Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1C=CC=CC=1>[CH:4]([C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[CH:3][CH3:2]
Reactant: OCCCc1ccc(-c2cccs2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 5-hydroxypropyl-2,2'-bithiophene was dissolved in 20 ml of benzene, followed by adding 0.1 g of p-toluene-sulfonic acid. The mixture was then stirred at room temperature for 2 hours while monitoring by thin layer chromatography. After completion of reaction, 30 ml of water and 100 ml of ethyl acetate were then added to the mixture. The ethyl acetate extract was further purified by column chromatography. The eluant was ethyl acetate/n-hexane (1/9). The slightly yellowish liquid product was thus obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.O.O.C(O)C>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccccc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Benzaldehyde (5.31 g, 50.0 mmol) was dissolved in ethanol (60 ml)-water (30 ml), and hydroxylamine hydrochloride (5.21 g, 1.5 Eq) and anhydrous sodium carbonate (Na2CO3, 3.97 g, 0.75 Eq) were added thereto at 0° C. When a large amount of solid was formed after about one minute, water-ethanol (1:1, 60 ml) was added, and the mixture was stirred for one hour. Saturated aqueous sodium chloride solution (100 ml) was added, and the mixture was extracted twice with ethyl acetate (300 ml). The extract was washed with 1.0 N aqueous sodium bicarbonate solution (NaHCO3, 100 ml×2), dried (anhydrous Na2SO4), and concentrated under reduced pressure to give the title compound (6.06 g, Yield 99%) as a white powder as a mixture of cis and trans.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:12]1[CH:17]=[C:16]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CCCCCC.CN(C)C=O>[CH2:9]([S:10][C:12]1[CH:17]=[C:16]([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:20][C:19]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(F)c2)c1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(SCc3ccccc3)c2)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
After sodium hydride (60% paraffin dispersion, 0.13 g, 3.2 mmol) was washed with hexane twice, it was suspended in N,N-dimethylformamide (15 mL). Phenylmethanethiol (0.35 mL, 3.0 mmol) was added to this suspension and stirred for 10 minutes. A solution of 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole (0.49 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was added to this mixture and stirred for 1 hour. An 8N aqueous solution of sodium hydroxide was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 0.48 g (yield 79%).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.CO.[Cl:27]Cl.C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[Cl:27][C:14]1[CH2:13][C@H:12]2[C@H:11]3[C@:2]([F:1])([C@@H:19]([OH:20])[CH2:18][C@:16]2([CH3:17])[C:15]=1[S:21][CH3:22])[C@:3]1([CH3:24])[C:8](=[CH:7][C:6](=[O:23])[CH:5]=[CH:4]1)[CH2:9][CH2:10]3
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CSC1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C

Procedure:
To a solution of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one (100 mg) in a mixture of dry dichloromethane (10 ml) and methanol (8 ml) is added a 0.31 molar solution of chlorine in dichloromethane (1.0 ml). After a few hours, the solution is poured into a dilute sodium bicarbonate solution. The product is isolated by extraction with chloroform and the chloroform solution is washed with water, dried (anhydrous MgSO4) evaporated and the residue is purified by preparative thin layer chromatography to afford the title compound (35 mg), melting point 262°-268° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Periodinane (26.9 g, 63.5 mmol) was added to 4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (10.5 g, 48.8 mmol) in CH2Cl2 (200 ml) and stirred for 90 min. Diethyl ether (560 mL) was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 300 mL). The organic layer was washed with 0.5 M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure. Purification using flash chromatography (hexane/EtOAc, 8:2) gave 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester (8.5 g, 81%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example I, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].B(F)(F)F.[CH3:16][CH2:17][O:18]CC.CC([O-])=O.[Na+]>C(O)(=O)C>[OH:10][C:7]1[CH:6]=[C:5]([OH:11])[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]=1[C:17](=[O:18])[CH3:16]
Reactant: CC(C)c1ccc(O)cc1O
Reactant: CCOCC
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C(C)C)c(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Isopropyl-benzene-1,3-diol (1 eq) was taken up in BF3.OEt2 (6 eq) and acetic acid was added (2 eq). The solution was heated for 16 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted in to EtOAc. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over MgSO4, filtered and concentrated in vacuo. The residual oil was purified by column chromatography, eluting with dichloromethane, to give 1-(2,4-Dihydroxy-5-isopropyl-phenyl)-ethanone as a white solid.
Reaction SMILES: C1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([OH:17])=O)[NH:13][CH:14]=2)C=CC=CC=1.[C:18]([O:22][C:23](=[O:34])[CH2:24][NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:18]([O:22][C:23](=[O:34])[CH2:24][N:25]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:15]([C:12]1[NH:11][C:10]([CH2:9][CH2:8][CH3:7])=[CH:14][N:13]=1)=[O:17])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CNCCc1ccccc1
Reactant: O=C(O)c1nc(CCCc2ccccc2)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cnc(C(=O)N(CCc2ccccc2)CC(=O)OC(C)(C)C)[nH]1
Reaction time: 36 h
Yield: 73 %

Procedure:
A 0° C. solution of 4-(3-phenylpropyl)-imidazole-2-carboxylic (13d) (150 mg, 0.65 mmol) and N-(2-phenylethyl)glycine tert-butyl ester (140 mg, 0.59 mmol) in 5 ml of anhydrous dimethylformamide was treated with diisopropylethylamine (154 μl, 0.89 mmol), hydroxy-benzotriazole (160 mg, 1.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (136 mg, 0.71 mmol). After stirring for 36 h, the reaction was poured onto saturated aqueous sodium chloride and extracted with ethyl acetate (3×50 ml) The combined organic extracts were washed twice with saturated aqueous sodium bicarbonate (2×) and saturated aqueous sodium chloride (1×), dried (Na2SO4), filtered, and concentrated in vacuo to give a brown oil. Chromatography (flash, SiO2, 30% ethyl acetate/hexane) to give 160 mg (61%) of 23 as a white solid: 1H NMR (CDCl3) δ 7.38-7.14 (10H, m), 6.85-6.8 (1H, m), 4.84-4.76 (1H, d), 4.5-4.42 (1H, m), 4.07-4.0 (1H, d), 3.78-3.72 (1H, m), 3.12-2.94 (2H, 2×m), 2.75-2.55 (4H, m), 2.1-1.95 (2H,m), 1.5-1.45 (9H, 3×s).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][C:14](=[CH:17]NC1C=CC=CC=1)[C:15]#[N:16])[CH3:2].Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C[O-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][C:14]1[C:15]([NH2:16])=[N:28][C:27]([NH2:29])=[N:26][CH:17]=1)[CH3:2]
Reactant: CCc1c(OC(C#N)=CNc2ccccc2)cc(C)c2sccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1c(Oc2cnc(N)nc2N)cc(C)c2sccc12
Yield: 80.2 %

Procedure:
2-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-3-phenylamino-acrylonitrile (360 mg, 1 mmol), guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 5 mL absolute ethanol were heated to reflux in 5 ml absolute ethanol for 2 hours. Premixed guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 1 ml EtOH was added via pipette, and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled, diluted with water, extracted twice with EtOAc, washed with brine, and dried over magnesium sulfate. Solvent was removed in vacuo to give 241 mg of 5-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-pyrimidine-2,4-diamine as a white solid (74%). Mass Spec M+H=301, M.P.=181° C. Recrystallization of 175 mg of this product from MeOH and HO/diethyl ether afforded 98 mg of the corresponding HCl salt 49%, Mass Spec M+H=301, M.P.>300 C.
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)=[CH:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:52][CH2:53][C:54]([N:56]1[CH2:61][CH2:60][N:59]([C:62](=[O:73])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=2[C:69]([F:72])([F:71])[F:70])[CH2:58][CH2:57]1)=[O:55]>CN(C=O)C.O>[O:55]=[C:54]([N:56]1[CH2:57][CH2:58][N:59]([C:62](=[O:73])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=2[C:69]([F:72])([F:71])[F:70])[CH2:60][CH2:61]1)[CH2:53][NH:52][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(-c2ccsc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 48.3 %

Procedure:
DIPEA (74.9 mg, 0.09 mL, 0.58 mmol) was added to a stirred solution of 4-thiophen-3-yl-benzoic acid (40 mg, 0.19 mmol) in DMF (1 mL). HOBT (32 mg, 0.23 mmol) and EDCI (45 mg, 0.23 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone trifluoroacetic acid salt (100 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 46 mg (46.9% yield) of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-thiophen-3-yl-benzamide. LCMS Purity: 97.5%. 1H NMR (DMSO-d6): δ 8.7-8.6 (m, 1H), 8.1-8.0 (s, 1H), 7.96-7.9 (m, 2H), 7.88-7.8 (m, 3H), 7.8-7.74 (m, 1H), 7.72-7.62 (m, 3H), 7.6-7.5 (bt, 1H), 4.24-4.08 (m, 2H), 3.78-3.56 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.06 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][OH:12])=[O:10])=[CH:5][CH:4]=1.[OH:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(N(C(C)C)C(C)C)C.C(OCC)C>CN(C)C=O.[I-].[K+]>[OH:12][NH:11][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=C(NO)c1ccc(CCl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NO)c1ccc(CON2C(=O)c3ccccc3C2=O)cc1

Procedure:
α-Chloro-N-hydroxy-p-toluamide, 6.52 g (40 mmol) of N-hydroxyphthalimide (7.4 g) (40 mmol) and 0.28 g of potassium iodide are dissolved in 50 ml of absolute dimethylformamide and treated with 5.16 g (40 mmol) of N-ethyldiisopropylamine while stirring. After stirring at room temperature for 16 hours 50 ml of diethyl ether are added. The precipitated product is filtered off under suction and washed with diethyl ether. There are obtained 7.5 g of N-hydroxy-α-(phthalimidooxy)-p-toluamide as a white powder of m.p. 202° C. (dec.).
Reaction SMILES: [NH:1]1[C:6](=O)[CH2:5][O:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cnccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc2c(cn1)OCCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
1H-pyrido[3,4-b][1,4]-oxazin-2-one (510 mg, 3.397 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere and then cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (6.8 ml, 6.794 mmol) was added thereto dropwise. The mixture was stirred for 30 minutes, and the temperature was raised to room temperature, and then the mixture was stirred for 1 hour. After completion of the reaction, the mixture was cooled to 0□ again, and then water (0.25 ml), 10% aqueous solution of sodium hydroxide (0.5 ml) and water (0.8 ml) were added thereto dropwise in this order, and the resulting solution was vigorously stirred at room temperature for 1 hour. The produced solid was filtered and washed with excessive ethyl acetate, and then the filtrate was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid (300 mg, 65%).
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:1]([C:13]1[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCC#Cc1cccc(C=O)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC#Cc1cccc(/C=C/C(=O)OCC)c1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of 3-(1-dodecynyl)benzaldehyde (23.0 g) in toluene (150 ml) was added carbethoxymethylenetriphenylphosphorane (35.5 g) in one portion. The mixture was warmed at 80° C. for 5 hr, allowed to cool to room temperature, and concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with ethyl acetate/hexane/1:15). The appropriate fractions were collected and evaporated to afford 21.1 g (73% ) of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1C=CC=CC=1.[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:18](=[O:19])[CH2:17][O:16][CH3:15])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COCC(=O)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-aminopyridine (173 mmol) and pyridine (347 mol) in 250 mL dichloromethane was added dropwise 2-methoxyacetyl chloride (208 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was washed with hexane to afford 35.0 g of N-(4-bromopyridin-2-yl)-2-methoxyacetamide (82% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[O:8]([C:5]1[N:6]=[CH:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc(Oc2ccccc2)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 36.5 %

Procedure:
To a solution of 5-bromo-2-phenoxy-pyridine (3.85 g, 15.4 mmol) described in Manufacturing Example 40-1-1 in tetrahydrofuran (60 mL) was added n-butyl lithium (10.6 mL, 1.60 M hexane solution, 16.9 mmol) under nitrogen atmosphere at −78° C., which was stirred for 35 minutes at −78° C. N,N-Dimethylformamide (1.55 mL, 20.0 mmol) was then added to this reaction solution at −78° C., which was stirred for further 10 minutes at room temperature. After allowing to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (1.12 g, 37%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]#[N:27]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: Cc1cccc(CBr)c1OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1OCC#N

Procedure:
3-(Quinolin-2-ylmethoxy)-phenol (1.3 g, 5.4 mmol, example 3), (2-bromomethyl-6-methyl-phenoxy)-acetonitrile (1.56 g, 6.5 mmol, example 24), tetrabutylammonium iodide (99 mg, 0.27 mmol) and potassium carbonate (0.45 g, 3.3 mmol) are refluxed in acetone (20 mL) for 16 h. The reaction is filtered, washed with dichloromethane, concentrated and purified by column chromatography (silica, 1% ether in dichloromethane) to provide the title compound. MS (ESI) 411 (M+H)+.
Reaction SMILES: [C@@H:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16]O.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.O.C([O-])(O)=O.[Na+]>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][O:7][C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[C:9]([OH:11])=[O:10])=[O:8]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H]2CCC[C@H]2C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (trans)-cyclopentane-1,2-dicarboxylic acid (1.90 g, 12 mmol), 2,4-dimethoxy-benzyl alcohol (2.02 g, 12 mmol), DMAP (73 mg, 0.6 mmol) in DMF (30 mL), chilled in an ice bath, was added EDC.HCl (2.53 g, 13.2 mmol) in two portions. The mixture was stirred at ice bath temperature for 15 min and warmed to RT for 4 hrs. The reaction mixture was diluted with H2O (100 mL) and saturated NaHCO3 (40 mL). The aqueous mixture was extracted with EtOAC (3×30 mL), acidified to pH 3 with saturated KHSO4 and extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (2×25 mL), saturated NaCl (25 mL), dried over MgSO4, filtered and evaporated. The crude material was re-dissolved in CHCl3 and eluted through a silica gel plug with CHCl3 (100 mL) and then EtOAc (100 mL). The EtOAc fraction was evaporated and pumped to a clear oil, 2.6 g (70%), and used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(Cl)Cl>[CH3:7][S:8]([O:6][CH2:5][C:2]1([CH3:1])[CH2:4][CH2:3]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)CC1
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Treat a 0° C. solution of (1-methylcyclopropyl)methanol (1.0 g, 11.61 mmol) in DCM (50 mL) with TEA (1.29 g, 12.77 mmol), add methanesulfonyl chloride (1.46 g, 12.77 mmol) drop-wise and stir at 0° C. for 2 h. Warm the mixture to RT, wash with H2O, then brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (1.85 g, 97%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (s, 2H), 3.20 (s, 3H), 1.17 (s, 3H), 0.59 (m, 2H), 0.47 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.CS(O)(=O)=O.FC1C=CC=CC=1C1OC(C([NH:36][C:37]([NH2:39])=[NH:38])=O)=CC=1>CO.[Cl-].[Na+].O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:6][C:5]([C:3]([NH:38][C:37]([NH2:39])=[NH:36])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)o1
Reactant: N=C(N)NC(=O)c1ccc(-c2ccccc2F)o1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(N)NC(=O)c1ccc(-c2ccc(F)cc2)o1
Yield: 51.4 %

Procedure:
5-(4-fluorophenyl)furan-2-carboxylic acid methyl ester (220 mg, 1.0 mmol) was dissolved in methanol (4 ml), to which 2 M guanidine solution (3.0 ml, 6.0 mmol) prepared in Example 1 was added, and the mixture was heated at reflux for 12 hours. After completion of the reaction, the solution was added with saturated brine (20 ml) and extracted with ethyl acetate (30 ml×3). The organic layer was washed with 10% brine, dried over anhydrous magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane), to give 127 mg of a title compound (yield: 51%).