Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:56][CH2:55][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][NH:68][CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:53][CH2:52]1>CC(N(C)C)=O>[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:52][CH2:53][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][N:68]([C:3](=[O:4])[CH:2]([F:6])[F:1])[CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:55][CH2:56]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C(F)F)C2
Temperature: 60 °C

Procedure:
A solution of 2,2-difluoroacetic acid (8.2 μL, 0.13 mmol) in DMA (0.4 mL) was treated with HATU (49.6 mg, 0.130 mmol) and DIPEA (45.6 μL, 0.261 mmol). To this was added a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45 mg, 0.087 mmol) in DMA (0.47 mL). The reaction mixture was heated at 60° C. for 50 min. The reaction mixture was allowed to cool to room temperature and was purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 55% to 90% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (10.0 mg, 19.3%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.28 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.79 (t, J=5.9 Hz, 0.7H), 2.85 (t, J=5.8 Hz, 1.3H), 3.05 (m, 2H), 3.42 (m, 2H), 3.92 (dt, J=11.3, 5.8 Hz, 2H), 4.15 (m, 1H), 4.48 (m, 1H), 4.65 (s, 2H), 6.56 (m, 1H), 6.88 (m, 1H), 6.98 (ddd, J=11.3, 8.5, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 482.5.
Reaction SMILES: C([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:22])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[F:23][CH:24]([F:35])[CH:25]=[N:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:22][CH:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:24]([F:35])[F:23])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Reactant: COc1ccc(N=CC(F)F)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)OC(C)(C)C)C(F)F)cc1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
sec-Butyl-lithium (1.3 M in cyclohexane, 10.72 mL) was added to a stirred solution of tert-butyl 5-chloro-2-methylbenzylcarbamate (1.781 g, 6.96 mmol) in THF (14 mL) at −78° C. under nitrogen to give a deep red solution. After 10 min N-(-2,2-difluoroethylidene)-N-(4-methoxyphenyl)amine (1.29 g, 6.96 mmol) was added and after a further 5 min the solution was quenched with excess saturated aqueous NH4Cl and warmed to ambient temperature. The solution was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-15% ethyl acetate/hexanes gradient) to give tert-butyl 5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzylcarbamate (0.516 g) as a foam; MS m/z=441.1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].[CH:15]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.O1CCCC1.Cl.O>O1CCCC1>[CH:15]1([CH:7]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:3][C:2]=2[CH3:1])[OH:8])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: Br[Mg]C1CCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)cc1C(O)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (1.3 g) in tetrahydrofuran (30 mL) was added dropwise 1N cyclopentylmagnesium bromide-tetrahydrofuran solution (10.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (0.9 g, 50%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]#[N:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C[Sn]([N:39]=[N+:40]=[N-:41])(C)C>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:41][N:40]=[N:39][N:31]=4)=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C#N)cc2)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3-c3nnn[nH]3)cc2)cc1
Temperature: 120 °C
Yield: 60.7 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-cyanophenyl)benzamide (350 mg) and trimethyltin azide (453 mg) in xylene (15 ml) heated at 120° C. for 2 days and cooled to ambient temperature. The solution was directly applied to silica gel column (the column was pre-packed with chloroform as a solvent). The column was eluted with 2% methanol in chloroform and the solvent was evaporated in vacuo. The residue was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(tetrazol-5-yl)phenyl]benzamide (233 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CC[O:10][C:11]([CH:13]([C:17]([CH3:19])=O)[C:14]([CH3:16])=O)=[O:12]>C(O)(=O)C>[CH3:7][C:5]1[CH:6]=[C:2]2[N:1]=[C:14]([CH3:16])[C:13]([C:11]([OH:12])=[O:10])=[C:17]([CH3:19])[N:3]2[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(C(=O)O)c(C)n2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
3-Amino-5-methylpyrazole (970 mg) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (5 ml) and 5 N sodium hydroxide solution (2 ml) were added to the residue and stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (1.6 g, Y.:80%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:3]=1[NH2:4].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[CH3:19][O:18][C:12]([C:13]1[C:2]2[C:3](=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([F:9])[CH:8]=2)[NH:4][C:14]=1[CH3:16])=[O:17]
Reactant: COc1cc(F)cc(Br)c1N
Reactant: COC(=O)CC(C)=O
Product: COC(=O)c1c(C)[nH]c2c(OC)cc(F)cc12

Procedure:
The above compound A was prepared from 2-bromo-4-fluoro-6-methoxy aniline and methyl acetoacetate according to the general procedure described above for Example 83, steps D and E. 238.0 (M+H), ret t: 3.64 min (A).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3N.N([O-])=O.[Na+].[I-:32].[K+].[Cu](C#N)C#N>S(=O)(=O)(O)O.O>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3[I:32]
Reactant: [I-]
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: N#C[Cu]C#N
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Clc1cnc2nc1Nc1ccc(I)c(c1)CCc1cncc(c1)N2
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a suspension of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (30.0 mg, 0.067 mmol) (prepared in Example B19, step F) in 2.0 M of sulfuric acid in water (0.502 mL) was added a solution of sodium nitrite (6.93 mg, 0.10 mmol) in water dropwise at 0° C. After addition, the resultant cloudy solution was stirred at same temperature for 1 h. Then this cold solution was added dropwise to a solution of potassium iodide (16.7 mg, 0.10 mmol) and copper cyanide (0.90 mg, 0.01 mmol) in water at 0° C. The resultant mixture was stirred at rt overnight. The precipite was filtered and washed by water and dried to give the desired product as a light brown powder (28 mg, 93%). LCMS for C17H14ClIN5 (M+H)+: m/z=449.9.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=O.CC(O)C.[ClH:27]>C1(CCCCN2N=CC=N2)C=CC=CC=1.[C].[Pd]>[ClH:27].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)CCCN)cc1
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(C)O
Product: COc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
4-Amino-4′-methoxybutyrophenone trifluoromethanesulfonate (60 g, 174.8 mmol) was dissolved in tetrahydrofuran/water-1/1 (600 ml) and 10% palladium carbon (water-containing product, 6 g) was added. The mixture was subjected to catalytic reduction at 50° C. for 7 hours under hydrogen pressure (0.8 Mpa). The catalyst was filtered off and toluene (360 ml) and 2N-potassium hydroxide (180 ml) were added. The mixture was partitioned and the aqueous layer was extracted with toluene (360 ml). The organic layers were combined and washed with 20% brine (3 times). To the residue obtained by concentration under reduced pressure was added 2-propanol (300 ml) and con. hydrochloric acid (34 ml) was added dropwise under ice-cooling. To the residue obtained by concentration under reduced pressure was added 2-propanol (300 ml) and the mixture was concentrated under reduced pressure. 2-Propanol (300 ml) was added and the mixture was concentrated under reduced pressure. To the obtained residue was added isopropyl ether (200 ml) and the mixture was stirred at room temperature for 10 min. The precipitated crystals were collected by filtration and dried under reduced pressure to give 1-(4-aminobutyl)-4-methoxybenzene hydrochloride (32.1 g, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl 2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example 89c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)OCC[O:27]1.[Mg].Cl>O.CCOCC.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:26](=[O:27])[CH3:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CCCCCCBr)OCCO1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)CCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
To a mixture of 12.7 g of 3,4-dibenzyloxybenzaldehyde and 150 ml of tetrahydrofuran was added dropwise an ether solution of Grignard reagent prepared from 10.4 g of 2-methyl-2-(6-bromohexyl)-1,3-dioxolane and 1.1 g of magnesium at a temperature below 5° C. After stirring the mixture for 2 hours at room temperature, water was added to the mixture and acidifying the mixture by the addition of diluted hydrochloric acid, the reaction mixture thus obtained was extracted with toluene. The extract was washed with water, dried by anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added 300 ml of acetone and 0.1 g of p-toluenesulfonic acid, the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was extracted with toluene and the extract was washed with an aqueous 5% sodium hydrogencarbonate solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide an oily product. The product was applied to silica gel (500 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate (19:1) to provide 4.4 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanedione. Melting point 64°-66° C.
Reaction SMILES: [CH3:1][CH:2]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3][CH:4](NC(OCC)=O)[NH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>[Ni].C(O)C>[CH3:1][CH:2]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)NC(C)CC(NC(=O)OCC)NC(=O)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)NCCC(C)NC(=O)OCC

Procedure:
10 g of the 3-methyl-1,1,3-tri(ethoxycarbonylamino)propane prepared in Example 3a are hydrogenated at 165° C. and 200 bar of hydrogen in a stirred autoclave with 3 g of Raney nickel and 100 ml of ethanol in the course of 15 hours. Complete converion gives 1-methyl-1,3-di(ethoxycarbonylamino)propane with a selectivity of 96%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH2:25]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, methanesulfonyl chloride (7.6 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=NO)[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([O:22]CC=C)=[O:21])=[C:18]([OH:28])[CH:17]=2)=[CH:9][C:8]=1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:3])[CH3:2].N1CC[O:38]CC1>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>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:38])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:28])[CH:17]=2)=[CH:9][C:8]=1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: C=CCOC(=O)c1ccc(OCC(=NO)c2ccc(NCCC(C)=O)c(C(C)(C)C)c2)cc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)CCNc1ccc(C(=O)COc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Yield: 59 %

Procedure:
In a manner similar to that of Example 5.h, by reaction of 380 mg (0.8 mmol) of allyl 4-{2-[4-(acetylethylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}-2-hydroxybenzoate with 48 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium and 73 μl (0.8 mmol) of morpholine. A white powder is obtained (m.p.=199° C., m=200 mg, yield=59%); (1H NMR (DMSO): 1.05-1.08 (t, 3H); 1.29 (s, 9H); 1.64 (s, 3H); 2.7-2.8 (m, 1H); 4.1-4.2 (m, 1H); 5.34 (s, 2H); 6.44-6.47 (dd, J=6.8 Hz, J′=2.2 Hz, 1H); 6.53 (d, J=2 Hz, 1H); 7.07-7.09 (d, J=8.2 Hz, 1H); 7.51-7.53 (dd, J=6 Hz, J′=1.86Hz, 1H); 7.65-7.67 (d, J=8.8 Hz, 1H); 7.86 (d, J=1.78Hz, 1H); 12.2 (s, 1H)).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].C[O-]>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[O:2][CH3:1])[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A 1-L, 3-necked round bottom flask was charged with a solution prepared from sodium methoxide (9.41 g, 0.174 mol, 0.9 equiv) in anhydrous methanol (150 mL). A solution of diethoxyacetonitrile (25 g, 0.193 mol) in anhydrous methanol (70 mL), was added to the methoxide solution, slowly, over 15 min, via an addition funnel. The reaction was then stirred overnight at room temperature, and the excess methanol was evaporated, in vacuo. The resulting oil was diluted with water and extracted into ethyl acetate (2×250 mL), then CH2Cl2 (2×250 mL). The organic phases were combined and dried over Na2SO4, filtered and concentrated in vacuo affording 9 g, (29%) of crude methyl 2,2-diethoxyethanimidoate having a purity of 80–85% by 1H NMR. This was used in the next step without further purification. A 500-mL round bottom flask was charged with a solution of the amidrazone from Step 1, N′-methylpyridine-2-carbohydrazonamide (22 g, 0.0548 mol) in methanol (75 mL), along with a solution of the crude imidate ester (8.84 g, 0.0548 mol) in methanol (75 mL). The mixture was treated with glacial acetic acid (4.75 mL, 1.5 equiv), and stirred at room temperature overnight while monitoring by LC/MS for disappearance of the amidrazone. The methanol was evaporated in vacuo, and the resulting oil was neutralized with saturated, aqueous NaHCO3. The product was extracted into ethyl acetate (3×150 mL) and the organic phase dried over Na2SO4, filtered and concentrated, to give a yellow oil (11.06 g, 76% crude yield) of the acetal intermediate that was used in the next step without purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=C)[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[OH:16]>>[OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[O:16])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CO
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Product: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of (+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B (22.7 g, 121 mmol) in methanol (300 mL) cooled in a dry ice/acetone bath was bubbled ozone until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (25 mL) was added. After 30 min, the bath was removed and the reaction was allowed to warm to rt over 16 h. The volatiles were removed in vacuo and the residue was purified by FC (15-30% ethyl acetate in hexanes) to give the title compound (22.1 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23](Br)[C:24]#[CH:25].[OH-].[K+]>C(O)C.O>[CH2:25]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1)[C:24]#[CH:23]
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Reactant: C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (300 mg) in ethanol were added propargyl bromide (2.0 g) and potassium hydroxide (570 mg) in water at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. After ethanol was distilled off, water was added to the residue, and the resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(4-propargylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as crystalline material. M.P., 124° -125° C.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:4]1[C:3](=[O:8])[C:2]([CH3:1])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC1(c2ccccc2)CCCCC1=O
Product: CN(C)C=C1CCCC(C)(c2ccccc2)C1=O
Yield: 101.9 %

Procedure:
A mixture 2-methyl-2-phenylcyclohexanone (94 mg, 0.5 mmol) and tert.-butoxy-bis-(dimethylamino)-methane (0.16 mL, 0.77 mmol) was stirred at 110° C. for 1.5 h, whereupon it was cooled and evaporated under reduced pressure. Toluene (3 mL) was added to the residue and the solution was evaporated again to give the title compound (124 mg) as red oil which was used without further purification. MS ISP (m/e): 244.4 [(M+H)+].
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].Cl.[NH2:12][CH2:13][CH2:14][SH:15].C1(C=CC(O)=CC=1)O.[OH-].[Na+].[Cl-].[Na+]>CN(C)C=O>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:12][CH2:13][CH2:14][SH:15])#[N:2]
Reactant: NCCS
Reactant: C#CCN=C(NC#N)SC
Agent: Cl
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C#CCNC(=NCCS)NC#N
Reaction time: 17 h

Procedure:
A mixture of the product of Step A of Example 5 (1.53 g; 10 mmoles), cysteamine hydrochloride (1.136 g; 10 mmoles) and 0.055 g of hydroquinone in 10 ml of dimethylformamide is slightly warmed to dissolve. To this solution is added 10 ml of 1 N aqueous sodium hydroxide and nitrogen is bubbled through the solution. After standing at room temperature for 17 hours, the reaction mixture is evaporated to dryness to give a mixture of the title compound and sodium chloride. The title compound is extracted from the mixture with 10 ml of ethanol and the ethanolic solution is used in Step B below.