Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[N:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[ClH:20]>CO.[Ni].C(OCC)(=O)C>[ClH:20].[CH:1]1([O:6][C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(C=NO)c1OC1CCCC1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(CN)c1OC1CCCC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime (3 g, 12.448 mmol) in methanol (10 ml) was added catalytic amount of Raney nickel (0.30 g) at room temperature. The reaction mixture was stirred for 3 h at 50 psi hydrogen pressure in Paar hydrogenation apparatus. The reaction mixture was filtered through celite bed, dried (Na2SO4), filtered and concentrated to get the crude product. The crude product was then dissolved in ethyl acetate, to which hydrochloric acid in ethyl acetate was added dropwise at 10° C. and stirred for 20 min and then filtered and dried to yield 2.86 g of the product, 1H NMR (300 MHz, DMSO-d6) δ 1.57-1.63 (m, 4H), 1.65-1.72 (m, 4H), 3.81 (s, 3H), 3.94 (s, 2H), 4.90 (br s, 1H), 7.08 (s, 3H), 8.39 (br s, 3H).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH2:3][O:4][CH3:5].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:12])[CH2:3][O:4][CH3:5]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
DMF (2 drops) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (6.0 g, 19.0 mmol) and oxalyl chloride (1.99 mL, 22.8 mmol) in DCM (40 mL) The mixture was stirred at ambient temperature for 2 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride was dissolved in DCM and added dropwise to 2-amino-5 methylpyrazine [Tett lett. 2002, 9287-90] (2.28 g, 19.8 mmol) and pyridine (2.56 mL, 38 mmol) in DCM (40 mL), at 0° C. Stirred at ambient temperature for 24 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL), dried (MgSO4), and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 30-100% ethyl acetate in isohexane, to give the desired compound (7.6 g)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].Cl>C(Cl)Cl.CO>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1NCCCNC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of N1-(3-Aminopropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.89 g, 3.1 mmol) in 30 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was treated first with triethylamine (0.92 mL, 6.6 mmol) and then slowly with acetyl chloride (0.234 mL, 3.29 mmol). After 16 h, another equivalent of acetyl chloride was added. After 3 h, the reaction was concentrated under reduced pressure to yield an orange oil. The oil was then treated with 20 mL of 1 M HCl in MeOH and stirred at ambient temperature to hydrolyze any bis-amide. After 16 h, the reaction was quenched with 25 mL of 10% Na2CO3 solution. The mixture was concentrated under reduced pressure to remove MeOH. The aqueous oily suspension was treated with 75 mL of 95:5 CHCl3:MeOH, transferred to a separatory funnel and separated. The organic portion was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow foam. The foam was purified by chromatography (40 g SiO2, 25% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a light yellow solid. The solid was recrystallized from MeCN to give N-{3-[(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}acetamide (0.67 g) as yellow crystals. mp 167–169° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=8.1 Hz, 1H), 7.85 (t, J=5.2 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.44–7.38 (m, 1H), 7.25–7.20 (m, 1H), 6.96 (t, J=5.3 Hz, 1H), 6.51 (s, 2H), 3.19–3.08 (m, 4H), 2.97 (q, J=7.4 Hz, 2H), 1.78 (s, 3H), 1.69 (p, J=7.0 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 169.5, 154.9, 152.0, 144.9, 132.1, 126.9, 126.1, 124.2, 121.1, 121.0, 114.9, 49.7, 36.8, 28.0, 23.0, 19.5, 12.4; MS (ESI) m/z 327 (M+H)+; Anal. Calcd for C17H22N6O: C, 62.56; H, 6.79; N, 25.75; Found: C, 62.40; H, 7.06; N, 25.82.
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(#N)C>[N+:28]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH2:10]4)[CH2:8]2)[CH2:14]3)=[CH:6][CH:5]=1)([O-:29])=[O:27]
Reactant: COC(=O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COC(=O)CC12CC3CC(C1)CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Temperature: 0 °C

Procedure:
Methyl 3-phenyl-1-adamantaneacetate, example 1, (78.8 g) was dissolved in acetonitrile (800 mL) and cooled in an ice bath while stirring under a nitrogen atmosphere. Nitronium tetrafluoroborate (40.8 g) in acetonitrile (800 mL) was added dropwise over 45 minutes. The reaction was stirred for 45 minutes after the addition, then poured into ice (985 g). The resulting solid was collected by filtration and dried in vacuo to give methyl 3-(4-nitrophenyl)-1-adamantaneacetate (55.9 g). Mass spectrum: (M+NH4)+ @347. Extraction of the aqueous phase with t-butyl methyl ether (2×800 mL) yeilded additional material including the lesser products, methyl 3-(2-nitrophenyl)-1-adamantaneacetate; Mass spectrum: (M+NH4)+ @347 and methyl 3-(2,4-dinitrophenyl)-1-adamantaneacetate; Mass spectrum: (M+NH4)+ @392.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[C:21]([CH3:44])=[N:22][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:24]=4)[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.[Cl:52]CCl.[OH-].[Na+]>O.C(OCC)(=O)C>[ClH:52].[CH3:44][C:21]1[C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[C:8]2[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:24][NH:23][N:22]=1
Reactant: ClCCl
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(-c3ccc(S(C)(=O)=O)s3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]cc1-c1ccc2nccc(-c3ccc(S(C)(=O)=O)s3)c2c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 33 mg 4-[5-(methylsulfonyl)-2-thienyl]-6-(3-methyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 156, 0.5 mL trifluoroacetic acid and 2 mL dichloromethane was stirred overnight at room temperature. The reaction solution was cooled with iced water and basified with 5 N aqueous sodium hydroxide, then ethyl acetate and water were added thereto, and the organic layer was separated. The aqueous layer was saturated with common salt and then extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The residue was dissolved in methanol, and 0.15 mL of 4 N hydrochloric acid/ethyl acetate was added thereto. The reaction solution was evaporated, then ethyl acetate was added to the residue, and the formed crystals were separated by filtration to give 13 mg of the title compound as a pale yellow solid.
Reaction SMILES: BrCC[CH:4]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:19][CH2:20][O-].[Na+].[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26].[CH2:30]([CH:32]([CH2:36][CH3:37])[C:33]([NH2:35])=[O:34])[CH3:31]>C(O)C.CN(C)C=O>[CH2:30]([CH:32]([CH2:36][CH3:37])[C:33]([NH2:35])=[O:34])[CH3:31].[C:23]([O:29][CH2:19][CH2:20][C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:14][CH:13]=1)(=[O:28])[CH2:24][C:25]([O-:27])=[O:26]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCC(CCBr)CCC(=O)c1ccccc1
Reactant: CC[O-]
Agent: CCC(CC)C(N)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The fraction which contains 4-(2-bromoethyl)octanophenone prepared in the step N (500 mg) was dissolved in anhydrous ethanol (2 ml) to obtain a solution. Sodium ethylate (164 mg) was added to the solution. The mixture was stirred under atmosphere of nitrogen at 60° C. for 1 hour. The suspension was dissolved in N,N-dimethylformamide (10 ml) to obtain a solution. Diethyl acetamide malonate (1050 mg) and sodium ethylate (245 mg) were added to the solution, and the solution was stirred under atmosphere of nitrogen at 60° C. overnight. The reaction solution was poured into ice water, extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0e3:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (477 mg) in the form of colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzaldehyde (4.38 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess 2,6-dichlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the gummy oil which separates is extracted into ether. The ether extract is washed with brine solution, and dried (Na2SO4). Removal of the ether in vacuo, yields a yellowish residue which after recrystallization from a mixture of n-butyl chloride and petroleum ether (30°-60°C.) gives a white material, 1.75 g., m.p. 140.5°-143°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[N:41]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:39][N:40]1[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:27][CH2:26]4)[CH:20]=[N:19][CH:18]=2)=[CH:43][CH:42]=[N:41]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 150 °C
Yield: 100 %

Procedure:
(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, St. Louis, Mo.; 84 mg, 0.405 mmol), PdCl2(Amphos) (Aldrich, St. Louis, Mo.; 19.14 mg, 0.027 mmol), and potassium phosphate (172 mg, 0.811 mmol) in a mixture of dioxane (2.5 mL) and water (0.250 mL) was heated by microwave at 150° C. for 5 min. The resulting mixture was heated at 100° C. for 3 h. The mixture was subsequently concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-80% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-(1-methyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol, 100% yield) as a light-yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.06 (1 H, s), 8.43 (1 H, s), 8.21 (1H, br. s.), 7.76 (1 H, d, J=8.6 Hz), 7.58 (1 H, s), 7.49 (1 H, d, J=8.4 Hz), 6.33 (1H, s), 5.86 (1 H, d, J=7.6 Hz), 4.57 (1 H, br. s.), 4.31-4.40 (1 H, m), 4.19-4.29 (1 H, m), 4.06 (1 H, d, J=11.0 Hz), 3.93 (3 H, s), 3.75-3.87 (1 H, m), 3.15 (1 H, d, J=14.1 Hz), 2.92 (1 H, br. s.), 2.60-2.74 (1 H, m), 2.43 (1 H, br. s.), 2.25 (1 H, m, J=9.0, 4.1 Hz), 2.17 (1 H, d, J=14.9 Hz), 1.76-1.91 (2 H, m), 1.74 (2 H, br. s.), 1.13 (9 H, br. s.), 0.78-0.88 (2 H, m), 0.62-0.73 (2 H, m). MS (ESI, pos. ion) m/z: 586.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].Cl[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([S:31]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])(=[O:33])=[O:32])[CH:30]=1.[Li+].[Br-].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([S:31]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])(=[O:33])=[O:32])[CH:30]=3)[CH2:18][CH2:17]2)[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: COc1ccc(CCCl)cc1S(=O)(=O)NCC(N)=O
Reactant: CCOCc1nc(C2CCNCC2)oc1-c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc(C2CCN(CCc3ccc(OC)c(S(=O)(=O)NCC(N)=O)c3)CC2)oc1-c1ccccc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(4-ethoxymethyl-5-phenyl-oxazol-2-yl)-piperidine (450 mg, 1.4 mmol), prepared as in Intermediate 4, and 2-[5-(2-chloro-ethyl)-2-methoxy-benzenesulfonylamino]-acetamide (644 mg), prepared as in Intermediate 6, LiBr (182 mg), and diisopropyl ethylamine (0.73 mL) in dioxane (15 mL) is stirred at 100° C. for 18 h. The solvent is evaporated and the residue purified by chromatography on silica using 3% MeOH:CHCl3 as eluent to afford the product as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28].[C:29](O)(=[O:31])[CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28])(=[O:31])[CH3:30]
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2NC(C)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 19.6 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), acetic acid (9 mg, 0.15 mmol), EDCI.HCl (29 mg, 0.15 mmol), and HOBt (20 mg, 0.15 mmol) in acetonitrile (5 mL) was added DIPEA (0.052 mL, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep HPLC to give the title compound as a white solid (Yield: 9 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH:3](O)[CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH3:11].CN(C)P(=O)(N(C)C)N(C)C.[I+].C[P+](OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.CCCCC>C(OCC)C>[CH2:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH3:11].[CH2:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH3:11]
Reactant: C=CC(O)C/C=C\C/C=C\CC
Agent: C[P+](Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Agent: [I+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C/C=C/C=C/C/C=C\CC
Product: C=C/C=C/C=C\C/C=C\CC
Temperature: 50 °C
Reaction time: 1 h
Yield: 20 %
Yield: 20 %

Procedure:
(5Z,8Z)-1,5,8-undecatrien-3-ol (3.0 g, 18.1 mmol), 60 ml of hexamethylphosphoric triamide (HMPTA) and 16.4 g (36.2 mmol) of methyl(triphenoxy)phosphonium iodine (MTPI) were added to a reactor under a nitrogen atmosphere followed by stirring at room temperature for 3 hours and at 50° C. for 1 hour. The reaction was stopped by addition of 50 ml of ice water followed by extracting with pentane. After the organic layer was washed with a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was subjected to a chromatographic treatment using pentane to give 2.0 g (yield: 74%) of a crude product. The resultant crude product (0.5 g, 3.37 mmol) was further purified by a chromatography using pentane and diethyl ether to give 0.05 g (yield: 20%) of (3E,5Z,8Z)-1,3,5,8-undecatetraene and 0.05 g (yield: 20%) of (3E,5E,8Z)-1,3,5,8-undecatetraene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[S:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2)ccc1OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(=S)c2ccccc2)ccc1OC
Yield: 89.3 %

Procedure:
A 2 liter round bottom flask was charged with 15.7 grams (55 mmol) methyl-2-methoxy-5-benzamidobenzoate and 22.2 grams (55 mmol) of Lawesson's reagent followed by 500 mL of toluene. The reaction mixture was heated under reflux for 1.5 hours. The mixture was diluted with 500 mL of ethyl acetate, and washed with 250 mL of saturated aqueous bicarbonate solution, followed by washes with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with 96/4 methylene chloride-ether. There was obtained 14.8 grams (89%) of desired material.
Reaction SMILES: CO[CH:3]([O:17]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH:24]=O.[C:32]([C:38]([O:40][CH3:41])=[O:39])#[C:33][C:34]([O:36][CH3:37])=[O:35]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:24]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:17])=[C:33]([C:34]([O:36][CH3:37])=[O:35])[C:32]=2[C:38]([O:40][CH3:41])=[O:39])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Reactant: COC(=O)C#CC(=O)OC
Product: CCOc1ccc(-c2c(C(=O)OC)c(C(=O)OC)c(O)c3cc(OC)c(OC)c(OC)c23)cc1OC
Yield: 67 %

Procedure:
2-Bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal, 3-methoxy-4-ethoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated in the same manner as described in Example 1, whereby 1-(3-methoxy-4-ethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene is obtained as colorless needles. Yield: 67%
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1cccc(F)c1
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (64 mg, 77%), MS (ISP) m/z=334.6 [(M+H)+], mp 261° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:18])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(C(=O)Nc2ccccc2O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccccc2OC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A solution of N-(2-hydroxyphenyl)-4-methoxybenzamide (0.486 g, 2.00 mmol) in methylene chloride (35 mL) was cooled to 0° C. Triethylamine (0.281 mL, 2.00 mmol) was added followed by the dropwise addition of a solution of 4-tert-butylbenzoyl chloride (0.393 mL, 2.00 mmol) in methylene chloride (15 mL). The reaction mixture was allowed to warm to room temperature over 16 h and washed with cold water, dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from diethyl ether provided 0.563 g (70%) of the title compound.