Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([CH3:20])=[N:15][CH:16]=[CH:17][C:18]=1[Cl:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO>ClCCl>[Cl:12][C:13]1[C:14]([CH2:20][OH:9])=[N:15][CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Cc1nccc(Cl)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: OCc1nccc(Cl)c1Cl
Reaction time: 16 h

Procedure:
m-Chloroperbenzoic acid (32.63 g) in dichloromethane (400 ml) was added dropwise to a solution of 3,4 -dichloro-2 -picoline (25.53 g)in dichloromethane (100 ml) maintaining the temperature at 20°-25°. After standing for 16 hours at room temperature the solution was washed with 1 N NAOH, dried (K2CO3 ) and filtered to give a pale yellow solution. Trifluoroacetic anhydride (30 ml) was added dropwise to this solution maintaining the temperature at 15°-20°. After standing for 2 days at room temperature, methanol (100 ml) was added and the solution evaporated under reduced presure. The residue was treated with aqueous sodium carbonate and extracted into dichloromethane. After drying (K2CO3 ) and removal of solvent, the residue was recrystallised from pet. ether (60/80 ) to give 3,4 -dichloro-2 -hydroxymethylpyridine, 15.76 g, m.p. 66°-8°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]#[C:11][C:12]([OH:14])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1.C([O-])(O)=O.[Na+]>C1COCC1.N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:12](=[O:14])[C:11]#[C:10][CH2:9][N:5]4[CH2:6][CH2:7][CH2:8][C@H:4]4[CH2:3][O:2][CH3:1])[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: COC[C@@H]1CCCN1CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: COC[C@@H]1CCCN1CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 1.46 g (7.40 mmol) of 4-((2S)-2-methoxymethylpyrrolidin-1-yl)but-2-ynoic acid in 85 mL of THF under N2 was added 0.897 g (8.88 mmol) of N-methylmorpholine and 0.811 g (5.92 mmol) of isobutyl chloroformate. After stirring in the cold for 30 min, a solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile in 8 mL of pyridine was added dropwise. The reaction was slowly warmed to 25° C. over 3 h. The reaction was poured into ice water, satd NaHCO3 was added and the product was extracted with ethyl acetate. After drying and solvent evaporation, the residue was chromatographed on silica gel (10% methanol in ethyl acetate). The yield was 0.560 g of 4-((2S)-2-methoxymethylpyrrolidinyl-1-yl)but-2-ynoic acid[4-(3-bromophenylamino)-3-cyanoquinolin-6-yl]amide as a brown foam: mass spectrum (electrospray, m/e): M+H 518.0, 520.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[CH3:33][N:34](C)[C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH2:37]>O1CCCC1.CN(C)C=O>[CH3:33][NH:34][C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:37][C:16]([C@H:13]1[CH2:12][CH2:11][C@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:15][CH2:14]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To the compounds (I) (19.15 g) was added dry 1,4-dioxane (50 ml) and 4N hydrogen chloride/1,4-dioxane solution (250 ml), and the mixture was stirred under room temperature for 2 hours. The solvent was removed under a reduced pressure and toluene was added and reevaporated to give L-phenylalanine 4-carbamoylanilide hydrochloride (II) quantitatively as a white powder. On the other hand, trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (13.36 g) was dissolved in dry tetrahydrofuran (500 ml), and triethylamine (7.80 ml) was added under ice-cooling, followed by stirring at the same temperature for 10 minutes. Subsequently, a solution of ethyl chlorocarbonate (5.64 g) in dry tetrahydrofuran (50 ml) was added dropwise under ice-cooling for 3 minutes, and the mixture was again stirred at the same temperature for 20 minutes. The above mixture was added to the suspension of the hydrochloride (II) previously obtained and triethylamine (8.53 ml) in N,N-dimethylformamide (150 ml) under ice-cooling, followed by stirring at the same temperature for 2 hours, and under room temperature for 6 hours. Ice-water (1.4 liter) was added and the insolubles were collected by filtration, thoroughly washed with water, and further washed with 10% aqueous citric acid, water 5% aqueous sodium hydrogen carbonate, followed by washing with water at 40° to 50° C., and drying, to give N-[4-trans-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine 4-carbamoylanilide (III) (24.63 g). The structure was confirmed by NMR.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Br:11][C:12]1[S:16][C:15]2=[CH:17][N:18]=[CH:19][N:14]2[CH:13]=1.[OH-].[Na+]>C(Cl)Cl.O>[Br:11][C:12]1[S:16][C:15]2=[C:17]([CH:3]=[O:4])[N:18]=[CH:19][N:14]2[CH:13]=1
Reactant: Brc1cn2cncc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Dimethylformamide (0.13 ml) and 0.15 ml of phosphorus oxychloride were added in that order to a solution of 300 mg of 2-bromoimidazo[5,1-b]thiazole in 3 ml of methylene chloride under an argon atmosphere, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture to stop the reaction, and the reaction mixture was adjusted to pH 10 by the addition of a 1 N aqueous sodium hydroxide solution. The reaction mixture was then extracted with ethyl acetate, and the organic layer was then washed with saturated brine and was dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:10) to give 223 mg of 2-bromo-7-formylimidazo[5,1-b]thiazole.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:25].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]#[C:35][CH2:36]O>ClCCl>[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]#[C:35][CH2:36][I:25]
Reactant: OCC#CCOC1CCCCO1
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC#CCOC1CCCCO1
Reaction time: 0.05 h
Yield: 56.1 %

Procedure:
To a stirred solution of triphenylphosphine (1.4154 g, 5.34 mmol) in anhydrous dichlormethane (20 mL) at room temperature under nitrogen was added imidazole (360 mg, 5.24 mmol), followed by iodide (1.2688 g, 4.95 mmol). The mixture was stirred for three minutes, a solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (708.6 mg, 4.16 mmol) in dichloromethane was added dropwise via spring. The resulting mixture was continued to be stirred for 1.5 hours. The mixture was filtered through a pad of Celite. And the solid was washed with dichloromethane. The combined organic filtration was concentrated under reduced pressure. The residue was separated with flash column chromatography on silica using 0-20% EtOAc/hexane to afford 654 mg of product in 56% yield. 1H-NMR (CDCl3): δ 4.77 (t, J=3.0 Hz, 1 H), 4.33-4.18 (m, 2 H), 3.85-3.77 (m, 1 H), 3.70 (t, J=2.1 Hz, 2 H), 3.56-3.49 (m, 1 H), 1.85-1.62 (m, 6 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:12][C:5]2[S:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH2:3]1.[CH:14]([Mg]Br)=[CH2:15].[ClH:18].CCOCC>C1COCC1>[Cl:18][CH2:14][CH2:15][C:9]([C:7]1[S:6][C:5]2[CH2:12][C:2]([CH3:1])([CH3:13])[CH2:3][C:4]=2[CH:8]=1)=[O:11]
Reactant: CC1(C)Cc2cc(C(=O)O)sc2C1
Reactant: Cl
Reactant: C=C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)CCCl)sc2C1
Temperature: -70 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 106d (2.41 g, 10.0 mmol) and anhydrous THF (20 mL). The solution was cooled to −70° C., and 1 M vinylmagnesium bromide in THF (11 mL, 11.0 mmol) was added with the reaction temperature maintained below −60° C. The reaction mixture was stirred at −13 to −7° C. for 2 h and then warmed to room temperature over 30 min. The reaction was again cooled to −70° C., and a 2 M solution of hydrogen chloride in ether (22.5 ml, 45 mmol) was added. The reaction was then stored in a freezer at −10° C. overnight. After this time the mixture was evaporated under reduced pressure on a rotary evaporator, and the resulting residue partitioned between water (100 mL) and ether (100 mL). The ether extract was dried over sodium sulfate and evaporated under reduced pressure on a rotary evaporator to afford crude 106e (2.86 g, 118%) as a brown oil with approximately 75% purity (by NMR): 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), 3.89 (t, 2H, J=6.9 Hz), 3.30 (t, 2H, J=6.9 Hz), 2.75 (s, 2H), 2.59 (s, 2H), 1.24 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(Cl)c(Cl)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,4-dichloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.99 min; [M+H]+=302.2.
Reaction SMILES: [OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.C([N:47]([CH2:50]C)CC)C>O1CCCC1.O>[C:18]1([CH:2]2[O:1][C:50](=[O:35])[NH:47][CH:3]2[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2cccc3ccccc23)O1
Yield: 83.7 %

Procedure:
To a solution of (2RS,3RS)-3-hydroxy-3-(1-naphthalenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (2.64 g, 7.05 mmol) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (1.67 ml, 7.76 mmol) and triethylamine (1.5 ml, 10.6 mmol) and the mixture was heated under reflux for 1 hr. The reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced, pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-(1-naphthalenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (2.19 g, 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[N:8]=[CH:7]2.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[F:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[CH:3]=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[N:8]=[CH:7]3)=[CH:32][CH:33]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(Br)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(-c4ccc(F)nc4)c3n2)cc1

Procedure:
To a 0.050 M solution of 4-(8-bromo-6-(trifluoromethyl)quinazolin-2-ylamino)benzenesulfonamide (1.0 eq) in DME was added 2-fluoro-5-pyridineboronic acid (3.0 eq), (dppf)Pd(II)Cl2-CH2Cl2 (0.050 eq) and 2M aqueous potassium carbonate (8.0 eq). The mixture was microwaved at 120° C. for 10 min and then diluted with ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to give the desired product which was used without further purification. ES/MS m/z 464 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-phenol (46 mg, 0.12 mmol), prepared as described in Example 2, acetic anhydride (0.023 mL, 0.24 mmol), triethylamine (0.05 mL, 0.36 mmol) and CH2Cl2 (4 mL) was stirred at room temperature under N2 for 4 h. The reaction mixture was treated with saturated sodium bicarbonate, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (47 mg, 92%) as a white solid: mp 142–144° C.; 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (br s, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 6.92 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.01 (s, 6H); APCI MS m/z 426 [(M+H)+, calcd for C22H24N3O4S, 426.1].
Reaction SMILES: [CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10][C:9](=S)[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:21][NH2:22]>O>[CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10]/[C:9](=[N:21]\[NH2:22])/[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
The mixture of 8-cyclobutyl-3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (0.6 g, 2.0 mmol) in 20 M of hydrazine in water (20 mL) was stirred at 100° C. overnight. After cooling to room temperature, the solid formed was filtered and dried Cooled down, the solid was isolated to give yield the desired product (230 mg, 38.6%). LCMS calculated for C14H23N6O(M+H): 291.2; found: 291.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:24][C@@H:23]4[C@H:19]3[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22]4)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][CH:37]=1)CCC>O1CCCC1>[CH2:25]([N:21]1[CH2:20][C@@H:19]2[C@@H:23]([CH2:24][C@H:18]2[C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:13][CH:14]=2)[CH2:22]1)[CH2:26][CH3:27]
Reactant: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(Br)cc4)cc3)[C@@H]2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: C1CCOC1
Product: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(-c5ccco5)cc4)cc3)[C@@H]2C1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 8.7 %

Procedure:
4-Bromo-N-[4-((1R,5S,6R)-3-propyl-3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-benzenesulfonamide (50 mg, 0.11 mmol), 2-(tributylstannyl)-furan (199 mg, 0.56 mmol) and tetrakistriphenylphosphinpalladium(0) (26 mg, 0.02 mmol) were dissolved in 5 ml of tetrahydrofuran and stirred for 40 minutes at 150° C. in the microwave (CEM). The reaction mixture was filtered over celite, washed with methanol, and the filtrate evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography with ethyl acetate, and ethyl acetate/methanol (15%). Fractions containing the product were combined, the solvent evaporated to yield 4.2 mg of the title product (yield 9%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.[CH3:13][C-:14]1[CH:18]([CH3:19])[C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([CH:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25]O)[C:16]=2[O:15]1.[Cl:32]C(Cl)C>CC(C)=O.O.ClCCl>[ClH:32].[CH3:13][C:14]1[O:15][C:16]2[C:23]([CH:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25][F:7])=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19]
Reactant: CCN(CC)C(CO)c1cccc2c1O[C-](C)C2C
Reactant: CC(Cl)Cl
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)C(CF)c1cccc2c(C)c(C)oc12
Product: Cl
Reaction time: 1.5 h
Yield: 62 %

Procedure:
0.664 ml (3.72 mmol) of diethylaminosulphur trifluoride (DAST) and 5 ml of dichloromethane are placed in a 50 ml round-bottomed flask. The mixture is cooled to -78° C. by a bath of dry ice in acetone and a solution of 0.877 g (3.38 mmol) of 2,3-dimethyl-7-(1-diethylamino-2-hydroxyethyl)benzofuran id 5 ml of dichloroethane is added dropwise. Stirring is continued for 90 minutes at this temperature, before allowing the reaction mixture to return to room temperature. 10 ml of water are added and extraction is carried out with dichloroethane (3×15 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 5% methanol in dichloromethane). 700 mg (Yield: 62%) of 2,3-dimethyl-7-(1-diethylamino-2-fluoroethyl)benzofuran hydrochloride are obtained in the form of a colourless oil.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)[OH:12])=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.N1C=CC=CC=1>O>[C:13]1([C:11]([C:9]([C:1]2[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=2)=[O:10])=[O:12])[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A reaction mixture was prepared containing 1.2 kg. of anisoin, 3 kg. of cupric sulfate pentahydrate, 4.9 l. of pyridine and 1.2 l. of water. The mixture was heated with stirring overnight at a temperature of about 85° C. The resulting green suspension was poured over 20 kg. of ice and the mixture stirred until the ice had dissolved. Anisil, formed in the above reaction was collected by filtration. The filter cake was washed thoroughly with water to remove all traces of copper sulfate. Yield of anisil was 1167 g. melting at 125°-127° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of 2,5-di-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep about 130° C. for 3 hours in nitrogen atmosphere with distilling 23.5 ml (0.40 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 64.8 g (yield 52.4%) of 2-ethoxalyloxyethyl methacrylate (bp 95°-125° C./0.3 mmHg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(COC)OC.C(Cl)[Cl:35]>>[ClH:35].[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:35])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: ClCCl
Solvent: COCCOC
Product: Cl
Product: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A cold solution of 25 g. 4-(16-bromohexadecylamino)benzoic acid in 500 ml. dimethoxyethane-methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. thionyl chloride and refluxed until all of the precipitate has dissolved. The solvents are evaporated to yield an orange, semi-crystalline mass.
Reaction SMILES: C([NH:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([C:14]([NH:16][C@@H:17]([CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])=[O:15])=[CH:12][CH:11]=1)(OC(C)(C)C)=O.Cl.O1CCOCC1>CO>[NH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([C:14]([NH:16][C@@H:17]([CH2:21][CH2:22][NH2:23])[C:18]([OH:20])=[O:19])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 189.4 %

Procedure:
The compound obtained in Example 60-2 (49.7 mg) was dissolved in methanol (0.5 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.5 ml) was added. The mixture was stirred for 1.5 hours at room temperature. After the reaction, the solvent was removed by distillation and the residue was dried using a vacuum pump to obtain the title compound (52.4 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[I:17]I>C1COCC1.CCCCCC.[Cl-].[Na+].O>[I:17][C:9]1[S:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: II
Reactant: COc1cccc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(I)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
In a 4 L mechanically stirred reactor, a solution of 1-benzothien-7-yl methyl ether (105 g, 0.64 mol) in anhydrous THF (2 L) is cooled down to −74° C. n-Butyl lithium in hexane is added (2.5 N, 285 mL, 0.71 mol) within 45 min, keeping temperature below −70° C. The mixture is stirred 30 min at −78° C. and a solution of iodine (179 g, 0.70 mol) in anhydrous THF (1L) is added within 1 h, keeping temperature below −70° C. After addition, the mixture is allowed to come up to room temperature over 2 h and brine (500 mL) is added. The layers are roughly separated and the organic layer is partially evaporated. Additional brine (200 mL) is added to the residual aqueous layer (mixed with some THF). After decantation, the organic and aqueous layers are separated. The aqueous layer is extracted with ethyl acetate (500 mL). The organic layers are pooled, washed with aqueous sodium thiosulphate, dried (MgSO4) and the solvent evaporated in vacuo to give the crude iodo derivative (173.6 g, 93%) The solid is recrystallized from isopropanol (150 mL) to give pure compound (145.5 g, 88%); δH (600 MHz, CDCl3) 7.51 (s, 1 H), 7.32 (d(br), J=7.89 Hz, 1 H), 7.26 (t, J=7.89 Hz, 1 H), 6.72 (d(br), J=7.89 Hz, 1 H), 3.97 (s, 3 H).