Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]([C:9]1[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:24]
Reactant: COC(=O)C(=O)OC
Reactant: COc1cc(Br)c2c(ccn2C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc(OC)cc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of 1-methyl-5-methoxy-7-bromoindole (1.6 g, 6.66 mmol) in THF (44.5 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 8.62 mL, 14.7 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (1.96 g, 16.7 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the extracts washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (0.9 g, 54.7%) as bright yellow oil. 1HNMR (400 MHz, CDCl3) 3.83 (s, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 6.51 (d, J=3.12 Hz, 1 H), 7.07 (d, J=3.13 Hz, 1H), 7.21 (d, J=2.35 Hz, 1H), 7.7.40 (d, J=2.34 Hz, 1H); MS (ES, m/z): C13H13NO4: 188.06 (M++1).
Reaction SMILES: [C:1]([CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])(C)C)=[O:2].C(ON1C(=O)CCC1=O)(OCC1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=O.CCN(C(C)C)C(C)C.[ClH:47]>ClCCl.O1CCOCC1>[ClH:47].[C:1]([CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11])([O:3][CH2:4][CH:7]1[C:22]2[C:23](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:2]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)C(N)CCN
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NCCC(N)C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
BOC-1,3-diaminopropane was reacted with Fmoc-OSu in dichloromethane in the presence of DIPEA, and the resulting product treated with 4M HCl in dioxane to afford Fmoc-1,3-diaminopropane hydrochloride in quantitative yield. To a solution of Fmoc-diaminopropane hydrochloride (1.1 g, 3.3 mmol), Compound 1 (1.27 g, 3.3 mmol) and Py-BOP (1.46 g, 3.3 mmol) in DMF (10 ml), was added DIPEA (1.15 ml, 6.6 mmol) and the mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with EtOAc (200 ml), washed with water, saturated aqueous sodium hydrogen carbonate, 1M aqueous potassium hydrogen sulphate, brine, and concentrated under reduced pressure to afford Compound 22 as a white solid that was triturated with hexane, collected by filtration and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])=[O:25]
Reactant: Cc1ccccc1CSc1cccc[n+]1[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1CS(=O)c1cccc[n+]1[O-]

Procedure:
To a vigorously stirred solution of 6.9 gm (0.03 mol) of 2-(2-methylphenylmethylthio)pyridine N-oxide in 50 ml of chloroform maintained at 0° to 10° C. is slowly added a solution of 6 gm (0.03 mol) MCPBA (85%) in 100 ml of chloroform. When addition is complete the temperature is allowed to rise to ambient. After sixteen hours the reaction solution is washed up in the manner described in Example 139.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:16]([CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=O)(C)(C)C>Cl.O1CCOCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH:23]1[N:16]([C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1)[CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN(c1ncccn1)C1Cc2ccccc2C1
Agent: Cl
Solvent: C1COCCO1
Product: c1cnc(N(CCC2CCCCN2)C2Cc3ccccc3C2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To compound 47 (0.303 g, 0.72 mmol) was added dioxane-HCl (20 mL) at ice-cold condition and the solution was stirred for 4 hours at rt. The solution was then concentrated under reduced pressure and dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3 solution, water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide sticky compound 48.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([O:20]C)=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>C(O)C>[OH:20][C:18]1[NH:24][N:23]=[C:16]([C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[CH:17]=1
Reactant: COC(=O)C#Cc1c(-c2ccccc2)nn2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Yield: 42.7 %

Procedure:
A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propiolate (1.50 g), hydrazine monohydrate (0.544 g) and ethanol (15 ml) was heated under reflux for 2 hours. Ethanol was evaporated in vacuo. Water (50 ml) was added to the residue and the mixture was acidified with 1N hydrochloric acid. The resultant precipitates were collected by filtration and washed with water. Recrystallization from a mixture of N,N-dimethylformamide and water gave crystals of 3-(5-hydroxypyrazol-3-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.64 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[CH:6]Cl.[C:10]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])#[CH:11]>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[CH:6][C:11]#[C:10][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C#Cc1ccccc1C#N
Reactant: C[Si](C)(C)C#CC=CCl
Product: C[Si](C)(C)C#CC=CC#Cc1ccccc1C#N
Yield: 53 %

Procedure:
The Title compound may be produced in two steps using compound a1 Example 1 and compound a3 from Example 3 as starting materials. Firstly, compound a1 and compound a3 were reacted according to Method A set forth in the above-described General Synthesis Procedures I to form 2-(6-trimethylsilyl-3-hexen-1,5-diynyl)benzonitrile, which was subsequently dissolved into into dry methanol with K2CO3 to give a brown oil in 53% yield.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(c2ccc(/C=C/C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
In a mixed solvent of THF (250 ml) and water (125 ml), (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (9.80 g) was dissolved, and the resulting mixture was cooled to 0° C. Barium hydroxide octahydrate (3.14 g) was added thereto and the resulting mixture was stirred at 0° C. for 8 hours. The reaction solution was concentrated to remove THF, and water (150 ml) was added thereto, followed by washing the resulting mixture with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: chloroform/methanol=10/1). The obtained crude product was further purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=1/1→ethyl acetate) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (6.15 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[S:11](=[O:14])(=[O:13])[N:10]([CH2:15]CN(CC)CC)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.CI>O1CCCC1>[Br:3][C:4]1[C:12]2[S:11](=[O:14])(=[O:13])[N:10]([CH3:15])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCN(CC)CCN1Cc2cccc(Br)c2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1Cc2cccc(Br)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
To sodium hydride (40 mg, 1.0 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 7-bromo-N,N-diethyl-1,2-benzisothiazole-2(3H)-ethanamine 1,1-dioxide (0.26 g, 1.0 mmol). The reaction was stirred for 20 min and treated with methyl iodide (0.06 mL, 1.3 mmol). The resulting mixture was stirred at ambient temperature over 18 h, poured into ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by a flush chromatography ((ethyl acetate/hexane, 1:4) to afford 7-bromo-2,3-dihydro-2-methyl-1,2-benzisothiazole 1,1-dioxide (0.15 g, 56%). LRMS (ES−): 262.0 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>>[CH3:27][O:26][C:16]1[C:14]2[N:15]=[C:11]([C:9]3[NH:8][C:6]4=[N:7][C:2]([N:29]([CH3:30])[CH3:28])=[CH:3][CH:4]=[C:5]4[N:10]=3)[S:12][C:13]=2[C:19]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(Cl)nc4[nH]3)nc12
Reactant: CNC
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(N(C)C)nc4[nH]3)nc12
Temperature: 200 °C
Yield: 29 %

Procedure:
0.03 g 5-Chloro-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (0.07 mmol) was dissolved in dimethylamine (5 ml) in an autoclave and heated to 200° C. for 16 h. The residue was triturated in water whereupon a precipitate formed, which was isolated and dried in vacuo. 0.08 g [2-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-dimethyl-amine (29%) were obtained as a brown solid; M.p.: 120–130° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].C(Cl)Cl.N1C=CC=CC=1.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1.O>[C:22](=[O:23])([O:24][CH:25]([CH3:27])[CH3:26])[O:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[C:6]([F:11])[CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: O=Cc1c(F)cc(O)cc1F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)Oc1cc(F)c(C=O)c(F)c1
Yield: 84 %

Procedure:
To a 250 mL dry round bottom flask were added 2,6-difluoro-4-hydroxy-benzaldehyde (4.80 g, 30.4 mmol), anhydrous CH2Cl2 (30 mL) and pyridine (3.0 mL, 36.5 mmol). The mixture was stirred in an ice-water bath, then a solution of isopropyl chloroformate in toluene (1.0 M, 33.4 mL) was added. After stirring at 0° C. for 2 hours, the mixture was stirred at room temperature overnight. Water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (80 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl isopropyl carbonate (6.20 g) as a colorless oil. Yield: 84%. 1H NMR (CDCl3, 300 MHz): δ=10.30 (s, 1H), 7.02-6.96 (m, 2H), 5.03 (seventet, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (CDCl3, 75.5 MHz): δ=183.3, 163.6 (dd, J=262.5, 7.92 Hz), 156.3 (t, J=15.2 Hz), 151.1, 111.9 (t, J=11.5 Hz), 106.0 (dd, J=25.1, 3.62 Hz), 74.5, 21.5. 19F NMR (CDCl3, 282.3 MHz): δ=−113.0 (d, J=9.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=O)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:27]([NH2:29])[CH3:28].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:24]=[N:29]/[O:27][CH3:28])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C=O)c2s1
Reactant: CON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C=N/OC)c2s1
Temperature: 105 °C
Yield: 70.4 %

Procedure:
1-(5-(Benzyloxy)-7-formylbenzo[d]thiazol-2-yl)-3-ethylurea (425 mg, 1.20 mmol), methoxylamine hydrochloride (105.2 mg, 1.26 mmol) and N,N′-diisopropylethylamine (0.77 g, 1.05 ml) were stirred in DMF degassed with N2. The reaction was purged with N2, sealed and heated to 105° C. for 18 h. LCMS after indicated complete consumption of starting material. The solvents were removed under reduced pressure and the resulting residue absorbed onto silica and purified by flash column chromatography eluting with 0 to 100% EtOAc in petroleum-ether to afford the product as a white solid 325 mg (70%) which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][C:21]=1[Cl:31].N1C=CC=CC=1>O=S(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:19][C:20]4[CH:30]=[CH:29][C:23]([C:24](=[O:25])[N:26]([CH3:27])[CH3:28])=[CH:22][C:21]=4[Cl:31])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: CN(C)C(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)c1ccc(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A solution of 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid (25.00 g, 76.9 mmol) in SOCl2 (200 mL) was heated at 90-100° C. for 3 h. Concentration of the reaction mixture gave the crude acid chloride. A suspension of the acid chloride in THF (600 mL) was treated with a solution of 4-amino-3-chloro-N,N-dimethylbenzamide (18.23 g, 92.3 mmol) and pyridine (14 mL) in THF (200 mL) at 0° C. The mixture was allowed to reach room temperature and stirred overnight. After concentration, water (200 mL) was added into the mixture. The resulting precipitate was collected by filtration, washed with water and dried to give 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.88 g, yield: 77%). ESI-MS: 504.99. 1H NMR (DMSO-d6, 400 MHz): δ10.14 (s, 1H, NH), 7.86 (s, 1H, ArH), 7.67-7.57 (m, 3H, ArH), 7.40-7.25 (m, 3H, ArH), 4.32 (t, J=5.2 Hz, 2H, CH2), 3.21 (t, J=5.2 Hz, 2H, CH2), 2.95 (s, 3H, CH3), 2.92 (s, 3H, CH3).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])#[CH:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([NH:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[CH:2])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: C#Cc1ccc(C(=O)NC(C)=O)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 22.6 %

Procedure:
4 g (0.021 mol) 4-Ethynyl-3-nitrobenzamide (Compound I-1), 30 ml (0.320 mol) acetic anhydride and 20 ml acetic acid were added into a reaction flask, stirred, and heated to 120° C. for 15 hours. After completion of the reaction monitored by TLC, the mixture was extracted with 300 ml ethyl acetate, and the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, separated by column chromatography to obtain N-acetyl-4-ethynyl-3-nitrobenzamide (Compound I-11), 1.1 g (0.0047 mol), yield 22.6%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.C(O)=O>C([O-])(O)=O.[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([C:9]1([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1)[OH:8]
Reactant: O=C(c1ccccn1)C1(c2ccc(OC(F)(F)F)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O[C@H](c1ccccn1)C1(c2ccc(OC(F)(F)F)cc2)CCC1
Yield: 77.9 %

Procedure:
A mixture of Example 288B (6.63 g, 20.64 mmol), triethylamine (7.19 ml, 51.6 mmol), formic acid (3.40 ml, 89 mmol), and (S,S)—N-(p-touenesulfonyl)-1,2-diphenylethanediamine(chloro)(p-cumene)ruthenium (II) (0.131 g, 0.206 mmol) was heated at 35° C. for 16 hours. The reaction mixture was cooled, diluted with saturated NaHCO3 solution, and extracted twice with CH2Cl2. The combined organic layers were dried with MgSO4, filtered, and concentrated. The residue was chromatographed on an analogix SF40-150 g column and eluted with 20% to 50% EtOAc/hexanes to obtain the title compound (5.2 g). [α]D=−91.1° (c=0.805, MeOH). MS (DCI+) m/z 324 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5]>O>[CH3:1][O:2][C:3]1[C:4](=[O:5])[CH:6]=[CH:7][C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(O)ccc1O
Solvent: O
Product: COC1=CC(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 152 %

Procedure:
To a vigorously stirred solution of NaIO4 (33.5 g, 157 mmol, Baker) in H2O (1500 mL), there was added solid 2-methoxyhydroquinone (11.00 g, 50.0 mmol) in portions. The reaction immediately became dark orange. The reaction was allowed to stir for 1 h at rt and was extracted with CH2Cl2 (3×150 mL). The extract was washed with half saturated brine (1×150 mL), filtered through cotton and the solvent removed in vacuo to yield 2-methoxybenzoquinone as an orange solid (10.5 g) which was of sufficient purity (TLC analysis, 10% EtOAc/90% CHCl3) for further reaction. The crude quinone was combined with toluene (150 mL) and hydroquinone (1.0 g, Mallinkrodt). Neat 2,3-dimethyl-1,3-butadiene (8.3 g, 101 mmol, Aldrich) was added. The reaction was allowed to stir overnight at 65° C. under N2. TLC (10% EtOAc/90% CHCl3) indicated total consumption of the dienophile. The solvent was removed in vacuo to yield a dark solid. This was triturated with MeOH (100 mL) at n to give a beige solid. Crystallization from MeOH (dissolved in 140 mL, allowed to cool to rt) yielded a fluffy colorless solid (10.2 g, 64%, >95% pure by 1H NMR analysis); mp 133°-134° C. (MeOH); 1H NMR (CDCl3) δ1.62 (s, 6H), 2.12 (m, 2H), 2.42 (m, 2H), 3.09 (m, 1H), 3.20 (m, 1H), 3.78 (s, 3H), 5.88 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:6](=[N:11][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:10]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C1CCCCC1=O
Product: O=[N+]([O-])c1ccc2nc3c(nc2c1)CCCC3
Reaction time: 8 h

Procedure:
A mixture of 4-nitro-o-phenylenediamine (33.7 g, 0.22 mole) and 25.0 g (0.22 mole) of 1,2-cyclohexanedione in 500 ml of SDA#32 was heated at reflux for 24 hours. The reaction mixture was then stored overnight at room temperature and then filtered. The brown crystalline solid was then washed with ether, air dried, and dried to a consistent weight at 60°, m.p. 175°-178°. Yield: 22 g (96%).
Reaction SMILES: C(CCCCC(O)=O)=O.N.[H][H].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>O.[Ni].[Co].[Ru].[Zr]>[C:19]1(=[O:21])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: [H][H]
Agent: [Co]
Agent: [Ni]
Agent: [Ru]
Solvent: O
Product: O=C1CCCCCN1
Temperature: 300 °C

Procedure:
A process for preparing ε-caprolactam is described in U.S. Pat. No. 4,730,040. In this process, methyl 5-formylvalerate is first hydrolyzed (step a) in the presence of water and an acidic agent to yield 5-formylvaleric acid. In this process, the 5-formylvaleric acid is reductively aminated in water through contact with ammonia and hydrogen using a ruthenium/zirconium on alumina catalyst, a Raney Nickel catalyst or a Raney Cobalt catalyst to obtain a 6-aminocaproic acid containing reaction mixture. After separation of ammonia, the reaction mixture obtained from the reductive amination is heated to 300° C. to form ε-caprolactam by cyclization of the 6-aminocaproic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>ClC(Cl)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](OC(=N)C(Cl)(Cl)Cl)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 28.8 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), trichloroacetonitrile (0.1 mL, 1.0 mmol), 1,8-Diazobicylo[5.4.0]undec-7-ene (0.05 mL, 0.3 mmol) in dichloroethane (20 mL) was stirred at 0° C. for 24 h. The reaction mixture was then washed with saturated NaHCO3 (10 mL) and H2O (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a crude oil. The oil was purified by column chromatography (eluent: ethyl acetate/n-hexanes) to afford 21 (0.02 g, 37%) as a white solid, mp 120-123° C.; 1H NMR (CDCl3): δ 1.18 (s, 3H); 1.50 (s, 3H); 1.52-1.76 (m, 4H); 1.85 (dd, Ja=2.6, Jb=10.1, 1H); 2.10 (dd, Ja=2.9, Jb=11.6, 1H); 2.20 (m, 1H); 2.24 (s, 1H); 2.35-2.58 (m, 3H); 2.80 (dd, Ja=4.1, Jb=12.5, 1H); 3.75 (s, 3H); 5.34 (dd, Ja=7.7, Jb=12.2, 1H); 6.40 (dd, Ja=0.9, Jb=1.5, 1H); 7.41 (dd, 1H, 1.5, 1.5, 1H); 7.43 (dd, Ja=0.9, Jb=1.5, 1H); 8.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccccc1Br
Temperature: 120 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (0.203 g, 1 mmol) in DMA (2.5 mL) were added 2-bromophenol (0.182 g, 1.05 mmol) and potassium carbonate (0.138 g, 1 mmol), followed by stirring at 120° C. for 12 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue was purified through column chromatography (20% ethyl acetate/hexane) and concentrated to obtain the object compound (0.164 g, 46%).