Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:17])[CH:6]2[O:15][CH3:16].[Li]CCCC.[CH2:23]1[O:25][CH2:24]1.O>C1COCC1>[C:11]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:17])[CH:6]2[O:15][CH3:16])=[C:2]([CH2:23][CH2:24][OH:25])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC1c2cc(C(C)(C)C)cc(Br)c2CC1C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC1c2cc(C(C)(C)C)cc(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 40.0 g (134.5 mmol) of 4-bromo-6-tert-butyl-1-methoxy-2-methylindane in 250 ml of THF 107.7 ml of 2.5 M (269 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 11.85 g (269.15 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, l 90 mm; eluent: hexanes/ether=20/1). Yield 27.58 g (78%) of a ca. 1 to 2 mixture of two diastereomers.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]23[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[CH:13][C:12]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)([C:28]#[N:29])[CH2:24][CH2:23]2)=[CH:11][CH:10]3[C:9]1=[O:36].N1([C:43]([O-])=[O:44])CCCCC1.C(C1(C2C=CC=CN=2)CCN(C(OC(C)(C)C)=O)CC1)#N>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:12]([CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:44][CH3:43])[N:31]=4)([C:28]#[N:29])[CH2:24][CH2:23]3)=[CH:11][C:10]=2[C:9]1=[O:36]
Reactant: O=C([O-])N1CCCCC1
Reactant: N#CC1(c2ccccn2)CCN(CC2=CC3C(=O)N([C@H]4CCCC[C@@H]4O)CC34C=CC=CC4=C2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Product: COc1cccc(C2(C#N)CCN(Cc3cc4c(c5ccccc35)CN([C@H]3CCCC[C@@H]3O)C4=O)CC2)n1

Procedure:
The titled compound was prepared employing the procedures described for the construction of 1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[d]isoindol-5-yl}methyl)-4-(pyridine-2-yl)piperidine-4-carbonitrile in Example 1, substituting tert-butyl 4-cyano-4-methoxypyridin-2-yl)piperidine-1-carboxylate for tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate. The resultant white solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 511.2715 for [M+H]+[calc'd for C31H35N4O3, [M+H]+=511.2704]: 1H NMR (400 MHz, CDCl3) δ 8.19-8.11 (m, 2H), 7.90-7.83 (m, 2H), 7.68 (s, 1H), 7.67-7.52 (m, 3H), 5.04-4.92 (m, 2H), 4.59-4.54 (m, 2H), 4.17-4.11 (m, 2H), 3.78-3.71 (m, 2H), 2.23-2.19 (m, 2H), 1.96-1.81 (m, 4H), 1.64-1.20 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14]OC)=[C:8]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:7]([CH3:22])=[CH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].FC1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>Cl.O1CCOCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)=[C:8]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:7]([CH3:22])=[CH:6]2
Reactant: COCOc1c(-c2ccsc2)c(C)cc2cc(OC)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccsc3)c(C)cc2c1
Yield: 73.8 %

Procedure:
A solution of 3-(6-Methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-thiophene (199) (0.347 g, 1.10 mmol) in 4 N HCl/Dioxane (5 mL) was stirred at room temperature for 30 min. The solvent was removed from the reaction mixture, then dissolved in DMSO (3 mL) followed by addition of Cs2CO3 (0.899 g, 2.76 mmol) and 4-fluorobenzaldehye (0.142 mL, 1.32 mmol). The reaction mixture was irradiated with microwave at 80° C. for 4.5 h. Reaction mixture was diluted with water and EtOAc, separated the layers, then the aqueous layer was extracted with EtOAc. The combined organic layer was washed with water followed by brine, dried over Na2SO4, filtered and concentrated. The crude material was purified with a gradient of 5% EtOAc in hexanes over 50 min to afford 0.304 g (74%) of the title compound (200) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.32 (s, 3H), 3.93 (s, 3H), 6.74 (d, J=8.6 Hz, 2H), 6.90-6.91 (m, 1H), 7.02-7.06 (m, 2H), 7.13 (m, 1H), 7.20-7.22 (m, 1H), 7.58 (s, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 9.81 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[C:8]([CH3:16])=[C:7]([NH:17]C(=O)OC(C)(C)C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([CH3:31])=[CH2:30].[I-].[K+]>CN(C)C=O.CCCCCC>[C:1]([C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[C:8]([CH3:16])=[C:7]([NH:17][CH2:30][C:29]([CH3:31])=[CH2:28])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(NC(=O)OC(C)(C)C)cc(C(C)(C)C)c2c1CC(C)(C)O2
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=C(C)CNc1cc(C(C)(C)C)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
tert-Butyl N-[7-(tert-butyl)-2,3-dihydro-2,2,4-trimethyl-1-benzofuran-5-yl]carbamate (7.17 g, 21.5 mmol) was dissolved in N,N-dimethylformamide (72 ml), and sodium hydride (0.62 g, 25.8 mmol) which had been washed with hexane was added at 0° C. carefully. After stirring at room temperature for 30 minutes, 3-chloro-2-methyl-1-propene (2.53 ml, 25.8 mmol) and potassium iodide (0.36 g, 2.2 mmol) were added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by a column chromatography on a silica gel (hexane:ethyl acetate=4:1). The resultant oil was dissolved in methanol (85 ml), combined with concentrated hydrochloric acid (8.5 ml), and stirred under argon atmosphere at 50° C. for 2 hours. After cooling to 0° C., the mixture was made weakly basic using a 3N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure, and then crystallized from a cold hexane to obtain 6.20 g of the title compound.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[Li+].CC([N-]C(C)C)C.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[CH2:1]([N:4]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of tert-Butyl allylcarbamate (7.2 g, 46 mmol) in THF at −78° C. was added LDA (31 mL, 1.5 M in cyclohexane) by syringe. The reaction was allowed to stir for 10 minutes before methyl bromoacetate (7.0 g, 46 mmol) was added. The reaction was then allowed to warm to RT. The reaction was quenched with water, extracted with EtOAc, dried over magnesium sulfate, and purified by silica gel chromatography (with 15% EtOAc-Hexanes). Removal of solvents provided the title compound. LC-MS (IE, m/z): 130 [M−Boc+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[N:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[C:23]3[NH2:28])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[CH3:32][N:33]([CH2:35][C:36](Cl)=[O:37])[CH3:34]>CN(C=O)C>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]([NH:28][C:23]1[C:24]2[C:19](=[C:18]([C:16]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH:17]=3)[N:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1)=[O:37]
Reactant: Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 551 mg (1.5 mmol) 5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine in 10 ml DMF was treated with 108 mg (4.50 mmol) sodium hydride and stirred for 1 h at room temperature. Then 356 mg (2.25 mmol) dimethylaminoacetyl chloride hydrochloride were added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with ethyl acetate/methanol as eluent yielding 2-dimethylamino-N-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-yl}-acetamide as brown amorphous solid; HPLC/MS (B) 1.64 min, [M+H] 453.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[H-].[Na+].CI.[C:17]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH:6][CH3:17])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (10 mmol, 2.07 g) in DMF (10 mL) was added NaH (12 mmol, 480 mg of 60% suspension in mineral oil) (exothermic, gas evolution). After 15 min MeI (20 mmol, 1.2 mL) was added. The reaction mixture was allowed to stand at ambient temperature for 1 h, then poured into a solution of saturated NaHCO3 and brine, affording the product as an orange precipitate, which was filtered, washed with water and dried in vacuo. 1H NMR (500 MHz, d6-DMSO) δ 8.27 (m, 1H), 8.22 (s, 1H), 7.25 (s, 1H), 2.96 (d, J=4.9 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8]O)=[CH:5][CH:6]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.[N:22]1C=C[CH:25]=[CH:24][CH:23]=1>>[CH2:23]([NH:22][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:24][CH3:25]
Reactant: OCCc1ccccc1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: CCCNCCc1ccccc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
25.3 g of phenethanol (available commercially from, e.g., Aldrich Chemical Co.) is added to 41 g of p-toluenesulfonyl chloride in 200 ml of pyridine at 0° C. and allowed to stand for 24 h. Water is added, and the mixture extracted with ethyl acetate. The ethyl acetate extract was washed with 5% HCl, water, and brine, dried over Na2SO4, and evaporated to a residue. The resulting tosyloxyethylbenzene is then stirred with 12.2 g of n-propylamine in 100 ml of DMF at 65° C. for one hour. The solution is diluted with water and acidified with HCl. The mixture is then washed with Et2O, basified with NH4OH, and extracted with ethyl acetate. Evaporation of the solvent (after drying over Na2SO4) produces N-propyl-N-phenethylamine (HNR1R2).
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[C:13]([F:24])[CH:12]=1>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([NH:2][NH2:3])=[O:18])=[C:13]([F:24])[CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(Oc1ccc(Cl)cc1F)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(Oc1ccc(Cl)cc1F)C(=O)NN
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.6 %

Procedure:
WSC•monohydrochloride (18.1 g), tert-butyl carbazate (10.5 g) and 4-(dimethylamino)pyridine (461 mg) were sequentially added to a solution of 2-(4-chloro-2-fluorophenoxy)-2-methylpropanoic acid (17.6 g) in acetonitrile (170 ml), followed by stirring at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and ethyl acetate was then added thereto. The organic layer was washed with water, 0.5M hydrochloric acid, saturated aqueous sodium bicarbonate solution-water (1:1) and then saturated brine in this order and was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting oil (21.8 g) was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 5 hours and was then concentrated under reduced pressure. Ethyl acetate was added thereto, followed by stirring and the solid was thus separated by filtration. Saturated aqueous sodium bicarbonate was added to the solid thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine-water (1:1) and then saturated brine in this order and was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain, as a colorless oil, 2-(4-chloro-2-fluorophenoxy)-2-methylpropanohydrazide (12.8 g).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[O:19][CH:20]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[O:19][CH:20]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCOc2coc(C(=O)OC)cc2=O)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(OCCCCCOc2coc(C(=O)O)cc2=O)ccc(C(C)=O)c1O
Reaction time: 8 h

Procedure:
To a solution of 910 mg (2.1mmole) of the title product of Example 2 in 15 ml of ethanol was added 160 mg (4 mmole) of sodium hydroxide dissolved in 15 ml of water. The mixture was stirred overnight and then acidified (ca. pH 2) with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under reduced pressure to give 680 mg of analytically pure title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11]=3[CH:10]=2)[C:7]([C:27]#[N:28])=[C:6]([CH3:29])[NH:5][C:4]=1[CH3:30])#[N:2].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:27]([C:7]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18][C:19](=[O:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:11]=3[CH:10]=2)[C:3]([C:1]#[N:2])=[C:4]([CH3:30])[N:5]([CH3:31])[C:6]=1[CH3:29])#[N:28]
Reactant: O=C([O-])[O-]
Reactant: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.253 mmol) N-[2-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)furo-[3,2-c]pyridin-4-yl]benzamide (Example 4) in DMF (1.4 ml) was cooled to 0° C., and 99 mg (0.30 mmol) caesium carbonate were added at this temperature. After stirring for 30 min, 19 μl (0.30 mmol) methyl iodide were added dropwise at room temperature, and the mixture was stirred at rt overnight. After this, additional methyl iodide (20 μL) was added, and stirring at rt was continued for further 48 h. The reaction mixture was then filtered, and the filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA, isocratic 40:60 v/v) to give 5.6 mg (5% of th.) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH2:3]1.[N:9]#[C:10][N:11]=[N+]=[N-]>CCOCC>[C:10]([N:11]1[CH:3]2[CH:4]1[C:5]([CH3:8])=[CH:6][CH2:7][N:2]2[CH3:1])#[N:9]
Reactant: CC1=CCN(C)C=C1
Reactant: N#CN=[N+]=[N-]
Solvent: CCOCC
Product: CC1=CCN(C)C2C1N2C#N
Yield: 76.2 %

Procedure:
A solution of 1,4-dimethyl-1,2-dihydropyridine (9.69 g, 65 mmol) in ether (10 ml) was added slowly with stirring at 0° C. to a solution of cyanogen azide (5.1 g, 75 mmol). The reaction mixture was allowed to return to 25° C. and the solvent was removed in vacuo to give a reddish-brown product which was partitioned between 200 ml methylene chloride-water (1:1 v/v). The methylene chloride extract was dried (MgSo4) and the solvent removed in vacuo to give 7-cyano-2,5-dimethyl-2,7-diazabicyclo [4.1.0]hept-4-ene (7.39 g, 76.2%) as a tan solid with mp 117° C. 10% palladium on charcoal (400 mg) was added to a solution of 7-cyano-2,5-dimethyl-2,7-diazabicyclo[4.1.0]hept-4-ene (2.23 g, 15 mmol) in 50 ml methanol and the reduction was effected using 10% palladium on charcoal and hydrogen gas at 35 psi for 24 hours. Filtration and then removal of the solvent in vacuo gave 1,4-dimethylpiperidylidene-2-cyanamide as a white solid (2.26 g, 99.8%) with mp 94° C; IR (KBr) 2180 (C≡N) and 1598 cm-` (C=N); NMR (CDCl3) 3.44 (m, 2H, H-6), 3.05 (s, 3H, N--Me), 2.9 (m, 1H, H-3), 2.35 (m, 1H, H-3), 2.15-1.2 (m, 3H, H-4, H-5), 1.04 (d, J=5Hz, 3H, C-4 Me). Mass spectra (70 ev): Mass calc'd for C8H13N3 : 151,1109; found: 151.1107.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH:25]=[CH2:26])[NH:20]2)=[CH:15][CH:14]=1.[CH:27]([CH2:29][C:30](O)=[O:31])=[CH2:28].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C@H:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH:25]=[CH2:26])[N:20]2[C:30](=[O:31])[CH2:29][CH:27]=[CH2:28])=[CH:17][CH:18]=1
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(OC)cc2)N1
Reactant: C=CCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Diethyl cyanophosphonate (0.67 mL) was added to a solution of (2R*,6S*)-2-(4-methoxyphenyl)-6-vinylpiperidine (320 mg), vinylacetic acid (0.37 mL), and triethylamine (1.23 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for nine hours. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 100 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>C(O)C.O.CCOC(C)=O>[CH2:16]([NH:18][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)[CH3:17]
Reactant: CCN
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1cc(Oc2ccc(N)cc2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 5.0 g, 22.6 mmol) in ethylamine dissolved in ethanol (≈35%; 5 ml) under Nratmosphere is stirred for 16 h at rt. Then the resulting brown solution is diluted with water and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with 3 portions of water and brine, dried (Na2SO4) and concentrated. Re-crystallisaton from boiling AcOEt gives the title compound: m.p.: 143-145° C.; 1H-NMR (CDCl3): 8.24 (s, 1H), 7.24 (s, HN), 6.91 (d, 2H), 6.69 (d, 2H), 5.63 (s, 1H), 4.97 (s, H2N), 3.25 (m, 2H), 1.25 (t, 3H). More product can be isolated from the filtrate of the re-crystallization by column chromatography (SiO2; AcOEt→AcOEt/EtOH 19:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(O)[CH2:5]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5]2
Reactant: OC1(c2ccccc2)Cc2cc(Br)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Brc1ccc2c(c1)CC2c1ccccc1
Yield: 76 %

Procedure:
Using 3-bromo-7-phenyl-bicyclo[4.2.0]octa-1,3,5-triene-7-ol (4a) (2.1 g, 7.6 mmol), hexane (10 ml), triethylsilane (1.3 g, 11.5 mmol), trifluoro acetic acid (4.3 g, 38.2 mmol) afforded 3-Bromo-7-phenyl-bicyclo[4.2.0]octa-1,3,5-triene (5a) as a pale yellow oil (1.5 g, GC-MS: M+=258, M−=260, 76% yield, isolated as a mixture of isomers).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[C:23]1([S:29]([CH2:32][C:33]([CH:35]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:34])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:35][C:33](=[O:34])[CH2:32][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CS(=O)(=O)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)CS(=O)(=O)c3ccccc3)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 3.3 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 100 ml of benzene is treated at room temperature with 6 g of phenylsulphonylacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-7-oxo-6-[3-(phenylsulphonyl)-2-oxopropylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as yellow crystals of melting point 100°-102° [Rf: 0.25; cyclohexane/ethyl acetate (6:4)].
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Product: CN1CCC(Nc2cccc3nc(NC(=O)c4cccnc4)nn23)CC1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 4-amino-1-methyl-piperidine (1.0 mL) as a white powder (30 mg, 27%). 1H NMR (DMSO-d6) δ 11.25 (brs, 1H), 9.13 (d, J=1.9 Hz, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.32 (dd, J=8.0, 2.0 Hz, 1H), 7.56 (dd, J=8.1, 4.7 Hz, 1H), 7.51 (t, J=8.3 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.46 (d, J=8.3 Hz, 1H), 6.312 (d, J=7.5 Hz, 1H), 3.49 (m, 1H), 2.77 (m, 2H), 2.17 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.70 (m, 2H). HPLC, Rt: 1.07 min. (purity 100.0%). LC/MS, M+(ESI): 352.4, M−(ESI): 350.4.