stirred at room temperature overnight (18 hours) during which time a white precipitate formed. The contents were poured into water (500 mnL), the layers separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered and the solvent removed via rotary evaporation providing 29.6 g crude material. Distillation under reduced pressure (b.p. 109° C., 1.1 mm Hg) produced (2-ethylphenyl)-3-methylbutyl-dimethoxysilane (7.68 g, 28.8 mmol, 35.6% yield); C15H26SiO2 (Mw=266.45); 1H NMR (CDCl3) δ7.7 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 3.5 (s, 6H), 2.8 (q, 2H), 1.4 (m, 1H), 1.2(m, 5H), 0.8(m, 8H); 13C NMR (CDCl3) δ150.5, 135.9, 131.2, 130.3, 128.0, 124.9, 50.3, 31.5, 30.7, 28.6, 21.9, 16.1, 10.9; IR (capillary film) ν3054, 2974, 1590, 1467, 1370, 1200, 1118, 1023, 936, 874 803, MS m/z (relative abundance) 266 (0.02), 195 (100), 163 (59.1), 160 (28.8), 133 (25.5), 105 (11.2), 91 (12.3), 59 (18.4).
Reaction SMILES: [P:1]([OH:40])([OH:39])([O:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)[N:20]=3)=[N:17][C:6]1=2)=[O:2].O.O.O.O.O.O.P([O-])([O-])(OCN1C(=O)C(C)(C)OC2C=CC(NC3C(F)=CN=C(NC4C=C(OC)C(OC)=C(OC)C=4)N=3)=NC1=2)=O.[Na+].[Na+].[CH2:89]([N:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90]>C(O)(C)C.O>[F:25][C:24]1[C:19]([NH:18][C:16]2[CH:15]=[CH:14][C:7]3[O:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:5]([CH2:4][O:3][P:1]([O-:39])([O-:40])=[O:2])[C:6]=3[N:17]=2)=[N:20][C:21]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)=[N:22][CH:23]=1.[CH2:89]([NH+:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90].[CH2:89]([NH+:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90]
Reactant: CCN(CC)CC
Reactant: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)(O)O)C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)([O-])[O-])C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC[NH+](CC)CC
Temperature: 20 °C

Procedure:
To [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate; N,N-dimethylformamide solvate (Step E) (1.00 kg, 1.00 mol eq) is added a solution of triethylamine (0.34 kg, 2.20 mol eq) in isopropanol (1.32 kg) and water (3.33 kg). This is stirred at about 20° C. to give a solution which is then filtered. The resulting solution of the sub-title compound is used directly in the next step.
Reaction SMILES: [CH:1]([N:5]=[N:6][C:7]([N:13]=[C:14]=[O:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH2:3][CH3:4])[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCCCC>[CH:1]([N:5]=[N:6][C:7]([NH:13][C:14]([NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])([CH2:3][CH3:4])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCC(C)N=NC(C)(CC(C)C)N=C=O
Solvent: CCCCC
Product: CCC(C)N=NC(C)(CC(C)C)NC(=O)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
To 5.3 grams (.025 moles) of stirred 2-sec.-butylazo-2-isocyanato- 4-methylpentane (from Example XVII) in a 50 ml erlenmeyer flask was added 2.6 grams (.026 moles) of cyclohexylamine. A solid quickly formed so 25 ml of pentane was added and the slurry stirred for approximately 1/2 hour, the solid filtered, reslurried in 25 ml of fresh pentane and refiltered. The solid was air dried and weighed. The white powder weighed 4.4 grams (57% crude yield) and had a melting range of 118 to 123° C. The infrared spectrum of the product was in agreement with the structure of N-[1-(sec.-butylazo)-1,3-dimethylbutyl]-N'-cyclohexylurea(sharp NH at 3250 cm-1 and strong carbonyl band at 1625 cm-1).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:34][CH:35]3[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]3)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(S(C)(=O)=O)n2)C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(NS(C)(=O)=O)CC3)n2)C1
Yield: 73.3 %

Procedure:
4-[3-(t-Butyl-dimethylsilyloxy)pyrrolidin-1-yl]-1-(2-methylsulfonyl-pyrimidin-4-yl)-1H-indole (about 160 mg, 0.35 mmol), N-(4-amino-cyclohexyl)-methanesulfonamide hydro-chloride (743 mg, 3.255 mmol) and DIEA (0.169 mL, 4.32 mmol) were mixed in NMP (7 mL) under Ar at 130° C. for 2.5 h. The reaction mixture was washed with NH4Cl/H2O and extracted into EtOAc (6×15 mL), and further washed with H2O (6×30 mL). The solvent was removed in vacuo to yield N-[4-(4-{4-[3-(t-butyl-dimethylsilanyloxy)-pyrrolidin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (150 mg).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12>CC(C)=O.Cl.O>[C:4]1(=[O:16])[N:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: COC(=O)CCC/C=C\CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCC/C=C\CN1C(=O)c2ccccc2C1=O
Yield: 80.9 %

Procedure:
A solution of methyl (Z)-7-phthalimidohept-5-enoate (1.56 g) in acetone (30 ml), concentrated hydrochloric acid (15 ml) and water (15 ml) was refluxed for 2.5 hours. Water (180 ml) was added and the solution was cooled. The precipitate was collected by filtration to give the title compound (1.2 g). m.p. 86°-88° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[Si:7]([O:14][CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([BH3-])#N.[Na+].O>C(O)(=O)C>[Si:7]([O:14][CH:15]1[CH2:16][CH2:17][CH:18]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:19][CH2:20]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a solution (30 mL) of 1H-1,2,4-triazol-3-amine (3 g) and 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (10 g) in acetic acid was added sodium cyanoborohydride (9.3 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.2 g, 20%).