Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NC1C=CC=CC=1.N([O-])=O.[Na+].[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:22]([CH:24]([CH2:30][C:31](OCC)=[O:32])C(OCC)=O)#[N:23].[OH-].[Na+]>N1C=CC=CC=1.O>[C:22]([C:24]1[CH:30]=[C:31]([OH:32])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=1)#[N:23]
Reactant: CCOC(=O)CC(C#N)C(=O)OCC
Reactant: N#[N+]c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Solvent: Nc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1cc(O)n(-c2ccccc2)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
Water (120 mL) and 15 mL of 35% hydrochloric acid were added to 5.6 g (0.06 mol) of aniline, and the mixture was dissolved. Subsequently, 24 mL of water having dissolved therein 4.2 g (0.06 mol) of sodium nitrite was added dropwise thereto with stirring under ice cooling to 0 to 5° C., and the resulting solution was stirred for 1 hour to prepare benzenediazonium chloride. An aqueous solution of this diazonium salt was added dropwise to a 120 mL pyridine solution containing 10.2 g (0.06 mol) of diethyl α-cyanosuccinate with stirring under ice cooling. After the dropwise addition, the solution was stirred under ice cooling for 1 hour and then at room temperature for 1 hour. When the reaction was completed, 240 mL of an aqueous 2% sodium hydroxide solution was added, followed by stirring for 2 hours. The obtained reaction solution was added dropwise to 240 mL of 35% hydrochloric acid under ice cooling, and the precipitated crystal was collected by filtration, washed with 10 mL of water and dried by a hot air drier to obtain 8.4 g of the crude crystal of the title compound as a red-brown crystal. This crude crystal was recrystallized from diethyl ether-petroleum ether and dried by a hot air drier to obtain 5.7 g (yield: 51.3%) of the title compound as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25]C)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.ClC1C=C[N:32](CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)[C:31](=O)[N:30]=1.N1C=NC=N1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:25]=[N:32][CH:31]=[N:30]3)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Agent: c1nc[nH]n1
Solvent: CN(C)C=O
Product: O=c1nc(-n2cncn2)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and 1H-1,2,4-triazole in DMF. M/e+ 404 for C20H15ClN7O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.24 (d, J=1.8 Hz, 1H), 8.33 (d, J=6.6 Hz, 1H), 8.18 (d, J=1.8 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 7.67 (m, 1H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (dd, J=8.4, 1.8 Hz, 2H), 7.34 (m, 1H), 6.95 (t, J=6.6 Hz, 1H), 6.90 (dd, J=7.3, 1.8 Hz, 1H), 5.27 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:27][OH:28])[NH2:26])[C:9]2=[O:29])=[CH:4][CH:3]=1.[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:27][O:28][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:37])[NH2:26])[C:9]2=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)-N′-hydroxypropanimidamide (28.7 mg, 0.067 mmol) is dissolved in dichloromethane (2 mL). Cyclohexanecarbonyl chloride (14.8 mg, 0.10 mmol) and diisopropyl ethylamine (26.3 mg, 0.20 mmol) are then added. The reaction is stirred for 3 h at room temperature. The reaction is diluted with ethyl acetate followed by quenching with sat. sodium bicarbonate solution. The organic layer is washed with brine and dried with MgSO4. The solvents is removed under vacuum to afford crude (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N′-(cyclohexanecarbonyloxy)propanimidamide which is used directly in the next step without further purification. HPLC-MS calculated for C26H29ClF3N4O3 (M+H+) 537.1, found 537.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=[CH2:22])[CH:15]=1)[C@H:9]([OH:12])[CH2:10]Cl)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1.[Cl-].[NH4+]>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C@H:9]1[CH2:10][O:12]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=[CH2:22])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCc1cccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCc1cccc(C[C@H](NC(=O)OC(C)(C)C)[C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.20 g (10.5 mmol) of [(1S,2S)-1-(3-allyl-benzyl)-3-chloro-2-hydroxy-propyl]-carbamic acid tert-butyl ester in a mixture of 19 ml of THF, 19 ml of MeOH and 21 ml (21 mmol, 2 eq) of 1 N aq sodium hydroxide is stirred at rt for 3 h. The reaction mixture is diluted with 80 ml of saturated aq ammonium chloride solution and extracted with DCM. The organic layer is dried over sodium sulfate and evaporated to give the product.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: C=C(C(=O)OCC)C(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Yield: 111 %

Procedure:
This compound was prepared in the manner of Example 6, with 18.28 grams (0.0415 mole--1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 6.28 grams (0.0436 mole--1.05 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 15.4 grams (0.083 mole--2.0 equiv.) of tributylamine, and 0.233 gram (0.0010 mole--0.025 equiv.) of palladium(II) acetate as reagents. A yield of 20.3 grams of 75.6% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (87.9% yield) was obtained.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7](/[CH:9]=[N:10]/O)=O)=[CH:3][CH:2]=1.Cl.[NH2:13][CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]#[N:16]>Cl[Ti](Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:16][C:15]1[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:9][N:10]=1
Reactant: N#CC(N)Cc1ccccc1
Reactant: O=C(/C=N/O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A round bottomed flask was charged with 5 g (33.5 mmol) of 2-isonitrosoacetophenone, 6.7 g (36.8 mmol) of 2-amino-3-phenylpropanenitrile hydrochloride and 100 mL of dry pyridine. The mixture was cooled to −20° C. and 4.6 mL (40.0 mmol) of TiCl4 was added dropwise. The reaction was kept at −20° C. for 30 min and heated to 80° C. for 2.5 hrs. The solvent was evaporated, and the residue taken up in 1 L of DCM. This solution was washed with saturated NaHCO3 and brine. All volatiles were evaporated, and the residue redissolved in ethanol (400 mL). Raney Ni (2.0 g, aqueous suspension) was added, and the reaction allowed to stir for 5 days under 1 atm of hydrogen. The mixture was passed through celite, and volatiles removed. The residue was chromatographed on silica gel (heptanes/DCM) to give 2.5 g (29%) of 2-amino-3-benzyl-5-phenylpyrazine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[C:8]([O:45][CH3:46])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:44])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[C:8]([O:45][CH3:46])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:44])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCN(C(=O)OC(C)(C)C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCNC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
220 mg tert-butyl (S)-3-{4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carbonyl}-pyrrolidine-1-carboxylate are dissolved in 5 ml dichloromethane, combined with 231 μl trifluoroacetic acid and stirred for 12 hours at ambient temperature. Then the solvents are eliminated in vacuo, divided between saturated aqueous sodium hydrogen carbonate solution and dichloromethane and stirred vigorously for 30 minutes. The phases are separated, the aqueous phase is extracted twice with dichloromethane and the combined organic phases are dried on magnesium sulphate. Then the solvents are eliminated in vacuo and the crude product is chromatographed on silica gel (dichloromethane/(methanol-conc. ammonia 9:1) 90:10 to 80:20).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5].CCN(C(C)C)C(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:22])([F:23])[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])=[CH:10][CH:11]=1)=[N:4][O:5][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=NO)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)ON=C(c2ccc(C(C)NC(=O)OC(C)(C)C)cc2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
tert-Butyl 1-(4-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)phenyl)ethylcarbamate (640 mg, 1.93 mmol) was dissolved in CH2Cl2 (15 ml) together with DIPEA (367 μl, 2.11 mmol) and DMAP (23 mg, 0.19 mmol). The mixture was cooled to 0° C. before slow, portionwise addition of 4-toluenesulfonyl chloride (367 mg, 1.93 mmol). The reaction was allowed to reach room temperature over 2 h, washed with H2O (4*15 ml), dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography using Pet. Ether/EtOAc (3:1) as eluent to give 817 mg (87%) of the title compound as pale solids.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.F[B-](F)(F)F.B(F)(F)F.CCOCC.C(C1OC1)Cl.[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O>C(Cl)Cl>[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[N:1][CH2:2][CH2:3][S:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: NCCSc1cc2ccccc2[nH]1
Reactant: CN1CCCC1=O
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClCC1CO1
Product: CN1CCCC1=NCCSc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.9g (52 mM) of AlCl3 and 1.98g (52 mM) of lithium aluminum hydride in 257 ml of anhydrous ether is added 9.8g (52 mM) of this nitrile in 50 ml of anhydrous ether, and the whole is stirred for 2 hours at room temperature. A total of 10g of 50% NaOH and 2 ml of water is added to this reaction mixture over a period of 3 hours and the resulting solution is stirred for 16 hours. The ether is separated from the solids and dried over potassium carbonate. The dried solution is evaporated in vacuo to give 5.4g of product. Further extraction of the reaction solids with ether again after addition of 2.5 ml of water and 10g of 50% NaOH yields an organic layer which is then combined with the 5.4g of product and dried over potassium carbonate. The dried solution is filtered and the filtrate evaporated in vacuo to give 9.0 g of 2-(2-aminoethylthio)indole. This amine is converted to the hydrochloride salt with ethereal HCl and is recrystallized once from methanol/isopropanol to give 6.4g of crystalline solid. A solution of 3.0g (15 mM) of 2-(2-aminoethylthio)indole in 30 ml of dry CH2Cl2 is added to a solution of fluoroborate salt prepared from 3.42g (24 mM) of boron trifluoride etherate, 1.69g (18 mM) of epichlorohydrin, and 1.80g (18 mM) of N-methyl-2-pyrrolidinone, in 15 ml of dry CH2Cl2. The solution is stirred at room temperature under dry conditions for 4 hours, after which it is washed once with 1N NaOH and twice with brine, and dried over potassium carbonate. The dried solution is evaporated in vacuo to give 3.1g of crude product. Purification as the saccharine salt gives 2-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole saccharinate as cream colored crystals; m.p. 175°-177° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[OH-].[K+].[CH:14]#[CH:15]>CS(C)=O>[CH:14]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:10])[CH3:11])=[CH2:15]
Reactant: C#C
Reactant: C[Si](C)(C)CCCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=COCCCCCC[Si](C)(C)C
Yield: 99 %

Procedure:
In a similar manner to Example 1, 75 g (0.43 mol) of 6-(trimethylsilyl)hexanol, 7.5 g of KOH and 75 g of DMSO were reacted at 80° C. with acetylene. 6-(Trimethylsilyl)hexyl vinyl ether was obtained in 99% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1)C1CC1

Procedure:
Example 113 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.84–7.80 (br, 1H), 7.80–7.69 (br, 1H), 7.64–7.46 (br, 1H), 7.40–6.90 (m, 9H), 6.85–6.66 (m, 1H), 4.94–4.74 (br, 1H), 4.69 (s, 1H), 3.41–3.25 (m, 2H), 3.25–3.07 (m, 2H), 2.77–2.61 (m, 2H), 2.61–2.45 (m, 1H), 2.45–2.17 (m, 2H), 1.99–1.63 (m, 6H), 1.61–1.39 (m, 1H), 1.14–0.94 (m, 2H), 0.92–0.70 (m, 2H); ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10](O)[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>N1C=CC=CC=1.CN(C)C=O.O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][S:13](=[O:15])(=[O:14])[NH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)CCC(O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=S1(=O)CCC(COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of 4-benzyloxy-3-hydroxy-1-butane-sulfonamide (1.6 g., 0.0062 mole) in pyridine (15 ml.), which is stirred and cooled in an ice bath, is added p-toluenesulfonyl chloride (1.18 g., 0.0062 mole). The reaction mixture is stirred at room temperature for 20 hours and then poured into water (100 ml.). This mixture is extracted with ethyl acetate-ether (1:1) (2 × 100 ml.). The organic phase is washed with brine, 3N hydrochloric acid, brine again, and then dried over sodium sulfate. Evaporation affords an oil that is dissolved in dimethylformamide (15 ml.); potassium carbonate (1.2 g.) is added, and the mixture is heated on the steam bath for 2.5 hours. Water is added to the cooled mixture, which is acidified (dilute HCl) and then extracted with ethyl acetate (2 × 75 ml.). The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting oil is purified by chromatography over silica gel using ethyl acetate-hexane (60:40) to elute. From the proper fraction, there is obtained 1.2 g. (81%) of the title compound as a clear, viscous oil.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8]2.[C:20]([O-])(=[O:22])[CH3:21].[K+]>CN(C=O)C.O>[C:20]([C:6]1[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][CH:3]=2)[O:8][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: O=c1cc(-c2ccccc2)oc2cccc(CBr)c12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: 100 °C
Yield: 107.2 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-hydroxy-5-methoxymethyl acetophenone (1.62 g, 9.014 mmol), 4-methoxy-3-fluoro benzoyl chloride (1.7 g, 9.014 mmol) and pyridine (20 mL). The reaction mixture was stirred for 16 h at rt under nitrogen. The reaction mixture was poured into ice-water. The solids were filtered off, washed with water and dried to give the intermediate (2.33 g, 78%). To a solution of this intermediate (2.33 g, 7.01 m mol) in THF (50 mL), was added potassium t-butoxide (945 mg, 8.42 mmol) and the reaction mixture was stirred for 16 h at rt under N2. The reaction mixture was poured into saturated solution of NH4Cl. The organic layer was separated, washed with water, dried and concentrated to give crude intermediate diketone (2.3 g, 98.7%). The diketone compound (2.3 g, 6.92 mmol) was taken into a mixture of HCl (1 mL) and acetic acid (15 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to give 1.75 g of the intermediate in 80.6% yield. In a 100 mL dry round-bottomed flask fitted with condenser and magnetic stirrer were placed this intermediate (925 mg, 2.94 mmol) in CH2Cl2 (30 mL). BBr3 (2.21 g, 8.83 mmol, 1M solution in CH2Cl2) was added slowly at 0° C. The reaction mixture was stirred for 16 h at rt under nitrogen. The reaction mixture was quenched by carefully adding methanol. The solvent was removed under reduced pressure and the resulting solid was washed with water and dried to give 1.0 g of crude 3′-fluoro-4′-methoxy-5-bromo methyl flavone in 97% yield. To a solution of 5-bromomethyl flavone (1.0 g, 2.86 mmol) in DMF (20 mL), potassium acetate (845 mg, 8.60 mmol) was added. The mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give crude acetyl flavone (810 mg, 86%). To a solution of the acetyl flavone (810 mg, 2.47 mmol) in methanol (15 mL), K2CO3 (1.02 g, 7.41 mmol) was added and the reaction mixture was stirred for 2 h at rt. The solvent was removed and the product was taken in to water and neutralized by dilute HCl. The solid was separated by filtration, washed with water and dried to give 2-(3-fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-chromen-4-one in 38% yield. MS (ES) m/z: 286.96 (M); Mp. 256-258° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](Cl)[CH:10]=1>CN1C(=O)CCC1.O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH2:8])=[CH:10][C:11]=1[O:7][CH2:6][CH2:5][O:4][CH3:3])#[N:14]
Reactant: COCCO
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCOc1cc(N)ccc1C#N
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
Sodium hydride (300 mg of an 80% suspension in mineral oil, 10 mmol) was added to 2-methoxyethanol (0.76 g, 10 mmol) in NMP (5 ml) and the mixture stirred for 15 minutes. 4-Amino-2-chlorobenzonitrile (1.5 g, 10 mmol) was added and the mixture heated at 100° C. for 5 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography eluting with increasingly polar mixtures of methylene chloride/ethyl acetate to give 4-cyano-3-(2-methoxyethoxy)aniline (760 mg, 40%) as a dark yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]=[O:4].C(N(CC)CC)C.ClC(OC(Cl)=O)(Cl)Cl.[O:20]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1.O.CC(C)=O>[CH3:1][NH:2][C:3](=[O:4])[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:30]
Reactant: CNC=O
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CNC(=O)C(=O)c1ccccc1Oc1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
N-Methylformamide (2.36 g, 40.0 mmol) and triethyl amine (8.08 g, 80.0 mmol) were dissolved in toluene (40 ml). Trichloromethylchloroformate (3.96 g, 20.0 mmol) was added dropwise slowly under ice-cooling while maintaining the inner temperature at 10° C. or lower. The mixture was stirred at the same temperature for 1 hour. A large amount of insoluble materials were precipitated. To the mixture was added 2-phenoxybenzoyl chloride which was prepared from 2-phenoxybenzoic acid (4.28 g, 20.0 mmol) and thionyl chloride (2.86 g, 24.0 mmol). The resulting mixture was stirred at bath temperature of 40° to 50° C. for 26 hours. 5N-Hydrochloric acid (12 ml) and acetone (20 ml) were added, and the mixture was stirred for 12 hours. Water was added to the mixture, which was then extracted with toluene and purified by column chromatography on silica gel to obtain the title compound (3.11 g, Yield: 61.0%).