Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12](Cl)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[OH-].[Na+].C([OH:22])C.Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([OH:22])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: COC(=O)C(Cl)c1ccc2cc(C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(O)c1ccc2cc(C)ccc2c1

Procedure:
A mixture of 25 g. of methyl 6-methyl-2-naphthyl-α-chloroacetate, 10 g. of sodium hydroxide, and 200 ml. of ethanol is refluxed for two hours. The cooled mixture is acidified by the addition of 1N hydrochloric acid. The resulting product, methyl 6-methyl-2-naphthyl-α-hydroxyacetate, is isolated by extractions with methylene chloride. The product is oxidized by means of the oxidation procedure described in Example 6 to give methyl 6-methyl-2-naphthyl-α-oxoacetate. The latter product is refluxed with 31 g. of difluoromethylene triphenyl phosphorane (prepared by allowing sodium chlorodifluoroacetate to react with triphenyl phosphine in diethyl ether) in 150 ml. of benzene. The resulting mixture is distilled under vacuum. The distillate is evaporated to yield methyl 2-naphthyl-α,α-difluoromethyleneacetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:12]=1)=[O:10]
Reactant: COC(=O)c1cc[nH]c1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccn(-c2ccc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 65.8 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.625 g (5 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.82 g (5 mmol) of 2-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide. After stirring at 100° C. for 23 hours, the reaction mixture is poured into 30 mL of water and is then allowed to crystallise at 20° C. for 1 hour. After filtering off and air-drying the solid residue, 0.83 g of 3-methoxycarbonyl-1-(quinol-2-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 136° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[N:9][CH:10]=1)=[N+]=[N-].[ClH:19]>CO.[Pd]>[ClH:19].[F:18][C:13]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCc1ccc(OCC(F)(F)C(F)F)nc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(OCC(F)(F)C(F)F)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Palladium 10% on carbon (10 mg) is added to a stirred solution of 5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (110 mg, 2.1 mmol, Step-2) and 2M hydrochloric acid (0.2 mL) in methanol (3.5 mL). The mixture is stirred at rt under hydrogen atmosphere (1 atm) for 4 hours. The mixture is filtered through a pad of celite and washed with methanol. The filtrate is concentrated in vacuo to give 110 mg (93% yield) of the title compound as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])[CH2:25][CH2:24][O:23][CH2:22]C1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]([C:2]1[CH:1]=[CH:25][C:24]([O:23][CH3:22])=[CH:4][CH:3]=1)[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: COc1cccc(OCc2ccccc2)c1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: COc1ccc(C(O)c2c(OC)cccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 145 %

Procedure:
In a nitrogen stream, a solution of (2-benzyloxy-6-methoxyphenyl)-methanol (3.52 g, 14.41 mmol) and N-methylmorpholine N-oxide (NMO, 2.53 g, 21.61 mmol) in dichloromethane (14.5 mL) was cooled in a water bath, and tetra-n-propylammonium perruthenate (TPAP, 152 mg, 0.43 mmol) was added thereto. The reaction mixture was stirred for 20 minutes at the same temperature and at room temperature for 1.75 hours, and then subjected to Celite filtration and the solvent was distilled under reduced pressure. The obtained residue was treated by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:3 to 1:2.5)]. The obtained compound was dissolved in THF and cooled in a water bath, and a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 30.3 mL) was added dropwise thereto in a nitrogen stream. The reaction mixture was stirred at room temperature for 1.25 hours, and then a saturated ammonium chloride aqueous solution was added thereto at room temperature and the mixture was extracted with ether. The organic layer was washed with a saturated ammonium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4 to 1:3.5)] to obtain the title compound (3.66 g, 72%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 43.4 %

Procedure:
Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 mg (43%) of product as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>O1CCCC1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:14]
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=S)CCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)methylthiopropionic acid (2 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at the same temperature, and the mixture is further stirred for 3 hours. After distilling off the solvent, the resulting residue is subjected to column chromatography (Kieselgel 60, made by Merck & Co., eluting solvent, chloroform:methanol=50:1, V/V) to isolate N,N-diethyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (1.5 g), colorless liquid, nD25 =1.5200.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH:19](Br)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C>[CH3:16][CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:13])[CH3:14])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:18])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](C)N
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](C)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of (S)-2-amino-N-[2,6-bis(1-Methylethyl)phenyl]propanamide (5.0 g, 20 mmol), benzhydryl bromide (5.0 g, 20 mmol), and triethylamine (2.8 mL, 20 mmol) in acetonitrile (100 mL) was heated under reflux for 5 hours. The resulting solution was cooled (25° C.) and concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), washed with water (1×100 mL), washed with saturated sodium bicarbonate (1×100 mL), washed with brine (1×100 mL), then dried (MgSO4) and concentrated in vacuo. The resulting solid was recrystallized from ether/hexane to yield 4.77 g (57.1%) of the title compound as fine white needles, mp 134°-138.5° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:52]1[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]1>>[N:55]1([CH2:58][CH2:59][NH:60][C:15]([C@@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=5[N:19]=4)[CH:5]=3)[CH2:10]2)=[O:17])[CH2:56][CH2:57][O:52][CH2:53][CH2:54]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCCN1CCOCC1)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Method K—Step a To a mixture of (R)-1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.01 g, 0.27 mmol) in dcm (2 mL), HATU (0.10 g, 0.28 mmol), TEA (0.08 mL, 0.56 mmol) and 2-morpholinoethylamine (0.04 g, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with ammonium chloride solution (2 mL), filtered through a phase separator and organic solvent was removed. The crude was then purified by SCX column and flash chromatography (eluent: gradient from EtOAc to EtOAc:NH3 in MeOH (2M)/10:1) to obtain 0.05 g of the title compound (40%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[CH2:34][OH:35])=[C:17]([O:36][CH3:37])[CH:16]=1.O>C(Cl)Cl>[C:4]([Si:1]([O:35][CH2:34][C:25]1[CH:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:24]=1[C:18]1[CH:19]=[C:20]([CH:21]([CH3:23])[CH3:22])[C:15]([F:14])=[CH:16][C:17]=1[O:36][CH3:37])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
tert-Butyldimethylsilyl chloride (0.48 g, 3.21 mmol) and imidazole (0.50 g, 7.30 mmol) were added successively to a stirred solution of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (1.00 g, 2.93 mmol) in dry CH2Cl2 (13.4 mL) at room temperature under N2 and the reaction was stirred overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 1% EtOAc in hexanes) to afford tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane as a colorless oil. Rf=0.16 (1% EtOAc in hexanes). LCMS calc.=457.2; found=457.2 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.69 (d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 4.50 (br s, 1H), 3.75 (s, 3H), 3.29-3.21 (m, 1H), 1.28 (d, J=6.9 Hz, 6H), 0.93 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[N:24]=[C:23]([C:25]([OH:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[N:16]=[N:15][N:14]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([OH:28])([CH3:26])[CH3:27])[N:24]=4)[C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Reactant: CC(C)(O)c1cccc(CBr)n1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(C(C)(C)O)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine and 2-(6-bromomethylpyridine-2-yl)propan-2-ol by the alkylation method described in Example 36.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])O.[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17].[OH-].[Na+]>O.C(O)(C)C>[CH2:15]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[C:16]([CH3:17])=[O:18]
Reactant: Oc1ccccc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)COc1ccccc1O
Reaction time: 4 h
Yield: 46.6 %

Procedure:
11 g of catechol, 16.8 g of sodium hydrogencarbonate and 9.5 g of monochloroacetone were dissolved in a mixed solvent of 300 ml of water and 100 ml of isopropyl alcohol, and the solution was heated up to 50° to 60° C. and then stirred for 4 hours. Afterward, 50 ml of a 8% aqueous sodium hydroxide solution and 9.3 g of monochloroacetone were further added, followed by stirring at 50° C. for 5 hours. After standing for cooling, insolubles were removed from the solution by filtration, and the resultant filtrate was concentrated until the volume of the solution became about 300 ml, and then extracted with chloroform. The chloroform layer was washed with a dilute aqueous sodium hydroxide solution and then with water. The solvent was distilled off, and the residue was purified through a silica gel column chromatograph (chloroform/hexane=7/3 to chloroform alone in volume ratio), and then recrystallized from ether/hexane, thereby obtaining 7.73 g of crystals of 2-acetonyloxyphenol.
Reaction SMILES: [CH3:1][S:2]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24]>CC(C)=O>[CH2:21]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[C:4]([S:2]([CH3:1])=[O:3])=[CH:5]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: CS(=O)C1C=Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1cc(S(C)=O)c(=O)c2ccccc21

Procedure:
A mixture of 3-methylsulphinyl-4-quinolone (1.035 g.), anhydrous potassium carbonate (1.38 g.), n-butyl bromide (0.685 g.) and dry acetone (50 ml.) was refluxed for 24 hours. The mixture was filtered and the filtrate evaporated to dryness. The resulting oil was dissolved in chloroform (50 ml.). The solution was washed with water, dried and evaporated. The residue oil was triturated with light petroleum to give the solid product 1-n-butyl-3-methylsulphinyl-4-quinolone, m.p. 103°-105°.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5](COCC[Si](C)(C)C)[C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.7 %

Procedure:
To a solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-dihydro-1H-purine-2,6-dione (2.99 g, 8.08 mmol) in DCM (20 ml) was added TFA (10 ml) and the reaction stirred for 2.5 hours at room temperature. The reaction mixture was then concentrated and the residue treated with further DCM and evaporated once more. Purification by SPE (Si) eluting 1:9-4:1 ethylacetate/cyclohexane afforded impure product (1.31 g), which was dissolved in methanol (20 ml) and treated with sat. potassium carbonate aq. (20 ml). After stirring overnight the mixture was partitioned between water containing 2M HCl (1 ml) and ethyl acetate. The organic extract was separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound 0.87 g (45%); m/z 241.1 [MH+].
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([OH:23])[C:21]2[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-2-indolinone and 4-methyl-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and final purification by column chromatography on silica gel with CH2Cl2 as eluant.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([C:8]1[C:13]([I:14])=[C:12](O)[CH:11]=[CH:10][N:9]=1)[CH3:7].CCN(CC)CC>CC#N>[Cl:3][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:6][CH3:7])[C:13]=1[I:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nccc(O)c1I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nccc(Cl)c1I
Temperature: 60 °C

Procedure:
A solution of 165.1 g (1.08 mol) POCl3 in 100 mL CH3CN is added dropwise to a solution of 27.1 g (108 mmol) 2-ethyl-3-iodo-pyridin-4-ol in 150 mL CH3CN at RT. Then Et3N (21.9 g, 216 mmol) is added slowly over 20 min before the reaction mixture is heated to 60° C. for 3 h. The reaction mixture is evaporated in vaccuo to afford an oil. This crude oil is poured into the crushed ice, and the aqueous phase is extracted with petroleum ether/EtOAc (3×, 200 mL; 10:1). The organic phase is collected, dried over anhydrous Na2SO4. The solvent is removed in vacuo to afford desired product. Yield: 22.0 g (76%).
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C@@H:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:23]([NH:25][N:26]1[C:30](=[O:31])[C@H:29]([CH:32]([CH3:34])[CH3:33])[NH:28][C:27]1=[O:35])=[O:24])[C:12](=[O:21])[NH:13][O:14]C1CCCCO1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([NH:9][CH2:10][C@@H:11]([C@@H:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:23]([NH:25][N:26]1[C:30](=[O:31])[C@H:29]([CH:32]([CH3:33])[CH3:34])[NH:28][C:27]1=[O:35])=[O:24])[C:12](=[O:21])[NH:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)N[C@@H](C(C)C)C1=O)[C@H](CNC(=O)c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)N[C@@H](C(C)C)C1=O)[C@H](CNC(=O)c1ccccc1)C(=O)NO
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
A solution of 0.22 g of 2(R)-[2-benzamido-1(R)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]ethyl]-N-(4(S)-isopropyl-2,5-dioxo-1-imidazolidinyl)-4-methylvaleramide in 5 ml of methanol was treated with 0.022 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2.5 hours and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride. The organic fraction was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether to give 0.14 g of 2(R)-[2-benzamido-1(R)-(hydroxycarbamoyl)ethyl]-N-(4(S)-isopropyl-2,5-dioxo-1-imidazolidinyl)-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [N:1]1[NH:2]N=N[C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:24](Cl)(=[O:34])[C:25]1[CH:33]=[CH:32][CH:31]=[C:27]([C:28](Cl)=[O:29])[CH:26]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:34][C:24]([C:25]3[CH:33]=[CH:32][CH:31]=[C:27]([C:28]4[O:29][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[C:14]([C:18]7[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=7)[N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:1][N:2]=4)[CH:26]=3)=[N:2][N:1]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:13]=1
Reactant: c1ccc(-c2cccc(-c3cccc(-c4nn[nH]n4)n3)n2)nc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3cccc(-c4nnc(-c5cccc(-c6nnc(-c7cccc(-c8cccc(-c9ccccn9)n8)n7)o6)c5)o4)n3)n2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
2.0 g of 6-(2H-tetrazol-5-yl)-2,2′:6′2″-terpyridine was dissolved in 50 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 30 ml was dehydrated by azeotropy. After cooling to 50° C., 0.68 g of isophthaloyl dichloride was added. Temperature was elevated to 110° C., and stirring was conducted for 3 hours under flux. After cooling to room temperature, the reaction solution was poured into 200 ml water, and a precipitated yellowish-brown solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 80° C. for 20 hours, and purified with adsorption purification (carrier: NH silica gel, eluting solution: chloroform) to obtain 1.53 g (yield 67%) of TpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.12 ppm (1H), 8.85 ppm (2H), 8.62-8.73 ppm (6H), 8.37-8.51 ppm (6H), 7.79-8.12 ppm (7H), 7.35 ppm (2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17]>[N+](C1C=CC=CC=1)([O-])=O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5](=[O:15])[C:21]1[CH:22]=[CH:23][C:16]([OH:17])=[CH:18][C:19]=1[OH:20])([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1ccc(O)cc1O
Reaction time: 8 h

Procedure:
2′-Carboxy-2,4-dihydroxybenzophenone was prepared according to literature procedures. Smith, G. A.; Metcalfe, J. C.; Clarke, S. D J. Chem. Soc. Perkin Trans 2. 1993, 1195. AlCl3 (28.00 g, 210 mmol) was added to a solution of phthalic anhydride (13.85 g, 93.5 mmol) and resorcinol (10.0 g, 90.8 mmol) in 225 ml nitrobenzene and purged with N2. After stirring overnight, the solution was poured into a vigorously stirred biphasic solution of 750 ml hexanes and 1.0 L 0.5 M aqueous HCl. The solution was allowed to stir for 2 h and the light tan precipitate that formed was filtered and washed with 200 ml aqueous 0.1 M HCl and 200 ml hexanes. The crude material was crystallized as light green plates from hot MeOH/H2O (9.90 g, 42%). 1H NMR (acetone-d6) δ 6.33 (1H, dd, J=9.0, 2.3 Hz), 6.39 (1H, d, J=2.3 Hz), 7.00 (1 H, d, J=9.0 Hz), 7.45 (1 H, d, J=7.5 Hz), 7.65-7.80 (2 H, m), 8.12 (1 H, d, J=6.7 Hz). FTIR (KBr, cm−1) 1693, 1627, 1594, 1568, 1521, 1490, 1444, 1356, 1284, 1267, 1228, 1187, 1154, 1123, 1083, 1022, 981, 967, 930, 852, 813, 784, 769, 736, 713, 697, 665, 624, 592, 535, 458.