Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C(Br)SC=1C(N)=O.C(OC(N1CCC[C@H]1C(O)=O)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+].[Br:64][C:65]1[S:69][C:68]([C:70](=[O:72])[NH2:71])=[C:67]([NH:73][C:74]([C@@H:76]2[CH2:80][CH2:79][CH2:78][N:77]2[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=O)[CH:66]=1.[OH-].[Na+].Cl>CN(C)C=O.C(O)C.C(OCC)(=O)C>[Br:64][C:65]1[S:69][C:68]2[C:70](=[O:72])[NH:71][C:74]([C@@H:76]3[CH2:80][CH2:79][CH2:78][N:77]3[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[N:73][C:67]=2[CH:66]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of 3-amino-5-bromothiophene-2-carboxamide (300 mg) produced in Example 1, step D, 1-(tert-butoxycarbonyl)-L-proline (700 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.55 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.713 mL) in N,N-dimethylformamide (8 mL) was stirred at 90° C. for 16 hr. Ethyl acetate (40 mL) and aqueous sodium hydrogen carbonate (20 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give an inseparable mixture of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]pyrrolidine-1-carboxylate and 3-amino-5-bromothiophene-2-carboxamide (starting material) as a yellow oil. To a solution of the mixture of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]pyrrolidine-1-carboxylate and 3-amino-5-bromothiophene-2-carboxamide produced above in ethanol (6 mL) was added 2M aqueous sodium hydroxide solution (2.04 mL), and the mixture was stirred at 70° C. for 4 hr. 6M Hydrochloric acid (1 mL), ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL×2). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (175 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[N:14]=[C:13]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([O:12]2)[CH2:6]3)[CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([C@@H:7]1[C@@H:8]([CH2:10][OH:11])[O:9][C@@H:5]([N:4]2[CH:3]=[C:2]([CH3:1])[C:15](=[O:16])[NH:14][C:13]2=[O:12])[CH2:6]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
2,3'-Anhydrothymidine (25 O: 0.1115 mol) and NaN3 (29 g, 0.446 mol) was suspended in a mixture of 250 ml DMF and 38 ml H2O. The reaction was refluxed for 5 hours at which time it was poured into 1 liter of H2O. The aqueous solution was extracted with EtOAc (3×700 ml). The EtOAc was dried over Na2SO4, filtered and the EtOAoac was removed in vacuo to yield a viscous oil. This oil was stirred with 200 ml water resulting in a solid 9.15 g (0.0342 mol, 30.7%). mp=116°-118° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29]O)=[CH:24][CH:23]=1>CC#N>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:31]=[C:13]([CH:12]([N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[CH3:16])[O:15][N:29]=2)=[CH:24][CH:23]=1
Reactant: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Reactant: N=C(NO)c1ccc(F)cc1
Solvent: CC#N
Product: CC(c1nc(-c2ccc(F)cc2)no1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.7 %

Procedure:
To 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoic acid (0.06 g, 0.212 mmol) in CH3CN (3 mL) was added CDl (0.034 g, 0.212 mmol). After 5 min, 4-fluoro-N-hydroxybenzenecarboximidamide (0.033 g, 0.212 mmol) was added. The resulting mixture was stirred at rt and then heated to 150° C. in a microwave for 20 min. Concentration was followed by column chromatography (EtOAc/hexanes) to obtain the desired product (0.0065 g, 8% yield): MS (APCl) m/z 401 (M+1).
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>>[NH:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([F:29])([F:31])[F:30])=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(F)(F)F)ccc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared using the procedure as described in Example 1E, substituting the product of Example 4E for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.67 (s, 1H), 8.04 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.22 (m, 2H), 7.10 (m, 2H), 7.00 (d, J=7.5 Hz, 1H), 5.00 (m, 1H), 4.41-4.20 (m, 2H), 2.22-2.00 (m, 2H). S (ESI) m/e 377 (M+H)+. Calcd. For C18H15N4O2F3.0.7H2O: C, 55.59; H, 4.25; N, 14.40. Found: C, 55.51; H, 3.98; N, 14.65.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O=[C:11]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])[C:12](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[CH:29]1[CH:28]=[CH:27][C:26]([CH:25]=[C:12]([C:13]2[O:14][C:18](=[O:19])[C:17]3[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]=2)[C:11]2[O:36][C:35](=[O:37])[C:34]3[C:33](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=2)=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
Under nitrogen gas current, 2-chloro-N-methylpyridinium iodide (691 mg, 2.78 mmol) was suspensed in dry methylene chloride (5 ml) and a solution of Compound 11 (500 mg, 1.16 mmol) and dry triethylamine (0.76 ml, 5.57 mmol) in dry methylene chloride (5 ml) were added. The mixture was stirred at 40° C. for 3.5 hours. After the reaction, methylene chloride was added, and the mixture was washed with 1N.HCl, water, 4% NaHCO3 aqueous solution and water and dried over magnesium sulfate. The solvent was evaporated. The residue was crystallized rrcm isopropylether to give the desired compound 52 in crystal (410 mg, yield, 90%). m.p., IR, and NMR spectra of the product fully agreed with those of the one obtained in Example 19.
Reaction SMILES: [C:1]([O:4][CH:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[CH:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29]C(OCC1C=CC=CC=1)=O)=[N:18]C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2].[ClH:40].[H][H]>[Pd].CO.C(OCC)(=O)C>[ClH:40].[C:1]([O:4][CH:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[CH:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:29])=[NH:18])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC1C(CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 71 %

Procedure:
A methanol/ethyl acetate (1:1/5 mL:5 mL) solution of compound 40 (420 mg, 0.78 mmol) and 1N HCl (0.76 mL), containing 10% palladium on carbon, was shaken in a Parr hydrogenator at 45 psi hydrogen pressure for 2 h. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 170 mg (71%) of the title product as a mixture of trans and cis (2:1) isomers.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].N#N.O=O.[C:9]([OH:12])(=[O:11])[CH3:10]>>[C:9]([O:12][C:1]([O:12][C:9](=[O:11])[CH3:10])=[CH:2][CH2:3][CH3:4])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: C=CC=C
Agent: N#N
Agent: O=O
Product: CCC=C(OC(C)=O)OC(C)=O

Procedure:
Butadiene, acetic acid, air and N2 were passed at rates of 100 l./hr, 200 l./hr, 150 l./hr and 550 l./hr, respectively, by using the same catalyst as in Example 1. That is, the reaction was performed under the same conditions as in Example 1, except that air is oxygen source was used. As a result, diacetoxybutene was obtained at a space time yield of 0.73 mol/l.cat·hr and CO2 at a space time yield of 0.049 mol/l.cat·hr.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH2:16](I)[CH2:17][CH2:18][CH3:19].Cl>CCCCCCC.O1CCCC1.C1C=CC=CC=1.C1COCC1>[CH2:16]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)C1CCC1
Reactant: CCCCI
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of lithium di-isopropylamide (100 mL, 2.0 M, 200 mmol) in heptane/tetrahydrofuran/benzene was diluted with 100 mL of anhydrous THF. To the LDA solution at 0° C. was added dropwise 10 g (100 mmol) of cyclobutanecarboxylic acid in 15 mL of anhydrous THF over 20 minutes under Argon. The mixture was sired at room temperature for 3 hours. To the reaction mixture was added 11.4 mL (100 mmol) of butyl iodide at 0° C. The reaction mixture was warmed to RT and stirred overnight. HCl (2N) was used to adjust the pH to 2˜3. The mixture was extracted with EtOAc (3×200 mL). The combined organic phase was washed with 100 mL of brine, dried (MgSO4) and concentrated. Thus obtained crude product was used directly for next step.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37]>C(Cl)(=O)C.C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH2:20][O:39][C:36](=[O:38])[CH3:37])=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 10 ml. of dry toluene were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylene-cepham-4-carboxylate-1-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The mixture then was refluxed at 110°-112° C. for 18 hours. The resulting reaction mixture then was treated as in Example 1 to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate as well as a minor amount of the corresponding Δ3 isomer.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC1CCCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of piperidine-2-ethanol (20 g, 155 mmol) in ethanol (240 mL) was added K2CO3 (106 g, 775.1 mmol) followed by addition of benzyl bromide (18.4 mL, 155.04 mmol) at 0° C. The reaction mixture was stirred at rt overnight, filtered through a sintered funnel and concentrated. The crude material was dissolved in ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to get liquid compound 49.
Reaction SMILES: [CH3:1][CH:2]([CH:13](C([O-])=O)[C:14]([O:16]CC)=[O:15])[CH2:3][CH:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>>[CH3:1][CH:2]([CH2:3][CH:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCCCCCC(C)CC(C)C(C(=O)[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCC(C)CC(C)CC(=O)O
Yield: 88.2 %

Procedure:
In a nitrogen atmosphere, ethyl 2-(1,3-dimethyldecyl)malonate (4Et) (35.2 g, 0.107 mol) and a 13% by weight aqueous sodium hydroxide solution (104 g) were placed in a reaction vessel and stirred under refluxing with heating for one hour. Then, the resulting ethanol therein was distilled off in one hour. A 56% by weight aqueous sulfuric acid solution (93 g) was added thereto and the resulting mixture was under refluxing with heating for 30 hours. The reaction mixture was diluted with tetrahydrofuran. The organic phase was washed three times with an aqueous saturated sodium chloride solution and concentrated under reduced pressure. The concentrate thus obtained was distilled under reduced pressure (bp: from 130 to 140° C./2 mmHg) to obtain 3,5-dimethyldodecanoic acid (5) (21.6 g, 0.0944 mol). A total yield of three steps from the 2-methylnonyl chloride (1Cl) was 59%.
Reaction SMILES: [F-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].Br[C:15]([CH3:22])([CH3:21])[C:16](OCC)=[O:17]>CN(C)C=O>[CH3:21][C:15]1([CH3:22])[C:16](=[O:17])[NH:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=2[O:13]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a suspension of potassium fluoride (4.71 g) in N,N-dimethylformamide (40 mL) was added 2-amino-5-nitrophenol (5.00 g), and the mixture was stirred at room temperature for 1 hour. To the suspension was added dropwise a solution of ethyl α-bromoisobutyrate (6.33 g) in N,N-dimethylformamide (10 mL) over a period of 20 minutes, and the mixture was stirred at 60° C. for 20 hours. After cooling, to the reaction mixture was added cool, water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous 10% HCl solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was suspended in ethyl acetate, and the precipitates were collected by filtration and washed with ethyl acetate to give 2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (2.80 g) as a pale brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.C[Si]([C:20]#[N:21])(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:20]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1OC)CCC=C2C#N
Yield: 96.9 %

Procedure:
A solution of 5,6-dimethoxy-1-tetralone (30 g, 0.14 mole), trimethylsilylcyanide (15.8 g, 0.156 mole), ca. 15 mLs dry benzene, and catalytic AlCl3 was stirred under N2 at 70° (oil bath) for 15 hours. Benzene was removed (in-vacuo), 300 mL MeOH was added to the crude product, and the solution was stirred at 0°-10° C. as HCl was bubbled through the solution for 3 hours. Methanol was evaporated (in-vacuo) and ca. 500 mL water was added to the residue. The resultant solid was filtered, washed with water, and dried (under high-vacuum) to yield 29.2 g of yellow solid. (99.8%); M+ 215; mp 139°-40° C.
Reaction SMILES: C([Mg]Br)C.[CH:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:13]=[O:14]>CCOCC>[CH:5]1([C:11]#[C:12][CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C=O
Reactant: C#CC1CCCCC1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: OCC#CC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl magnesium bromide (prepared from 2.5 g of magnesium turning and 11.3 g of bromoethane) in ether was added dropwise a solution of 10.2 g of cyclohexylacetylene in ether and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and anhydrous formaldehyde (prepared from the thermal decomposition of 50 g of paraformaldehyde for 20 minutes) was bubbled into the mixture. After cooling, the reaction was quenched with saturated ammonium chloride and extracted with ether (2×100 ml). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated to yield the product which was distilled under high vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].Br[C:15]1[CH:16]=[C:17]([Cl:23])[C:18]([Cl:22])=[C:19]([CH3:21])[CH:20]=1.O1CCCC1.CCCCCC>CN(C)C=O>[Cl:23][C:17]1[CH:16]=[C:15]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])[CH:20]=[C:19]([CH3:21])[C:18]=1[Cl:22]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: Cc1cc(Br)cc(Cl)c1Cl
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(c1cc(C)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
In a nitrogen atmosphere, to 19 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, a solution of 2.2 g of 5-bromo-2,3-dichlorotoluene in 10 mL of N,N-dimethylformamide was added and tetrahydrofuran was distilled off under reduced pressure. To the remaining N,N-dimethylformamide solution, 0.26 g of dichlorobis(triphenylphosphine) palladium (II) was added and the resultant mixture was stirred at 100° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 200 mL of a tetrahydrofuran-hexane (2:5) mixture was added to the reaction mixture, followed by filtering off the deposited insoluble substance. The resultant filtrate was washed with water (100 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 2.3 g of the objective substance as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:16]=2)[NH:11][CH:10]=1.CCN=C=NCCCN(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:71][N:72]([CH3:81])[CH2:73][CH2:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CN(C=O)C>[CH3:71][N:72]([CH3:81])[CH2:73][CH2:74][N:75]1[CH2:80][CH2:79][N:78]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[N:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:22])[CH2:77][CH2:76]1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)nc12
Temperature: 70 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a mixture of 3-[7-(2-Methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (35 mg, 0.1 mmol), EDCI (77 mg, 0.40 mmol), HBTU (3.8 mg, 0.01 mmol) and diisopropylethylamine (175 μl, 1.0 mmol) in DMF (1 mL) was added 2-(dimethylamino)ethylpiperzine (55 μl, 0.3 mmol). The mixture was stirred at 70° C. for 5 hours before the solvents were removed. The resulting yellow oil was washed with water, dissolved in DMSO and purified on reverse phase HPLC to afford the title compound (8.6 mg, 12% over 2 steps) as yellow solid. MS: m/z 485.2 [MH+].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([O:20][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCOC(=O)/C=C\C(=O)O

Procedure:
Into an autoclave, were charged 295 parts of maleic anhydride and 560 parts of lauryl alcohol. The mixture was reacted at 60° C. for 5 hours under sealed condition, to obtain maleic acid monolauryl ester, containing 1.3% unreacted maleic anhydride. After adding to the mixture, 275 parts of allyl chloride and 375 parts of triethyl amine, an atmosphere was substituted with nitrogen. The mixture was reacted at 80° C. for 8 hours, and cooled to a room temperature. The mixture was rinsed by 90 parts of 10% hydrochloric acid aqueous solution, to obtain 960 parts of lauryl allyl maleate of 92.7% purity and of Gardner Color more than 10. A molar ratio of maleic anhydride:lauryl alcohol was 1:1, and maleic acid monolauryl ester:allyl chloride:triethyl amine was 1:1.19:1.23.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Yield: 86.6 %

Procedure:
In an analogous manner to 21, 4-formylbenzoic acid (600 mg, 3.99 mmol) was reacted with tert-butyl piperazine-1-carboxylate (818.8 mg, 4.40 mmol) to afford desired product as off-white solid (1.1 g, 86.6%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: C#CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To but-3-yn-1-ol (40.0 g, 570.0 mmol) and 3,4-dihydro-2H-pyran (48.0 g, 570.0 mmol) in anhydrous dichloromethane (350 mL) was added pyridium p-toluenesulfonate (0.45 g, 1.80 mmol). The mixture was stirred at room temperature for 16 hours. Solvent was evaporated, and the residue was purified by vacuum distillation to give 2-but-3-ynyloxy-tetrahydro-pyran as a light yellow liquid. Yield: 60.0 g (68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](C(O)=O)[CH:6]=[C:5]2[C:15]([OH:17])=[O:16]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(C(=O)O)c2cc(F)ccc2n1
Solvent: O
Product: O=C(O)c1ccnc2ccc(F)cc12
Temperature: 200 °C

Procedure:
6-Fluoroquinoline-2,4-dicarboxylic acid (0.103 g, 0.437 mmol) was transferred in a pressure tube, 6 mL water was added. The closed tube was heated to 200° C. for 4 h. After slow cooling of the tube, the resulting precipitate was filtered and washed with water to yield white crystals