Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]4[CH:19]=[CH:18][O:17][C:16](=[O:20])[C:12]4=[N:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]4[CH2:19][CH2:18][O:17][C:16](=[O:20])[C:12]4=[N:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: O=c1occc2c1ncc1c2ccn1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1OCCc2c1ncc1c2ccn1Cc1ccc(F)cc1
Yield: 926.5 %

Procedure:
A solution of 7-(4-fluorobenzyl)pyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(7H)-one (0.30 g, 0.102 mmol) and Pd/C (5% Pd, 50 mg) in methanol (100 mL) was shaken in a Parr shaker under hydrogen (20 psi) for 16 hours. The catalyst was filtered off, the filtrate was concentrated and dried in vacuum to provided the title compound as a solid (0.28 g, 4% yield). that was used without further purification in the next step 1H NMR (MeOD) δ; 8.77 (s, 1H), 7.76 (d, 1H, J=3.0 Hz), 7.28 (d, 2H, J=5.1 Hz), 7.07 (d, 2H, J=5.1 Hz), 6.86 (d, 1H, J=3.0 Hz), 4.66 (d, 2H, J=6 Hz), 7,28 (d, 2H, J=6 Hz). MS (APCl, M+H+): 297.1.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([Br:11])[C:5]=1Br.[OH-].[Na+].[Br:15]C(C1C=CC=CC=1)=C(Br)Br>[Br-].C([N+](CC)(CC)CCCC)C.N([O-])=O.[Na+].C(O)(C)C>[Br:15][C:9]1[CH:8]=[C:7]([Br:10])[C:6]([Br:11])=[CH:5][C:4]=1[CH:3]=[CH2:2]
Reactant: BrC(Br)=C(Br)c1ccccc1
Reactant: BrCCc1ccc(Br)c(Br)c1Br
Agent: CCCC[N+](CC)(CC)CC
Agent: O=N[O-]
Agent: [Br-]
Solvent: CC(C)O
Product: C=Cc1cc(Br)c(Br)cc1Br
Temperature: 35 °C

Procedure:
105.5 g β-bromoethyl tribromobenzene (as above) (0.25 mol), 1 g triethylbutyl ammonium bromide (as 50% aq.solution) 50 g isopropyl alcohol and 1 g sodium nitrite were stirred at about 500 rpm. in a 1 liter three-necked flask at room temperature. 55.6 g 45% NaOH solution (0.625 mol) were added slowly such that the reaction exotherm gradually raised the temperature to 35° C. When necessary an ice-water bath was raised under the flask to control the temperature. After about 5 minutes of reaction, tribromostyrene started to precipitate from the solution. The stirring was continued for a total of 45 mins. At the end of this period the reaction mixture was filtered using a water vacuum pump. The solid remaining in the funnel was tribromostyrene. The filtered liquid consisted of three separate phases--an aqueous mixture of sodium bromide and hydroxide, an isopropanol phase and a small dark layer containing the heavies. The tribromostyrene was dissolved in n-hexane (approx 150 g), washed with dilute HCl and water and dried over calcium chloride. After filtering off the calcium chloride, the hexane was removed under vacuum at 40° C. until the first crystals appeared. The hexane solution was allowed to cool slowly to room temperature and then in an ice-water bath. The crystals were filtered off, and dried overnight in a vacuum oven at 40° C. 62 g 2,4,5-tribromostyrene were obtained (m.p=64° C.). In the mother liquor (hexane) were dissolved approx. 12 g of products consisting of a mixture of tribromo and tetrabromostyrenes. The isopropanol phase contained about 8 g of product mixtures including dibromostyrene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: ClC(c1ccccc1)c1ccccc1
Product: O=Cc1cn(C(c2ccccc2)c2ccccc2)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and benzhydryl chloride in place of the benzyl bromide used in Example 1 to give 852 mg of 1-benzhydrylindole-3-carbaldehyde as brown crystals. The yield thereof was found to be 46%.
Reaction SMILES: C(OC([NH:8][CH2:9][C@@:10]1([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:16][C@H:15]2[C@@H:11]1[C:12]([CH3:18])=[C:13]([CH3:17])[CH2:14]2)=O)(C)(C)C.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C1(SC)C=CC=CC=1>[C:28]1([CH3:38])[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[NH2:8][CH2:9][C@@:10]1([CH2:19][C:20]([OH:22])=[O:21])[CH2:16][C@H:15]2[C@@H:11]1[C:12]([CH3:18])=[C:13]([CH3:17])[CH2:14]2
Reactant: CC1=C(C)[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CSc1ccccc1
Solvent: Cc1ccccc1
Product: CC1=C(C)[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Yield: 54.8 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-(tert-butoxycarbonylamino)methyl-3,4-dimethylbicyclo[3.2.0]hept-3-en-6-yl]acetate (4.0 g, 11 mmol) and p-toluenesulfonic acid monohydrate (2.5 g, 13 mmol) were suspended in toluene (30 mL) and thioanisole (3.8 mL), and the suspension was stirred at 80° C. for 2 hours. The reaction solution was concentrated, and the resulting oil substance was treated with ethyl acetate and hexane to obtain the title compound (2.3 g, 55%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]([C:35]2([NH2:38])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[F:27][C:28]([F:39])([F:40])[C:29]1[CH:30]=[C:31]([C:35]2([NH:38][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:36][CH2:37]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1(c2cccc(C(F)(F)F)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (40.0 mg, 0.156 mmol) in methylene chloride (1 mL) is added oxalyl chloride (14 μL, 0.16 mmol) dropwise. After 10 minutes, a drop of N,N-dimethylformamide is added and the suspension is stirred at room temperature. After 60 minutes, an additional portion of oxalyl chloride (14 μL, 0.16 mmol) and a drop of N,N-dimethylformamide are added. After stirring for 30 minutes, the solvent is removed in vacuo; the residue is suspended in methylene chloride (1 mL) and concentrated in vacuo. The residue is dried under vacuum for 30 minutes, suspended in methylene chloride (1 mL) and added to a solution of 1-(3-trifluoromethyl-phenyl)-cyclopropylamine hydrochloride (74.1 mg, 0.312 mmol) and N,N-diisopropylethylamine (0.080 mL, 0.46 mmol) in methylene chloride (500 μL). After shaking at room temperature for 15 hours, the reaction is quenched with methanol (500 μL) and concentrated. The residue is purified by reverse phase HPLC using a Water BEH column (2.1×50 mm C18 1.7 μM) and a gradient of 10-95% acetonitrile in water containing 0.05% formic acid to afford the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NCc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccccc1F)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (6.3 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-fluorobenzyl amine (51.0 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (50 mL). The organic layer was washed with aq. NaHCO3, dried over anhydrous Na2SO4 and concentrated to give the crude mixture. Flash column chromatography of the crude (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (79.2 mg, 98%) m.p. 110-111° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[CH:12].Br[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]>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>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][C:21]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]
Reactant: C#Cc1ccc2ccccc2c1
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=Cc1cccc(C#Cc2ccc3ccccc3c2)c1

Procedure:
To a solution of 15.3 g of naphth-2-yl-acetylene and 16.65 g of -bromobenzaldehyde in 120 ml of absolute triethylamine were added at a bath temperature of 50° C. while stirring in an atmosphere of dry nitrogen 1.05 g of bis-(triphenylphosphine)-palladium(II) chloride and 0.07 g of copper(I) iodide. Then the mixture was stirred at a bath temperature of 70°-80° C. (TLC: petroleum ether/ether-5:1). When the reaction was finished the mixture was filtered, the residue washed with ethyl acetate and then the filtrates were evaporated in a vacuum. By column chromatography with petroleum ether/ether (4:1) the residue is purified to yield 15.1 g (65.5% of the theoretical yield) of the title compound in the form of crystals melting at 90°-92° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH3:26])[O:15][C:14](=[O:27])[C@H:13]([NH:28]C(=O)OC(C)(C)C)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36].O1CCOCC1>C(Cl)Cl>[ClH:36].[NH2:28][C@@H:13]1[CH2:12][O:11][CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH3:26])[O:15][C:14]1=[O:27]
Reactant: C[C@H]1OC(=O)[C@H](NC(=O)OC(C)(C)C)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1OC(=O)[C@H](N)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of tert-butyl ((3R,7S,8S,9R)-7,8-bis(benzyloxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (104.0 mg, 0.214 mmol) in DCM (1.20 mL) was added a 4.0 M solution of HCl in dioxane (1.07 mL, 4.28 mmol) and the reaction was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was dried under high vacuum to yield the title compound as an off-white oil (85.0 mg, 94%): IR (neat) 3365, 1636, 1235, 1063 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.76 (bs, 2H), 7.35-7.20 (m, 10H), 5.30 (s, 1H), 4.69-4.45 (m, 5H), 4.20 (d, J=9.1 Hz, 2H), 3.89-3.75 (m, 2H), 3.59 (d, J=11.1 Hz, 1H), 3.47 (d, J=7.1 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H); HRMS-ESI (m/z) [M]+ calcd for C22H27NO5, 385.1889; found, 385.1890.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:11][CH2:10]2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C2=CC(c3ccc(F)cc3)=CCC2c2ccc(OC)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(-c3ccc(F)cc3)cc2-c2ccc(OC)cc2)cc1

Procedure:
To a solution of 13.91 g. of 1-[4,5-bis(4-methoxyphenyl)-1,5-cyclohexadien-1-yl]-4-fluorobenzene in 500 ml. of toluene were added 9.08 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The solution was allowed to reflux under a nitrogen atmosphere for 20 hours employing a Dean-Stark trap. After cooling, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography. The appropriate fractions were combined, evaporated, and recrystallized from diethyl ether/Skelly B to provide 6.08 g. of the desired product as a yellow solid, m.p. about 107°-110° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:38])[O:33][CH2:34][CH2:35][O:36][CH3:37]>CC(C)=O>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:32]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(C=O)c(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
A mixture of 2.0 g (11.35 mmol) of 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde, 1.2 g of anhydrous sodium carbonate, 0.17 g (1.14 mmol) of sodium iodide and 3.3 g (12.8 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate in 30 ml of acetone is stirred at RT for 24 h and poured onto 200 ml of ice-water. The precipitate is filtered off, dried and recrystallized from toluene/diisopropyl ether. 3.9 g (86.5%) of the title compound of m.p. 119°-120° C. are obtained.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C1C=CC=CC=1.C=CCCCC.C1(C)C=CC=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1
Agent: Nc1ccccn1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, aniline 0.3 mmol, bezoic acid 0.03 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various 2-aminopyridine derivatives 0.1 mmol as shown in the following table 3, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products from various aminopyridine derivatives. The results are presented in Table 3, below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14]C)=[O:13])[C:7]1=[O:16].[OH-].[Na+].Cl.[Cl-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]1=[O:16]
Reactant: COC(=O)c1nccn(Cc2ccc(F)c(F)c2)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1nccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
Methyl 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylate (110 mg, 0.39 zmol) was placed in a 10-mL RBF and dissolved in THF (3 mL). NaOH (1 mL, 2.000 mmol) (2N solution) was added, and the reaction was allowed to stir at room temp. The reaction was then left stirring overnight at room temp and then analyzed by LC-MS, showing the reaction to be complete. The reaction was then neutralized with the addition of 1N HCl (2 mL), and then saturated with saturated sodium chloride. The resultant mixture was then washed with ethyl acetate (3×50 mL), and then combined organic layers were washed with brine (25 mL) and concentrated in vacuo, affording 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid as a yellow solid. LRMS (ESI) calc'd for (C12H9F2N2O3) [M+H]+, 267.1; found 267.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([C:16]2[CH2:17][CH2:18][O:19][CH2:20][CH:21]=2)=[CH:14][N:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[O:19]1[CH2:20][CH:21]=[C:16]([C:15]2[C:14]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:13][CH:12]=[N:11][CH:10]=2)[CH2:17][CH2:18]1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncncc1C1=CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncncc2C2=CCOCC2)cc1
Temperature: 100 °C

Procedure:
To a 150 mL sealable tube was added 4-aminophenol (388 mg, 3.56 mmol), 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)pyrimidine (700 mg, 3.56 mmol), and cesium carbonate (1218 mg, 3.74 mmol) with DMSO (23.700 ml). The vessel was sealed and heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water before extracting with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to a dark brown oil that was used without purification. MS (ESI, pos. ion) m/z: 270.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2N)[CH:5]=[N:4][CH:3]=1.N([O-])=[O:14].[Na+].O.N>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:14])[CH:5]=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cncc2cccc(N)c12
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cncc2cccc(O)c12
Yield: 63.9 %

Procedure:
A solution of 4-methyl-5-aminoisoquinoline (869 mg) in concentrated sulfuric acid (8 ml) was added with sodium nitrite (379 mg) with ice cooling and stirring and stirred for 0.5 hours. The reaction mixture was added with water (12 ml) and then stirred at 130° C. for 16 hours. The reaction mixture was neutralized with 28% aqueous ammonia solution and extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain the title compound (559 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:7]([C:22](OC)=[O:23])=[CH:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.O.[NH2:28][NH2:29].O>C(O)C>[CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1[C:6]2[C:7](=[CH:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[C:22](=[O:23])[NH:28][N:29]=1
Reactant: NN
Reactant: COC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Solvent: O
Solvent: CCO
Product: CC(C)Cc1n[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrrole-3-carboxylate (0.35 g) prepared as described in Example 1c) above and hydrazine hydrate (0.2 ml) were stirred in ethanol (10 ml) for 2 days. The reaction mixture was poured into water to give a solid which was collected and recrystallised from ethyl acetate-cyclohexane to afford the sub-title pyrrole (0.22 g).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH2:11]N(C)C)=[C:7]([OH:15])[C:6]1=[S:16])[CH2:2][CH2:3][CH3:4].IC>C(Cl)Cl>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:15])[C:6]1=[S:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc(CN(C)C)c(O)c1=S
Solvent: ClCCl
Solvent: CI
Product: CCCCn1ccc(C)c(O)c1=S
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 1-butyl-3-hydroxy-4(N,N-dimethylaminomethyl)pyridine-2-thione (2-034-05) (1.0 g) in methylene chloride (20 mL) was added iodomethane (2.1 g) at room temperature. After the reaction mixture was stirred for 1 h, the solvent was evaporated under reduced pressure. To the residue were added ethanol (20 mL) and triphenylphosphine (1.6 g), and the reaction mixture was stirred at 75° C. for 20 h, and evaporated under reduced pressure. To the residue were added methanol (10 mL) and 1 mol/L aqueous sodium hydroxide solution (8 mL), and the reaction mixture was stirred at 60° C. for 2 h, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (toluene/acetone=4/1) to give 1-butyl-3-hydroxy-4-methylpyridine-2-thione (2-034-06) (0.57 g, 70%) as an oil.
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][C:9]#[CH:10])[CH:3]([OH:6])[C:4]#[CH:5].[CH:11]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:15](Cl)=[O:16])([CH3:13])[CH3:12].N1C=CC=CC=1>>[CH:11]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:15]([O:6][CH:3]([C:2]([CH3:1])=[CH:7][CH2:8][C:9]#[CH:10])[C:4]#[CH:5])=[O:16])([CH3:13])[CH3:12]
Reactant: C#CCC=C(C)C(O)C#C
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: C#CCC=C(C)C(C#C)OC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)C
Yield: 87.5 %

Procedure:
By the same procedure as in Example 1, 1.22 g (10.0 millimoles) of 4-methylocta-4-ene-1,7-diyne-3-ol, 2.66 g (10.0 millimoles) of α-isopropyl-3,4-dichlorophenylacetyl chloride and 1.58 g (20.0 millimoles) of pyridine are reacted, followed by purification on silica gel column. Thus, 3.18 g of the objective ester is obtained as a pale yellow oily substance (87.5% of theoretical yield). nD24.0 1.5314
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].Cl.[NH:22]1[CH2:37][CH2:36][CH2:35][C@H:23]1[C:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:22]1[CH2:37][CH2:36][CH2:35][C@H:23]1[C:24]([O:26][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:28])=[O:25])=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: O=C(OC(=O)[C@@H]1CCCN1)c1ccccc1
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
Boc-Gly-Nleu-OH (12.5 g, 0.043 mol.), HCl.Pro-OBz (11 g, 0.046 mol.) and HOBt (6.0 g, 0.045 mol.) were dissolved in 300 ml DMF and the solution was chilled to 0° C. Triethylamine (12 ml) was added slowly while stirring the solution. After 5 minutes, EDC (8.5 g, 0.043 mol.) was added to the solution and the stirring was continued at room temperature overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 350 ml ethyl acetate. The ethyl acetate solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again until the pH of the brine layer was about 7. The organic layer was dried by Na2SO4 and the ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 3:1) was carried out to obtain the pure product (17.5 g, 85%). TLC Rf=0.45 (developing solvents: E/H, 3:1).