Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([F:15])=[CH:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6].[Br-].[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][Zn+])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1.Cl>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Zn].CCCCCC.C(OCC)(=O)C.CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:4]([CH:5]([CH3:7])[CH3:6])/[CH:3]=[C:2](\[F:15])/[CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: [Zn+]Cc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C=C(F)Br)c1ccc(Cl)cc1
Agent: [Pd]
Agent: BrCc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C(/C=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a mixture of 1-bromo-3-(p-chlorophenyl)-1-fluoro-4-methyl-1-pentene, (E)- and (Z)- (0,9 g, 3,1 mmol), tetrakis(triphenylphosphine)-palladium(0) (0,25 g, 0,22 mmol), and N,N-dimethyl-formamide (20 ml) was treated with 5 ml of a 3-phenoxybenzylzinc bromide solution (prepared from 3-phenoxybenzyl bromide (1,3 g, 5,4 mmol) and Rieke zinc (4 ml of a 1,5 molar solution in tetrahydrofuran), and tetrahydrofuran 2.0 ml). The resultant reaction mixture was stirred at room temperature for one hour, treated with an additional 5 ml of the 3-phenoxybenzylzinc bromide solution, stirred at room temperature, and poured into 2 N hydrochloric acid solution. The resultant aqueous mixture was extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel, and 100:1 and 200:1 hexane/ethyl acetate solutions gave the title product (0,35 g) predominately in the (Z)-configuration.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH:6]=[CH:7][CH2:8]Cl)([O-:3])=[O:2].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=[N+]([O-])c1ccccc1C=CCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1[N+](=O)[O-])CC2
Yield: 57 %

Procedure:
Prepared from 2-nitro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 57% of theory, Melting point: 125°-128° C. (ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:68]([NH2:72])([CH2:70][CH3:71])[CH3:69]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[N:7]=[C:6]([NH:72][C@H:68]([CH2:70][CH3:71])[CH3:69])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(CC(C)=O)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(CC(C)=O)n1
Yield: 22 %

Procedure:
Dissolve 2-chloro-6-(2-oxopropyl)-isonicotinic acid methyl ester (200 mg, 0.88 mmol), palladium (II) acetate (2.0 mg, 0.009 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8.2 mg, 0.014 mmol) and cesium carbonate (458 mg, 1.23 mmol) in toluene (2 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (0.105 mL, 1.0 mmol) to the solution under nitrogen and heat the sealed mixture overnight at 100° C. Cool the reaction to room temperature. Dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound (22%).
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23]CC2C=CC=CC=2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6]>C(O)C>[F:31][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6]
Reactant: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CCO
Product: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-N-(1-methylpyrazol-3-yl)-5-phenylmethoxy-benzamide (0.1 g, 0.23 mmol) was dissolved in ethanol (3 mL) and THF (3 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (0.01 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at RT for 20 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite and the filtrate concentrated in vacuo to give the desired compound (70 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>C(Cl)Cl.CN(C=O)C>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)c1cccc(Cl)c1Br
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3-chlorobenzoic acid (7.29 mmol) in 20 mL DCM and 1 mL DMF was added 1.06 mL thionyl chloride. After stirring at RT overnight, 5 mL MeOH were added and stirring was continued at RT for 1 h. The reaction mixture was cooled in an ice bath, quenched by adding a sat. aq. NaHCO3 solution and extracted twice with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as colorless oil.
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:47][CH:46]([OH:48])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:49])=[CH:30][C:29]=1[NH:50][C:51]([C:53]1([C:56](O)=[O:57])[CH2:55][CH2:54]1)=[O:52].[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:47][CH:46]([OH:48])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:49])=[CH:30][C:29]=1[NH:50][C:51]([C:53]1([C:56]([NH:64][C:63]2[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=2)=[O:57])[CH2:54][CH2:55]1)=[O:52]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC(O)C1
Reactant: Nc1ccc(F)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC(O)C1
Reaction time: 5 h
Yield: 92 %

Procedure:
4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (80.8 mg) was added to a mixture of 1-[({2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt (75.3 mg), 4-fluoroaniline (0.026 ml) and tetrahydrofuran (1.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 hours. 4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (80.8 mg) was added again at room temperature, and the mixture was stirred for 87 hours. A saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture and stirred, and the mixture was partitioned after the addition of ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with brine (10 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (68.1 mg, 92%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH2:22]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:23]([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 150 °C
Yield: 78 %

Procedure:
A 2-5 mL microwave vial was charged with 4-bromo-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (108 mg, 0.248 mmol), 4-(methanesulfonyl)benzene boronic acid (60 mg, 0.298 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (18 mg, 0.025 mmol), 1M Na2CO3 solution (496 μL, 0.496 mmol) and 1,4-dioxane (2.5 mL). The mixture was degassed, purged with nitrogen and heated at 150° C. for 30 minutes using microwave irradiation. The mixture was diluted with EtOAc, washed with water (2×) and brine dried over Na2SO4 and concentrated under vacuum. Purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) and triturating with diethyl ether gave the title compound (99 mg, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.06-8.03 (m, 6H), 7.85 (dd, J=7.4, 2.1 Hz, 1H), 7.80-7.74 (m, 2H), 7.69-7.60 (m, 2H), 7.07 (d, J=7.7 Hz, 1H), 3.47 (dd, J=13.4, 8.7 Hz, 1H), 3.29 (s, 3H), 3.21 (dd, J=13.4, 4.8 Hz, 1H), 1.56-1.45 (m, 1H), 0.91 (d, J=6.5 Hz, 3H), 0.74 (d, J=6.7 Hz, 3H), LCMS (m/z Method B) ES+ 512.0 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]#[CH:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(NC(C)C)(C)C.Cl>C1COCC1.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.Cl[Pd]Cl.[Cu]I.CCOC(C)=O>[CH2:1]([O:3][P:4]([C:9]#[C:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C#CP(=O)(OCC)OCC
Reactant: O=[N+]([O-])c1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(C#Cc1ccccc1[N+](=O)[O-])OCC

Procedure:
To a solution of 300 mg of ethynyl-phosphonic acid diethyl ester, 494 mg of 1-iodo-2-nitrobenzene and 0.28 ml of di-isopropylamine in 15 ml THF are sequentially added 43 mg of bis-(triphenylphosphin)-palladium(II)-dichloride and 12 mg of copper(I)iodide and the mixture obtained is refluxed for approximately 2 hours. Following an acidic work-up (1N aqueous HCl and EtOAc) and subsequent column chromatography (2-nitro-phenylethynyl)-phosphonic acid diethyl ester is obtained in the form of a slightly brownish oil.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10](N)[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].C(Cl)(Cl)=O.C(Cl)(Cl)=S>>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C(Cl)Cl
Agent: S=C(Cl)Cl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1

Procedure:
reaction of 7-ACA with phosgene (or thiophosgene) to yield isocyanato (or isothiocyanato) cephalosporanic acid which is reacted with the appropriate amine of formula R1NH2 and then either catalytic hydrogenation of the 3-acetoxy group to yield the 3-methyl group or displacement of the 3-acetoxy group of 7-ACA with the desired mercaptoheterocyclic compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[C:4]([F:15])[CH:3]=1.Cl.C([N:19]=C=NCCCN(C)C)C.[OH-].[NH4+]>ClCCl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH2:19])=[O:9])=[C:4]([F:15])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(Oc1ccc(Cl)cc1F)C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1F)C(N)=O
Reaction time: 1 h

Procedure:
To a solution of Example 53B (14.6 g, 62.8 mmol) in dichloromethane (200 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (8.50 g, 55.5 mmol), and the reaction mixture was stirred for 1 hour. Ammonium hydroxide (87 mL, 628 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (100 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with saturated NaHCO3, brine (100 mL), dried (MgSO4), filtered and concentrated. The residue was triturated with hexane/ethyl acetate (95/5) to provide the titled compound. MS (DCI+) m/z 232 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:13][C@@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN(C=O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:3]=[C:2]([NH:13][C@H:14]([CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19])[CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:9]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: CCOC(=O)c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(N[C@@H](C(=O)O)C(C)C)c1
Temperature: 140 °C

Procedure:
Ethyl 3-iodobenzoate (857 mg, 3.10 mmol), DMF (5 mL), copper(I) iodide (65 mg, 0.34 mmol), N1,N2-dimethylaminoethylene (62.9 mg, 0.714 mmol), D-valine (400 mg, 3.41 mmol) and potassium carbonate (429 mg, 3.10 mmol) were charged into a flask. The flask was evacuated, then filled with nitrogen over several cycles to remove oxygen, then the reaction was heated to 140° C. under nitrogen for 4 hrs. The reaction was cooled, the DMF removed by evaporation, and 1 N HCl added. The reaction mixture was partitioned between EtOAc and water, and the organic layer was dried over sodium sulfate, filtered, and concentrated to yield a brown oil. This was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[C:80](=[NH:93])([C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)[C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:87]1([C:80]([C:81]2[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=2)=[N:93][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[CH:11][N:10]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[N:9]=3)[CH:3]=2)[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1
Reactant: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc(Br)c3)n2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
1.9 g (4.5 mmol) of 4-[3-(3-bromophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine were dissolved in 60 ml of dry toluene under nitrogen atmosphere and 366 mg (0.4 mmol) of tris(dibenzylidene-acetone)dipalladium(0), 498 mg (0.8 mmol) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene, 562 mg (5.85 mmol) of sodium tertbutoxide and 975 L (5.85 mmol) of benzophenonimine were added to the solution successively. The mixture was refluxed for 3 hours. After cooling to room temperature the reaction mixture was filtered over a celite pad and the solvent evaporated. The residue was redissolved with ethylacetate and washed with water. The organic layer was dried over Na2SO4 and evaporated again to dryness. The crude was purified by chromatography on a silica gel column eluted by dichloromethane-methanol 95/5, affording 1.5 g (65% yield) of the title compound.
Reaction SMILES: [C:1]([CH2:6][NH:7][C:8]1[CH:9]=[C:10]([OH:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16](=[O:30])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([O:3]CC)=[O:2].[OH-].[Na+].Cl>CO.O>[C:1]([CH2:6][NH:7][C:8]1[CH:9]=[C:10]([OH:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16](=[O:30])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCNC(=O)COc1ccc(O)cc1NCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCNC(=O)COc1ccc(O)cc1NCC(=O)O
Reaction time: 0.17 h

Procedure:
To a suspension of 40 g of 3-carboethoxymethylamino-4-dodecylcarbamoylmethoxyphenol in 500 ml of methanol was added over 20 minutes a solution of 12 g of sodium hydroxide in 100 ml of water kept at below 20° C., and the mixture was stirred for 10 minutes to obtain a perfect solution. The resulting solution was poured into 2 liters of a 5% hydrochloric acid solution, whereupon pale green crystals were separated. The crystals were recrystallized from a water-methanol mixture to obtain the title compound. The yield was 32 g, and the melting point was 122°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])[C:11]([CH3:21])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]=3[O:20][CH3:22])[C:11]([CH3:21])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cnc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)ncc2C)C(=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-cyclopentane-1,3-dione (650 mg, 2.16 mmol) was slurried in acetone (20 ml) and potassium carbonate (300 mg, 2.16 mmol) was added. After stirring at room temperature for 5 minutes, dimethyl sulphate (0.20 ml, 2.16 ml) was added in one portion and the reaction was heated to reflux. After 3 hours at reflux the reaction was complete and subsequently cooled to room temperature, before stripping to dryness. The resulting orange solid was re-solubilised in ethyl acetate (20 ml) and 1M sodium hydroxide (20 ml) and the biphasic mixture separated. The aqueous layer was further extracted with ethyl acetate (2×10 ml) before combining the organic layers, drying over magnesium sulphate, filtering and stripping to dryness to isolate a brown solid. This was purified by normal phase chromatography (gradient system of 100% dichloromethane−5% methanol:dichloromethane) to isolate 2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-3-methoxy-cyclopent-2-enone as a yellow foam (526 mg, 1.67 mmol, 77% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23](OCC)=[O:24])[C:13]1=[O:28].[NH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[C:13]1=[O:28]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Temperature: 100 °C
Yield: 43 %

Procedure:
To a stirring suspension of ethyl 1-(benzo[d]thiazol-2-ylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (930 mg, 2.346 mmol), tert-butyl 2-aminoacetate (369 mg, 2.82 mmol) in dioxane (5 mL) was added DIPEA (410 μl, 2.346 mmol). Reaction mixture was heated at 100° C. for 12 h. Solvent from reaction mixture was distilled out to get crude product which was then column purified using 15% EtOAC in hexane to get titled product in 43% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH3:30]
Reactant: CCBr
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 85.8 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.391 ml (5.181 mmol) of ethyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 184 mg (0.4444 mmol, 86%) of 2-ethoxy-2'-hydroxy-5, 5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.36 (3H, t, CH3), 1.7-2.2 (4H, m, 2CH2), 2.36 (4H, t, 2CH2), 2.64 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.10 (2H, q, CH2), 6.66 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 413 (M+)