Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[C:29](O)(=[O:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)(Cl)Cl>O>[C:29]([NH:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:12]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF (300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazine dissolved in DMF (200 ml) and stirred at room temperature for 2 hours. The reaction solution was poured into water and the resulting precipitates were washed with water and methanol to obtain 17.7 g (yield: 93%) of 2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine. (2) 0.38 g (1.0 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g (4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) of DCC was added to chloroform (5 ml) and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.31 g (yield: 73%) of the titled compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CS(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}methanesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[CH:5]=[C:4]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[C:3]=1[CH2:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[OH:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[CH:5]=[C:4]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[C:3]=1[CH2:18][CH2:19][CH:20]([OH:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)N(C)c1cc2c(nc(C)n2C)c(O)c1CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N(C)c1cc2c(nc(C)n2C)c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A suspension of 0.8 g (2.2 mmol) N-[7-hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazol-5-yl]-N-methyl-acetamide in ethanol (200 ml) was treated with 100 mg (3.6 mmol) sodium borohydride and the reaction was stirred at room temperature for 1 h. A saturated ammonium chloride solution was added and the reaction was extracted with ethyl acetate (3×20 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue afforded 0.77 g (95%) of the title compound as a beige foam.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[O:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[O:38])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromo-1-(4-methoxyphenyl)ethanone (0.77 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 48%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]([F:34])[F:33])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.S(Cl)(C)(=O)=O.[NH2:49][C@@H:50]1[C:75](=[O:76])[N:52]2[C:53]([C:59]([O:61][CH:62]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[O:60])=[C:54]([CH2:57][Cl:58])[CH2:55][S:56][C@H:51]12.C[Si](C)(C)NC(=O)C>CN(C)C=O.C(Cl)Cl.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]([F:33])[F:34])[C:27]([NH:49][C@@H:50]2[C:75](=[O:76])[N:52]3[C:53]([C:59]([O:61][CH:62]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[O:60])=[C:54]([CH2:57][Cl:58])[CH2:55][S:56][C@H:51]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 105.8 %

Procedure:
A mixture of 2-(2-tritylaminothiazol-4-yl)-2difluoromethoxyiminoacetic acid (syn isomer) (2.4 g) and diisopropylethylamine (1.29 g) in N,N-dimethylformamide (35 ml) was cooled to -30° C. and mesyl chloride (1.15 g) was added dropwise thereto. The mixture was stirred at -20° to -30° C. for 30 minutes to give an activated acid solution. On the other hand, a mixture of benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate (2.18 g) and N-trimethylsilylacetamide (5.25 g) in methylene chloride (20 ml) was stirred to be a clear solution for 30 minutes at room temperature and then cooled to -20° C. To this solution was added the activated acid solution obtained above in one portion. The mixture was stirred for 30 minutes at -15° to -10° C., poured into water and extracted with ethyl acetate. The extract was washed with water three times, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give benzhydryl 7β-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (4.64 g).
Reaction SMILES: Cl.[N:2]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[N:3]1.C[O-].[Na+].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.[OH-].[K+].Cl>CCO.O.CCOCC>[OH:15][C:16]1[C:17]([C:18]([OH:20])=[O:19])=[CH:23][N:8]=[C:7]([N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)[N:9]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)n1cccn1
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1cnc(-n2cccn2)nc1O
Temperature: 75 °C

Procedure:
To 1H-pyrazole-1-carboximidamide hydrochloride (44.22 g, 299 mmol) in EtOH (500 mL) was added sodium methoxide (102 mL, 448 mmol, 25 wt % in MeOH) and diethyl ethoxymethylenemalonate (61.0 mL, 299 mmol, 99%). The reaction was heated for about 40 min at 75° C. and then cooled slightly (71° C.) before adding potassium hydroxide (33.5 g, 597) in water (125 mL). The reaction was heated to 75° C. for 1 h. During this time an additional portion of EtOH (100 mL) was added to improve mixing. The reaction was cooled to 40° C. before adding aq. HCl (81.3 mL, 991 mmol, 37%) in portions. The reaction aged for 1 h 40 min and then Et2O (180 mL) was added. The solids were filtered and rinsed with EtOH, Et2O and then hexane. The solid was then suspended in aq. HCl (300 mL, 0.67 M), filtered and washed with aq. HCl (300 mL, 1 M), 2:1 Et2O:EtOH (350 mL), 1:1 Et2O:EtOH (200 mL), Et2O (150 mL) and hexane (150 mL) to afford the title compound. HPLC/MS: 207.2 (M+1); Rt=0.61 min.
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([C:36]([OH:38])=O)[CH:29]=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C.O>[Br:25][C:26]1[CH:27]=[C:28]([C:36]([NH:15][CH:14]2[CH2:12][CH2:13]2)=[O:38])[CH:29]=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)c2ncccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Br)c2ncccc2c1
Reaction time: 2 h

Procedure:
A solution of HATU (1.2 eq), 8-bromoquinoline-6-carboxylic acid (1 eq), diisopropylethylamine (2.5 eq) and cyclopropylamine (1.1 eq) was stirred at rt for 1 h in DMF (0.2 M). The reaction mixture was diluted with water, stirred for 2 h and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was crystallized in EtOAc and title product isolated by filtration as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@H:12]4[CH:17]=[N:16][CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].C(N(CC)CC)C.[I-].[K+]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@@H:12]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CN1CCN2c3c(cccc31)[C@H]1C=NCC[C@@H]12
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12

Procedure:
A suspension of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline (ca. 11.8 g, ca.50 mmol), 4-chloro-4′-fluorobutyrophenone (15.0 g, 74.8 mmol), triethylamine (30 mL, 214 mmol), and potassium iodide (12.6 g, 76 mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2SO4) and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5N HCl ether solution. The solid is filtered off and washed with ether and then dissolved in water. The resulting aqueous solution is basified with 2N NaOH and extracted with DCM. The DCM layers are combined, washed with brine (2×200 mL) and dried (Na2SO4). Evaporation of the solvent and chromatography of the residue over silica gel gives 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[C:10]([OH:13])=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:14][C:15]([CH3:21])([CH3:20])[CH2:16]C(O)=O.S(O[O-])([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:14][C:15]([CH3:21])([CH3:20])[CH2:16][C:9]1[C:7](=[O:8])[C:5]2[C:4]([C:11](=[O:12])[C:10]=1[OH:13])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)(C)CC(=O)O
Agent: [Ag+]
Agent: O=S(=O)([O-])O[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
This compound was prepared by the general methods as described in Examples 1 to 15. Lawsone (0.15 g), 3,3-dimethylbutyric acid (0.15 g), and silver nitrate (0.15 g) were heated in a mixture of acetonitrile (5 ml) and water (5 ml) at 60-65° C. A solution of ammonium peroxysulphate (0.3 g) in water (5 ml) was added dropwise and the mixture heated for 1 hour and then processed as for Example 3 to yield the title compound . The crude product was purified on a silica gel column using 20% diethyl ether in petroleum ether eluant and recrystallised from petroleum ether to yield 38 mg of the title compound.
Reaction SMILES: [NH:1]([CH:8]=[C:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:15]([O:29][CH3:30])[CH:14]=1)[C:10]#N)C1C=CC=CC=1.Cl.[NH2:32][C:33]([NH2:35])=[NH:34].C[O-].[Na+].[OH-].[Na+]>C(O)C.CCCCCC>[CH3:30][O:29][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:12][C:9]1[C:8]([NH2:1])=[N:34][C:33]([NH2:35])=[N:32][CH:10]=1
Reactant: COc1ccc(COc2ccc(CC(C#N)=CNc3ccccc3)cc2OC)cc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(COc2ccc(Cc3cnc(N)nc3N)cc2OC)cc1
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A suspension of 3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl) oxy]benzyl}prop-2-enenitrile (300 mg, 0.75 mmol) and guanidine hydrochloride (108 mg, 1.13 mmol) in ethanol (5 mL) was stirred at room temperature while sodium methoxide was added. The mixture was stirred at reflux overnight. The solution was cooled 5 C and 2N sodium hydroxide (2 mL) was added. After 15 minutes, a white precipitate was filtered off and washed with water then hexane to give product as a white solid (199 mg, 0.54 mmol). 1H NMR (300 MHz, d6-DMSO): δ 7.45 (s, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.93-6.85 (m, 4H), 6.66 (dd, J=8.3 and 1.5 Hz, 1H), 6.02 (s, 2H), 5.65 (s, 2H), 4.91 (s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 3.50 (s, 2H). MS (ES+, m/z)=367 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.FC(F)(F)C(O)=[O:24].OO.S(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5](=[O:24])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (4 g, 11.45 mmol) in DCM (20.02 mL) at room temperature was added trifluoroacetic acid (20.02 mL) dropwise, the reaction went from orange to dark brown in color. Upon addition the resulting mixture was stirred at room temp for 10 min and then hydrogen peroxide (30% wt. aq) (1.583 mL, 16.47 mmol) was added dropwise. After 90 min at room temperature the reaction mixture was quenched with sodium bisulfite (1.714 g, 16.47 mmol) (vigorous bubbling was observed) followed by 3.0 mL of water. The resulting suspension was stirred vigorously for 15 min and then concentrated in vacuo to remove DCM and most of the TFA. The residue was partitioned between DCM (40 mL) and sat. aq. NaHCO3 solution (40 mL) and separated. The organic layer was collected (phase separator) and concentrated in vacuo to afford the crude product, which was purified by column chromatography (SiO2, 1-40% EtOAc/Heptane) to afford 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (4.6 g, 10.08 mmol, 88% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.51-7.65 (m, 2H), 7.37-7.51 (m, 2H), 7.08 (dd, J=2.27, 8.34 Hz, 1H), 6.79-6.96 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[CH:14]1[C:19]([CH2:20][CH2:21]O)=[CH:18][C:17]([OH:23])=[C:16]([OH:24])[CH:15]=1.C1C(CCO)=CC=C(O)C=1.OC1C=C(CCC2C(O)=C(O)C=CC=2/C=C/C([O-])=O)C=CC=1O>>[C:1]([O:13][CH2:21][CH2:20][C:19]1[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([OH:23])[CH:18]=1)(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: OCCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: O=C([O-])/C=C/c1ccc(O)c(O)c1CCc1ccc(O)c(O)c1
Agent: OCCc1ccc(O)cc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccc(O)c(O)c1

Procedure:
The protocol derived from Example 14 above is applied with caffeic acid and 3-hydroxytyrosol instead of caffeic acid and tyrosol; the compound obtained is 2-(3,4-dihydroxyphenylethyl)trans-caffeoate (formula IVb2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]1[C:41]([N+:50]([O-:52])=[O:51])=[C:42](/[CH:46]=[CH:47]/[CH2:48][OH:49])[CH:43]=[CH:44][CH:45]=1.[Na+].[I-]>C1C=CC=CC=1.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([O:13][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](/[CH:46]=[CH:47]/[CH2:48][OH:49])[C:41]=1[N+:50]([O-:52])=[O:51])=[O:12]
Reactant: O=[N+]([O-])c1c(/C=C/CO)cccc1CBr
Reactant: O=C(O)CCSSc1ccccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(CCSSc1ccccn1)OCc1cccc(/C=C/CO)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To acid 20 (40.0 mg, 0.18 mmol) in benzene (0.3 mL) was added 18-crown-6 (48.0 mg, 0.18 mmol) and K2CO3 (23.1 mg, 0.18 mmol). The mixture was stirred for 1 h and alcohol 18 (41.0 mg, 0.15 mmol) was added followed by NaI (27.2 mg, 0.18 mmol). The reaction mixture was heated to 50° C. for 3 h, and then cooled. The mixture was diluted with CH2Cl2 (1.0 mL), washed with saturated NaHCO3 solution (3.0 mL), extracted with CH2Cl2 (3×3.0 mL), drying over anhydrous Na2SO4, and concentration under reduced pressure. FCC on silica gel with 40% EtOAc in hexane yielded ester 21 (41.8 mg, 68.0%) as a cream oil. 1H NMR (400 MHz, CDCl3): δ 8.44 (1H, s), 7.62 (3H, m), 7.46 (1H, m), 7.37 (1H, m), 7.09 (1H, t, J=5.2), 6.59 (1H, d, J=15.7), 6.42 (1H, m), 5.16 (2H, d, J=3.8), 4.34 (2H, m), 3.03 (2H, t, J=7.1), 2.80 (2H, t, J=7.0), 2.03 (1H, bs); 13C NMR: δ 171.6, 159.7, 150.0, 149.6, 148.8, 135.3, 131.1, 130.6, 130.3, 129.3, 128.8, 128.2, 121.3, 120.7, 62.5, 34.1, 33.7, 33.2; HRFABMS m/z 407.0741 (+1.4 ppm/+0.6 mmu) [M+H+] (calcd for C18H19N2O5S2, 407.0735).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:15])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([O:31]C)=[O:30])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O>[CH2:1]([C:5]1[N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:15])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([OH:31])=[O:30])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c(=O)nc2n1CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C(=O)O)cc2)c(=O)nc2n1CC(=O)N2
Yield: 51.7 %

Procedure:
A solution of 0.17 g of 5-butyl-6-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]imidazo[1,2-a]pyrimidin-2,7-dione in 2 ml of MeOH is added with 32 mg of NaOH dissolved in 0.05 ml of H2O. After 24 h under reflux, the solvent is evaporated under reduced pressure and the residue is taken up in H2O and acidified to pH 5, to separate a solid which is filtered off and washed thoroughly with H2O. The purification is carried out by FC (eluent CH2Cl2 --MeOH--AcOH 89:10:1), to obtain 85 mg of a white solid (51% yield; m.p.=220°-222° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(N(CC)CC)C>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[C:17]([O:22][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(=CCc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 4-(4-benzyloxyphenyl)-1,1,1-trifluoro-2-butanone (2.25 g, 7.26 mmol) and trimethylsilyl chloride (1.84 ml, 14.5 mmol) in THF (20 ml) at 0° C. was added dropwise triethylamine (3.1 ml, 21.8 mmol). The mixture was stirred at room temperature for 1 hour, diluted with hexane (200 ml), filtered and washed with hexane. The filtrate was washed with brine (2×50 ml), dried over sodium sulfate for 2 minutes and concentrated in vacuo to give the title material (2.58 g, 93%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH3:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[C:7]([F:8])=[C:2]([O:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=2[F:20])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Oc1cccc(F)c1F
Reactant: CC#CCOc1ncnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(Oc2cccc(F)c2F)c1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.1 g of 4-chloro-6-(2-butynyloxy)-5-fluoropyrimidine, 0.1 g of potassium carbonate, and 0.08 g of 2,3-difluorophenol, followed by stirring at 80° C. for 2 hours. The reaction mixture was left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(2-butynyloxy)-6-(2,3-difluorophenoxy)-5-fluoropyrimidine (the present compound (180)).