Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][O:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>O1CCCC1>[C:12]1([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:9][O:8][CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CC1(N2CCCC2)COC1
Reactant: [Li]c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(c1ccccc1)C1(N2CCCC2)COC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Pyrrolidin-1-yl-oxetane-3-carbonitrile (intermediate A, 1.6 g, 91% purity, 10 mmol) was dissolved in 10 mL tetrahydrofurane. Phenyllithium (2M in dibutylether, 9.8 mL, 20 mmol) was added dropwise at −5° C. The reaction mixture was stirred at room temperature for 1.5 hours and poured into cold saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was dissolved in 35 mL methanol and sodiumborohydride (0.77 g, 20 mmol) was added portion-wise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and quenched by addition of water. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product (brown oil, 2.26 g, 99%) was used for the next step without further purification, MS: m/e=216.3 [(M−NH2)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16]Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:22]=1[CH2:23][OH:24].[H-].[Na+]>CN(C)C=O>[F:20][C:21]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:22]=1[CH2:23][O:24][CH2:16][CH2:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: OCc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCBr)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCOCc2cc(Br)ccc2F)C1

Procedure:
An amount of 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (180 mg, 0.588 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) in a 10 ml flask under a nitrogen atmosphere. Sodium iodide (176 mg, 1.18 mmol) was added at ambient temperature, and the resulting mixture was stirred for ten minutes. The reaction mixture was treated with 2-fluoro-5-bromobenzyl alcohol (121 mg, 0.588 mmol), delivered as a solution in 0.5 ml of N,N-dimethylformamide. To this mixture was then added sodium hydride (60%, 35 mg, 0.882 mmol) and the resulting mixture was stirred at ambient temperature for three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by liquid chromatography.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:11][O:10][C:9]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])=[N:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:9]1[O:10][CH2:11][CH:7]([C:5]2[S:6][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)[N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)s2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccccc3)s2)CO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 100 mg (0.3 mmol) of the product of Step D of Example 2 in 0.6 mL toluene was added successively 10.4 mg (0.009 mmol) of Pd (PPh3)4, 0.3 mL of 2.0 m sodium carbonate, and 44 mg (0.36 mmol) of phenylboronic acid in 0.15 mL of methanol. The mixture was stirred at 80° C. for 2 h. It was cooled and partitioned between 25 mL of 2.0 m sodium carbonate containing 2.5 mL of ammonium hydroxide solution and 25 mL of methylene chloride. The methylene chloride layer was washed with brine, dried (MgSO4), and concentrated. The residue was passed through a silica gel flash column eluting with ethyl acetate: hexanes (1:4) to give 85 mg of an oil. 1H-NMR (CDCl3) δ6.90-7.20 (m, 10H), 5.70 (dd,1H), 4.80 (t, 1H), 4.45 (t, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]2OCC[O:12]2)[CH:8]=[CH:9][CH:10]=1)#[N:2].Cl>O1CCCC1>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:12])#[N:2]
Reactant: N#CCCc1cccc(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Product: N#CCCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To 3.52 g of 2-[3-(2-cyanoethyl)phenyl]-[1,3]dioxolane was added 60 ml of tetrahydrofuran to dissolve this, and 20 ml of 6 N hydrochloric acid was added. After stirred at room temperature overnight and then concentrated under reduced pressure, ethyl acetate was added, and this was washed successively with an aqueous potassium carbonate solution and an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, concentration under reduced pressure afforded 2.68 g of 3-(2-cyanoethyl)benzaldehyde [Compound No. (m)].
Reaction SMILES: Cl[C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18](O)([CH3:20])[CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C(O)=O.CN1CCCC1=O>O>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH:36][C:2]3[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18]([CH3:20])=[CH2:19])=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=4)[N:7]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of 3-chloro-6-(2-hydroxypropan-2-yl)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (1.48 g), 4-(4-methylpiperazin-1-yl)aniline (883 mg), trifluoroacetic acid (385 μL), and N-methylpyrrolidone (14.8 mL) was heated to 160° C. for 5 hours. To the reaction mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration and then dried. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-30:1:0.1) and washed with ethyl acetate to obtain 3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (1.15 g) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[CH:10]([C:6]1[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[C:7]=1[O:8][CH3:9])=[O:11]
Reactant: COc1ccccc1B(O)O
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Product: COc1ccccc1-c1cc(S(N)(=O)=O)cc(C=O)c1OC
Yield: 75.3 %

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide (0.9 g, 3.1 mmol) and 2-methoxybenzene boronic acid (0.51 g, 3.37 mmol), gave 5-formyl-6,2′-dimethoxy-biphenyl-3-sulfonamide (0.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:28])[CH2:19][CH:20]([CH3:27])[CH2:21][C:22](=[O:26])C(O)=O.[C:29]1([C@H:35]([NH2:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:28])[CH2:19][CH:20]([CH3:27])[CH2:21][C:22]([NH:37][CH:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:36])=[O:26]
Reactant: CCCCCCc1c(C(=O)CC(C)CC(=O)C(=O)O)c2cc(Cl)ccc2n1C
Reactant: C[C@@H](N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCCCCc1c(C(=O)CC(C)CC(=O)NC(C)c2ccccc2)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 6-(5-chloro-2-hexyl-1-methyl-1H-indol-3-yl)-4-methyl-2,6-dioxohexanoic acid in methylene chloride was added (R)-1-phenylethanamine followed by the addition of DCC and DMAP and was stirred for 30 minutes. The reaction mixture was treated with sodium bicarbonate and methylene chloride. The product was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([OH:11])=O)[CH2:6][CH2:5]1.C(Cl)(=O)[C:13]([Cl:15])=O>ClCCl.CN(C)C=O>[Cl:15][CH2:13][C:9]([CH:7]1[CH2:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8]1)=[O:11]
Reactant: COCC1CCC(C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC1CCC(C(=O)CCl)O1
Reaction time: 1 h

Procedure:
A solution of (2RS,5SR)-5-methoxymethyltetrahydrofuran-2-carboxylic acid (3.1 g) in dichloromethane (50 ml) was treated with oxalyl chloride (2.68 ml) and dimethylformamide (1 drop). The mixture was stirred for 1 h and heated to reflux for 10 mins. The solvent was evaporated and then dichloromethane was evaporated from the residue twice. The product was dissolved in dichloromethane (100 ml) and the solution cooled in an ice bath. Diazomethane was then passed into the solution as described in Example 14(a). When the addition was complete the mixture was stirred at 0° C. for 0.5 h and then hydrogen chloride gas was passed into the solution until all the diazoketone had been consumed. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.44 g) was isolated by column chromatography using gradient elution (silica gel, 4:1 going to 1:1 hexane:ethyl acetate); νmax (film) 1740 cm-1 ; δH (CDCl3) 1.6-2.35 (4H,m), 3.30-3.75 (2H,m), 3.37 (3H,s) and 4.05-4.75 (4H,m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:12]=[CH:13][C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C([O:28][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=O)[CH:30]=1)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:13][C:14]=1[C:31]1[CH2:32][CH2:33][CH2:34][C:29](=[O:28])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: CCOC1=CC(=O)CCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 3.89 g. (10 mmoles) of 2-(3-benzyloxy-4-bromophenyl)-2-methyloctane in 10 ml. of tetrahydrofuran was slowly added to 360 mg. (14.4 mmoles) of 70-80 mesh magnesium metal. The resulting mixture was refluxed for 30 minutes and then cooled to 0° C. To this solution was slowly added a solution of 1.40 g. (10 mmoles) of 3-ethoxy-2-cyclohexen-1-one in 3 ml. of tetrahydrofuran. The reaction mixture was stirred for 30 minutes at 0° C. and then quenched by the addition of 20 ml. of 1N sulfuric acid and heating on the steam bath for 30 minutes. It was then cooled and added to 200 ml. of ether-200 ml. of water. The organic extract was washed successively with 200 ml. of saturated sodium bicarbonate and 200 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified via column chromatography on 170 g. of silica gel eluted with 1:1 ether:pentane to yield 2.5 g. (54%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:17]=1)[CH2:7][CH2:8][C:9]1[C:10](/[C:15]/2=[C:19]2/[CH2:20][CH:10]([CH3:9])[NH:11][CH2:12][CH:18]/2[CH3:22])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Reactant: C1CCOC1
Product: CC1C/C(=C2\c3ccc(Cl)cc3CCc3cccnc32)C(C)CN1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a cooled (ice-bath), stirred solution of 8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (6.3 g, 26 mmol) in THF (50 mL) was added the above Grignard reagent. The reaction was allowed to stir for 1 hr. at this temperature and then quenched with NH4Cl solution. The product was extracted 3× with EtOAc, washed once with brine, dried (Na2SO4), filtered and solvent removed to give a crude brown material which was chromatographed to give the title compound (5.1 g, 53% yield) as a yellowish glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:10][N:11]([CH2:15][CH2:16]O)[CH2:12][CH2:13]O.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:10][N:11]1[CH2:15][CH2:16][N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[CH2:13][CH2:12]1
Reactant: CN(CCO)CCO
Agent: O=S(=O)(O)O
Solvent: COc1ccccc1N
Product: COc1ccccc1N1CCN(C)CC1
Reaction time: 15 h

Procedure:
Here, 123 g of 2-methoxyaniline, 120 g of N-methyl-2,2'-iminodiethanol and 119 g of sulfuric acid, 100% strength, were employed. After a nitrogen pressure of 2 bar had been applied (final pressure 4.8 bar), the autoclave was kept at 160° C. for 15 h. Again, work-up was carried out as described in Example 1. 52.71 g of unreacted 2-methoxyaniline (bp. 740 to 80° C. at 1.3 to 1.7 mbar; Vigreux column 10 cm) and 52.1 g of N-methyl-N'-(2-methoxyphenyl)-piperazine (bp. 113° to 127° C. at 2.0 to 2.2 mbar) were obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](Cl)=[O:13])=[CH:7][CH:6]=1>O.C1C=CC=CC=1>[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([N:2]([CH3:3])[CH3:1])=[O:13])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O
Product: CN(C)C(=O)c1cccnc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a rapidly stirred mixture of 10 mL of benzene and dimethylamine (2.6 mL of a 40% solution) was added a slurry of 2-(4-chlorophenoxy)nicotinoyl chloride (0.536 g, 2 mmol, Maybridge Chemical Co.) over 5 min. The biphasic mixture was stirred at room temperature for 18 h and then diluted with water and benzene. The aqueous layer was further extracted with benzene and the organic layers were combined and washed (brine, water), dried (Na2SO4) and concentrated in vacuo to produce the product as a pale yellow oil (0.432 g); δH (CDCl3, 400 MHz) 8.14 (dd, 1H), 7.72 (dd, 1H), 7.33 (m, 2H), 7.03 (m, 3H), 3.12 (s, 3H), 2.99 (s, 3H); MS m/z279, 277 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:12]=[C:13]([Si:14]([CH3:16])([CH3:15])[CH3:17])[NH:11][C:5]2=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C#Cc1cc(Br)c(C2CC2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[Si](C)(C)c1cc2cc(Br)c(C3CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 121.3 %

Procedure:
A stirred solution of 5-bromo-6-cyclopropyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1 g, 3.2 mmol), tert-butanol (10 mL) was added potassium tert-butoxide (1.45 g, 12.9 mmol) and stirred at ambient temperature for 15 min. RM was quenched with water and extracted with ethyl acetate, organic portion was dried over sodium sulfate and concentrated to give 1.2 g of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 7.86-7.85 (m, 1H), 6.45-6.42 (m, 1H), 4.98-4.96 (m, 1H), 4.88-4.7 (m, 1H), 4.55 (s, 2H), 2.35-2.31 (m, 1H), 2.0 (s, 9H), 1.04-0.86 (m, 4H). LCMS: m/z=311.1 (M+1).
Reaction SMILES: [CH:1]([CH2:3][C:4]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8])=O.C(=O)([O-])[O-].[K+].[K+].[Br-].[C:44]1([CH2:50][CH2:51][CH2:52][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:9][CH:7]([CH3:8])[CH2:6][C@@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:4]([CH2:3][CH:1]=[CH:52][CH2:51][CH2:50][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=CCCc1ccccc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 66.4 %

Procedure:
A mixture of 0.496 g of 1,2-dibenzyl 1-tert.butyl 1-(formylmethyl)-4-methyl-1,1,2(R)-pentane tricarboxylate, 0.176 g of potassium carbonate and 0.576 g of 3-phenylpropyltriphenylphosphonium bromide in 8 ml of dry tetrahydrofuran was heated at reflux under a nitrogen atmosphere for 3 days. The solvent was removed by evaporation and stirred with diethyl acetate. The solids which separated were filtered off and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (6:1) for the elution. There was obtained 0.397 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(5-phenyl-pent-2-en-1-yl)-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23])=[O:17].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])=[O:17]
Reactant: COCCOC(=O)Nc1cccc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: COCCOC(=O)Nc1cccc(C=O)c1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
To a mixture of 13 ml of oxalyl chloride and 400 ml of dichloromethane was added dropwise a solution of 23 ml of dimethyl sulfoxide in 40 ml of dichloromethane at −60° C. for 15 minutes. After stirred at −60° C. for 10 minutes, a solution of 30.2 g of 3-[(2-methoxyethoxy)carbonylamino]benzyl alcohol in 100 ml of dichloromethane was added dropwise at −60° C. for 25 minutes. After stirred at −60° C. for 20 minutes, 56 ml of triethylamine was added dropwise at −60° C. for 15 minutes. After stirred at room temperature for 45 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed successively with water and then an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate and then concentration, the resulting crude crystals were washed with t-butyl methyl ether and then dried to obtain 17.55 g of 3-[(2-methoxyethoxy)carbonylamino]benzaldehyde [Compound No. (h)] as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:27])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]1)#[CH:20]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:27][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]4)[C:6]=3[CH:18]=2)[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1
Temperature: 100 °C
Yield: 9.9 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure E. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.64 mmol) in acetonitrile (3 mL) and triethylamine (3 mL) were added, Pd(PPh3)2Cl2 (44 mg, 0.06 mmol), 3-Ethynyl-1-methyl-pyrrolidin-3-ol (160 mg, 1.3 mmol) and CuI (12 mg, 0.06 mmol). Then the solution was bubbled N2 for 5 min and heated by microwave for 1 h at 100° C. under nitrogen. The reaction mixture was filtered and the filtrate was purified by column to afford crude product. The crude product was purified by Prep HPLC to afford the titled compound (22.3 mg, 10%). 1H NMR (DMSO-d6, 400 MHz): δ 8.52 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.48 (s, 4H), 2.95 (m, 1H), 2.77 (m, 2H), 2.67 (m, 1H), 2.31 (s, 3H), 2.28 (m, 1H), 2.08 (m, 1H). LCMS=353.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[NH2:16][C:15]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH:10]=2)[O:14][C:31]=1[C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 0.5 g (1.46 mmol) of the product of Step B in 10 mL DMF was added 0.954 g Cs2CO3 and 0.197 mL of 1-bromopinacolone. The reaction was stirred 17 hours at room temperature at which point the reaction mixture was diluted with ethyl acetate and washed with saturated NaCl/NaHCO3 solution (1:1). The residue from the concentrated solution was purified via silica gel flash chromatography eluting with a gradient of 0 to 75% ethyl acetate/hexane to afford the title compound. HPLC-MS: 439.1 (M+1), 441.1 (M+3); Rt=4.53 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
To a solution of 1.37 g of 3-aminobenzoic acid and 0.4 g of sodium hydroxide added to 50 ml of water was added dropwise a solution of 1.41 g of benzoyl chloride and 0.4 g of sodium hydroxide dissolved in 5 ml of water under an ice bath at the same time, and the resulting mixture was stirred at room temperature for 6 hours. 1N hydrochloric acid was added to the reaction solution which was adjusted to pH 1, and then the precipitated solid was filtered off and collected to obtain 1.92 g of the desired product (Yield: 80%) as a white solid.