Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:29])[CH:3]=1.[Na+].[CH3:31][S:32]([O-:34])=[O:33].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O>[F:29][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Reactant: CS(=O)[O-]
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 110 °C
Yield: 29.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.214 g, 0.46 mmol), methanesulfinic acid sodium salt (71 mg, 80%, 0.55 mmol), L-proline (11 mg, 0.09 mmol), Cul (9 mg, 0.05 mmol) and NaOH (4 mg, 0.09 mmol) in DMSO (2.5 mL) was degassed, purged with N2 and heated at 110° C. for 48 h. The mixture was cooled to ambient temperature and was poured into water and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 to give 62.5 mg (29%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=3.0 Hz), 8.15-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.20-4.10 (m, 2H), 4.00 (d, 2H, J=6.4 Hz), 3.18 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24](Br)[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2].[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C(#N)C.CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of ester 112 (3.0 g, 7.07 mmol) and bis(triphenylphosphine)palladium(II) acetate (0.42 g, 0.57 mmol) was dissolved in a mixed solvent system of acetonitrile (80 mL) and TEA (120 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (2 mL, 14.14 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 112 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). Conditions for TLC were EtOAc. A white solid 113 (2.60 g, 83.3%) was obtained. mp 160-162° C.; IR (KBr, cm−1) 3365, 2925, 1706, 1616, 1553, 1498; 1H NMR (CDCl3) δ 7.89 (s, 1H), 7.73 (dd, J=1.73 Hz, 1H), 7.51-7.36 (m, 7H), 6.66 (q, J=7.30, 1H), 4.45-4.30(m, 2H), 1.40 (t, J=7.11, 3H), 1.25 (d, J=7.38 Hz, 3H), 0.15 (s, 9H). MS (EI) m/e (relative intensity) 441 (M+, 15), 369 (25), 323 (55), 295 (100), 267 (15).
Reaction SMILES: [CH2:1]([C:3]1[C:23]2=[N:24][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[N:29]=[C:16]([CH:17]=[C:18]5[NH:25][C:21](=[CH:22]2)[C:20]([CH2:26][CH3:27])=[C:19]5[CH3:28])[C:15]([CH3:30])=[CH:14]4)=[CH:9][C:8]=3[CH3:31])[C:4]=1[CH3:32])[CH3:2].C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[Cl-].[In+3:58].[Cl-].[Cl-].C([O-])(=[O:63])C.[Na+]>C(O)(=O)C>[CH2:26]([C:20]1[C:21]2=[N:25][C:18](=[CH:17][C:16]3[NH:29][C:13]([CH:12]=[C:10]4[N:11]=[C:7]([CH:6]=[C:5]5[NH:24][C:23](=[CH:22]2)[C:3]([CH2:1][CH3:2])=[C:4]5[CH3:32])[C:8]([CH3:31])=[CH:9]4)=[CH:14][C:15]=3[CH3:30])[C:19]=1[CH3:28])[CH3:27].[OH-:63].[In+3:58].[OH-:63].[OH-:63]
Reactant: CC(=O)[O-]
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: CCC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(CC)c5C)C(C)=C4)cc3C
Agent: [Cl-]
Solvent: CC(=O)O
Product: [OH-]

Procedure:
The porphyrin prepared in Example 11 (100 mg) is metallated by refluxing a solution of the porphyrin, indium chloride (100 mg) and sodium acetate (100 mg) in acetic acid for 2 hrs. The solvent is removed and the solid dissolved in dichloromethane (50 mL) and washed with a saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate, filtered, evaporated to 10 ml, and hexane (10 mL) is added. The dichloromethane is slowly removed by rotary evaporation and the precipitated porphyrin collected by filtration. Yield of title compound=(100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]>CCO>[Cl:1][C:2]1[C:3]([C:19]([F:22])([F:20])[F:21])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)c(C(F)(F)F)nn1C
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Yield: 66.7 %

Procedure:
To a stirred solution of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.11 g, 0.33 mmol) in EtOH (1.0 mL) was added SnCl22H2O (0.30 g, 1.31 mmol, 4.0 eq.) and the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.067 g, 0.22 mmol, 66% yield after two steps) as a white solid: LCMS m/z (%)=306 (M+H35Cl, 100), 308 (M+H37Cl, 33). 1H NMR (400 MHz, CDCl3) δ: 6.86 (dd, J=14.0, 6.0 Hz, 1H), 6.84 (dd, J=8.0, 4.0 Hz, 1H), 6.63 (d, J=4.0 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.N([O-])=O.[Na+].[BrH:19]>O1CCOCC1.O.[Cu]Br>[Br:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Nc1ccc(F)c(-c2cccnc2)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(Br)cc1-c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A warm solution of 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 19.3 mmol) in 1,4-dioxane (10 ml) was treated with a solution of 48% aqueous hydrobromic acid (100 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with a solution of sodium nitrite (1.53 g, 22.2 mmol) in water (4 ml). After stirring at 0° C. for 2 h, a cooled (0° C.) solution of copper(I) bromide (8.31 g, 57.9 mmol) in 48% aqueous hydrobromic acid (30 ml) was added to the reaction which was stirred at 0° C. for 10 min then heated at 50° C. for 20 min. The reaction was cooled to ambient temperature, poured onto ice-cold concentrated ammonia (500 ml) and the product was extracted into ethyl acetate (500 ml). The organics were washed with water (300 ml) and brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a dark oil. Purification by dry flash column chromatography (silica gel, 10-30% EtOAc/isohexane) gave 3-(5-bromo-2-fluorophenyl)pyridine (3.1 g, 64%) as a white solid: 1H NMR (360 MHz, CDCl3) δ 7.09 (1H, dd, J 9, 1 Hz), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 1-(4-bromophenyl)piperazine hydrochloride (5.09 g, 18.3 mmol) and triethylamine (7.67 ml) in dichloromethane (100 ml) was added methanesulfonyl chloride (2.83 ml, 36.3 mmol) dropwise. The mixture was stirred for 1 hour at room temperature then dichloromethane (100 ml) was added. The organics were washed with water (2×), brine and dried (Na2SO4) and evaporated in vacuo to a yellow solid which crystallised from Ethanol and washed with diethyl ether to give 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (4.74 g, 81% yield) as a white fluffy powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[Cr](Cl)([O-])(=O)=[O:13].[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cc1ccccc1Cl
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1Cl
Reaction time: 22 h

Procedure:
To a solution of 2-chlorophenylacetone (10.800 g, 64.049 mmol) in 279 mL of CH2Cl2, pyridinium chlorochromate (41.418 g, 192.15 mmol), and pyidine (16 mL) in three portions were added over 2.5 hours and the mixture was refluxed under vigorous stirring. After 22 h, he mixture was removed from heat. The mixture was concentrated in vacuo to give a dark red syrup. The crude mixture was purified by column chromatography on a 120 g of Redi-Sep™ column using 0-10% gradient of EtOAc in hexane over 28 min as eluent to give 1-(2-chlorophenyl)propane-1,2-dione as yellow liquid: 1H NMR (400 MHz, choroform-d) δ ppm 7.66 (1 H, dd, J=7.6, 1.8 Hz), 7.49-7.54 (1 H, m), 7.38-7.45 (2 H, m), 2.58 (3 H, s); LC-MS: m/z 182.9 [M+H]+.
Reaction SMILES: C[C@H]1O[C@H]([O:8][CH:9]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[CH:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@@H](N)C[C@@H]1N=C(N)C(O)=O.Cl>O>[CH:9]1([OH:8])[CH:10]([OH:19])[CH:11]([OH:18])[CH:12]([OH:17])[CH:13]([OH:16])[CH:14]1[OH:15]
Reactant: C[C@H]1O[C@H](OC2[C@@H](O)[C@@H](O)C(O)[C@H](O)[C@H]2O)[C@@H](N)C[C@@H]1N=C(N)C(=O)O
Agent: Cl
Solvent: O
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 85 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
Kasugamycin hydrochloride (1 g), 5 mL deionized H2O and Diaion™ SK 116 resin (6 g) were combined and heated 4 h at 85° C., and then at 100° C. for 3 h. The catalyst was removed by filtration through a course scintered glass funnel and washed with deionized H2O (20 mL). The mixture was purified as above, using ion exchange resins and charcoal, yielding D-chiro-inositol (15%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=O)C(Cl)=O.Cl.CNOC.C[Mg]I>ClCCl.C(N(CC)CC)C.CN(C=O)C>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1
Agent: CNOC
Agent: C[Mg]I
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1

Procedure:
Scheme 9 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (37) (wherein R4, R5, R6, R7, R8 and R9 are as defined above in description) which is prepared from acetophenones of the formula (36) using known approaches. Certain di- and tri-substituted acetophenones were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (32) in three steps. Thus, acid of formula (32) was converted to the corresponding acid chloride of formula (33) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (33) was converted to corresponding Weinerb amide of formula (35) by treating with N,O-dimethylhydroxylamine hydrochloride of formula (34) in the presence of a suitable base such as triethylamine. The addition of methyl magnesium iodide to Weinreb amide of formula (35) afforded acetophenone derivative of formula (36).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([OH:24])[C:12](=[NH:23])[NH:13][O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>COCCOCCOC>[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][N:13]=1)[OH:24]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOCCOC
Product: CCC(N)C(O)c1noc(-c2ccccc2)n1
Yield: 29.9 %

Procedure:
A solution of (3) (1.5 g, 4.3 mmol) in diglyme was heated at 150° C. in a microwave (Smith Creator, S00219) for 40 minutes. Solvent evaporated under vacuum in Genevac Evaporator at 80° C. for 3 hours to give a brown solid. This was taken in dichloromethyl (40 ml) and treated with trifluoroacetic acid at room temperature for 2 hours. Solvent evaporated to dryness under reduced pressure, crude taken in water, washed with DCM, aqueous layer basified with 1M NaOH solution and extracted with dichloromethyl. Organic layer dried over Na2SO4 to give pale brown solid (300 mg); 1HNMR (CDCl3) 8.14–8.10 (m, 2H), 7.59–7.47 (m, 3H), 4.83 & 4.65 (d, J=5 Hz, 1H), 3.18–3.05 (2m, 1H), 1.71–1.20(m, 2H), 1.05–0.97 (dt, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1

Procedure:
38.1 g (0.2 mol) of 4-methylbenzenesulphonyl chloride are dissolved in 300 ml of carbon tetrachloride, 35.6 g (0.2 mol) of N-bromosuccinimide are added and, after addition of 0.2 g (1.2 mmol) of azobisisobutyronitrile (AIBN),the mixture is heated under reflux for 4 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography (petroleum ether/toluene 4:1, 50 μm particle size) and subsequent recrystallisation from 100 ml of cyclohexane give 24.0 g (45% of theory) of the title compound. Rf =0.75 (toluene).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.[Br:30]N1C(=O)CCC1=O>ClCC(Cl)C>[Br:30][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(Cl)CCl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
At 20° C. benzoyl peroxide (600 mg) was added to a suspension of 4-methyl-benzenesulfonyl chloride (9.5 g) and N-bromosuccinimide (8.9 g) in 1,2-dichloropropane (60 ml). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated and the title compound was obtained as a white solid after recrystallization from heptane. Yield: 2.26 g.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCCl)cc1

Procedure:
A suspension of 4-hydroxybenzaldehyde (40 g), 1-bromo-3-chloropropane (63 mL), and potassium carbonate (136 g) in acetone (920 mL) was heated to reflux for 16 h. The resulting mixture was filtered, and the filtrate was evaporated. Distillation of the residue (0.5 mm Hg, 220° C.) gave the title compound as a pale yellow oil that crystallized on standing (46 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7]1.CCN(CC)CC.O>C(Cl)Cl>[CH3:1][S:2]([O:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][S:6][CH:7]=1)(=[O:4])=[O:3]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccsc1

Procedure:
Methylsulfonyl chloride (2.22 ml, 28.75 mmol) was added dropwise to a solution of 3-thiopheneethanol (2.46 g, 19.2 mmol) and Et3N (5.3 ml) in DCM (50 ml) as 0° C. The mixture was stirred for 15 min before DCM and water was added. Organic phase was separated and residue purified by flash chromatography using 20-25% EtOAc in iso-hexane as eluents. Yield: 3.93 g (99%); colourless oil. HPLC: RT=2.20 min, 96% (254 nm, 10-90% MeCN in 0.1% TFA, 3 min ACE). 1H NMR (400 MHz, CDCl3): δ 2.90 (s, 3H), 3.13 (t, J 6.8 Hz, 2H), 4.44 (t, J 6.8 Hz, 2H), 7.00-7.02 (m, 1H), 7.11-7.12 (m, 1H), 7.32-7.36 m, 1H).
Reaction SMILES: [C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1)(=O)C.CO.C(O)(=O)C>CN(C)C1C=CN=CC=1.O>[C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:8]2[CH2:16][CH:12]3[CH2:11][CH:10]([CH2:15][CH:14]1[CH2:13]3)[CH2:9]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1ccc(O)cc1
Reaction time: 20 h

Procedure:
Into a flask were charged 250 g of the copolymer of 2-ethyl-2-adamantyl methacrylate and p-acetoxystyrene (20:80) obtained in Synthesis Example 4, 10.4 g (0.084 mol) of 4-dimethylaminopyridine and 202 g of methanol, and aged for 20 hours under reflux. After cooling, the reaction liquid was neutralized with 7.6 g (0.126 mol) of glacial acetic acid and poured into a large amount of water to precipitate a polymer. The deposited polymer was filtrated, dissolved in acetone, then, poured into a large amount of water to cause precipitation, and this operation was repeated three times in total for purification.
Reaction SMILES: [C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1)(=O)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.CO>[C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:8]2[CH2:16][CH:12]3[CH2:11][CH:10]([CH2:15][CH:14]1[CH2:13]3)[CH2:9]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1ccc(O)cc1
Reaction time: 20 h

Procedure:
Into a flask were charged 250 g of the copolymer of 2-ethyl-2-adamantyl methacrylate and p-acetoxystyrene (30:70) obtained in Reference Example 7, 10.8 g (0.088 mol) of 4-dimethylaminopyridine and 239 g of methanol and the mixture was aged for 20 hours under reflux. After cooling, the reaction solution was neutralized with 8.0 g (0.133 mol) of glacial acetic acid, and precipitated by pouring into a large amount of water. The precipitated polymer was dissolved in acetone, then, poured into a large amount of water to cause precipitation. This operation was repeated three times in total, to effect purification. The amount of the resulted copolymer of 2-ethyl-2-adamentyl methacrylate and p-hydroxystyrene was 102.8 g. The weight-average molecular weight was about 8200, the degree of dispersion was 1.68 (GPC method: reduced by polystyrene), and the copolymerization ratio was determined to be about 30:70 by a nuclear magnetic resonance (13C-NMR) spectrometer. This resin is called resin A6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Product: COc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the procedure described in Ex. 1, 4-methoxybenzaldehyde (17 g) and 4-picoline (9.3 g) 4.76 g were reacted to obtain 4-(4-methoxystyryl) pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([OH:22])=O)[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)Nc3ccccc3)C2=O)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) (100 mg, 0.3 mmol), aniline (33 mg, 0.36 mmol), Pybop (187 mg, 0.36 mmol) and triethyl ammine (0.05 mL, 0.36 mmol) were mixed in DMF (1 mL). The reaction stirred at 65° C. for 4 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl aceate (2 mL). The organic phase was washed with saturated sodium bicarbonate solution (2×, 2 mL) and then with saturated NaCl solution (1 ml). The organic phase was extracted, dried over anhydrous Na2SO4, and filtered. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O; 16 minute gradient). The pure fractions were combined and solvent was removed on the rotovap to afford 2-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)-N-phenylacetamide as a white solid (50%). 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.40 (s, 3H), 2.72 (m, 1H), 3.14-3.13 (d, 1H, J=4 Hz), 4.54-4.51 (d, J=8 Hz, 1H), 5.04 (s, 2H), 6.53 (bs, 1H), 7.15-7.13 (m, 1H), 7.33-7.22 (m, 2H), 7.47-7.45 (d, J=8 Hz, 2H), 7.78 (bs, 1H), 7.09 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.75 μM.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:9](=[O:22])[NH:8]2)[CH:5]=[N:4][CH:3]=[N:2]1>CCO.CO.[Pd]>[N:1]1([CH2:6][C@H:7]2[NH:8][C:9](=[O:22])[C@H:10]2[NH2:11])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1

Procedure:
Prepared in an analogous manner to example 4, step 3 using benzyl ((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (250 mg, 0.830 mmol) and Pd on C (10%, 125 mg) in EtOH:MeOH (4:1, 8.3 mL) for 3 h. The crude residue was used as such in following step. LCMS: Rt=0.13 min, m/z=168.1 (M+1) Method 2m_acidic.