Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:23].[CH3:24][OH:25]>>[CH3:24][O:25][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]1([C:10]2[C:3]3[C:2]([NH2:23])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: N
Reactant: CO
Product: COc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Product: Nc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
56.9 mg (0.185 mmol) of 4-chloro-5,6-diphenylfuro[2,3-d]pyrimidine 51 and 0.930 mL (1.85 mmol) of 2.0 M ammonia in methanol were combined in a disposable sealed tube and stirred at RT for 15 minutes. The reaction was then heated at 70° C. for 1.5 h. At this point, an additional 0.930 mL (1.85 mmol) of 2.0 M ammonia in methanol was added and the resulting mixture was heated at 70° C. for 3 days, cooled to RT and concentrated. Flash chromatography (SiO2, gradient eluent: 2:1 hexanes-ethylacetate, 2:1 ethyl acetate-hexanes, 9:1 CH2Cl2-MeOH), afforded the title compound 4-methoxy-5,6-diphenylfuro[2,3-d]pyrimidine 53 and 5,6-diphenylfuro[2,3-d]pyrimidin-4-amine 52. Mass found: 303.0 (M+H+); Calculated for C19H14N2O2: 302.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(C(=O)C2CC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccnc(OC)c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.99 g) in THF (200 ml) was added ethyl diethylphosphonoacetate (29.7 mL) at 0° C., and the mixture was stirred at 0° C. for 5 min. To the obtained colorless solution was added cyclopropyl(2-methoxypyridin-4-yl)methanone (4.42 g) at 0° C., and the mixture was heated under reflux for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([N:43]1[CH2:47][CH2:46][C@@H:45]([NH2:48])[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:36]([N:43]1[CH2:47][CH2:46][C@@H:45]([NH:48][C:28]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][N:11]=3)=[CH:8][C:2]=2[Cl:1])=[O:34])[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N[C@@H]4CCN(Cc5ccccc5)C4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Chloroform (15 ml) and triethylamine (3 ml) were added to 2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (200 mg) to prepare a solution. Triphosgene (198 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3R)-(−)-1-Benzyl-3-aminopyrrolidine (80 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (189 mg, yield 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>N1C=CC=CC=1>[S:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1)([CH3:21])(=[O:24])=[O:23]
Reactant: O=C1NCC[C@@H](c2ccc(O)cc2)[C@@H]1c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc([C@@H]2CCNC(=O)[C@H]2c2ccccc2)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1.34 g (0.005 mol) of 27 in 10 cm3 of anhydrous pyridine, 1.14 g (0.01 mol; 0.77 cm3) of methanesulfonyl chloride are added under an atmosphere of nitrogen at 0° C. The mixture is stirred for 1 hour at between 0° and 3° C. before being poured into 70 cm3 of cold water. This mixture is extracted with methylene chloride and washed to neutrality. After evaporation and recrystallization in methanol, 29 is obtained in 61% yield. M.p. 199° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH2:16])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]([O:30][C:31]1[N:32]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH2:16])[O:13][N:12]=4)[CH:9]=3)[N:4]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:19])=[O:18])[CH:3]=2)[CH:34]=[CH:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(N)n4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
Argon gas was bubbled through a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (350 mg, 0.73 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (374 mg, 0.87 mmol) in dry DMF (3.5 mL) for 15 min. To the mixture was added CuI (139 mg, 0.73 mmol) and Pd(PPh3)4 (84 mg, 0.073 mmol) and argon gas was further bubbled for additional 15 min. The reaction was heated at 90° C. for 1 h then cooled to RT. The reaction was quenched with ice cold water. The resulting suspension was filtered and washed with water. The solid was purified with basic alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (220 mg, 61.5%). MS (ESI, pos. ion) m/z: 490.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:11]([CH3:13])[CH3:12])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]([N:10]([CH:11]([CH3:13])[CH3:12])[C:9]1[CH:8]=[C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:23]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Cl)cc1Cl)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (3) (345 mg, 0.77 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (30 mL) and then 4.6 ml of LiOH 1N was added to it. After 120 min of stirring at room temperature, solvent was removed and then partitioned between 25 ml of H2O, 4 ml of KHSO4 5% and 25 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 175 mg (53%) as a white solid of 3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (DMSO, 400 MHz): Rotamer 95/05: 7.82 ppm (m, Haro, minor rotamer); 7.69 ppm (d, 2H, Haro); 7.61 ppm (d, 1H, Haro); 7.51-7.37 ppm (m, 4H, Haro); 7.35-7.28 ppm (m, 2H, Haro); 4.89 ppm (hex, 1H, N—CH(CH3), major rotamer); 3.84 ppm (hex, N—CH(CH3), minor rotamer); 1.36 ppm (d, 3H, N—CH(CH3), major rotamer); 1.25 ppm (d, N—CH(CH3), minor rotamer); 1.03 ppm (d, 3H, N—CH(CH3), major rotamer); 0.93 ppm (d, N—CH(CH3), minor rotamere).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
151 g (1 mol) of p-nitrobenzaldehyde was dissolved in 350 ml of methanol and an aqueous solution of 80.3 g (1.1 mol) of hydroxylamine hydrochloride in 100 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. Thereafter the mixture was stirred at the same temperature for 2 hours and diluted with 1000 ml of water. White crystals deposited were filtered, washed with water and dried. Thus, 161 g of p-nitrobenzaldoxime was obtained. Yield 97%; M.P. 128°-131° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:5](=[O:19])[N:4]([CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[C:3]=1[CH3:31]>[OH-].[Pd+2].[OH-]>[ClH:1].[CH:16]1([CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[CH2:9][NH:8][C:6]2[C:5](=[O:19])[N:4]([CH2:20][C:21]([OH:23])=[O:22])[C:3]([CH3:31])=[CH:2][N:7]=2)[CH2:17][CH2:18]1
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1cnc(NC[C@H]2CCCN2CC2CC2)c(=O)n1CC(=O)O
Product: Cl

Procedure:
The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2R)-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 47] and palladium hydroxide to afford the product as a oil, 352 mg, (100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)(C)C)c1O
Reaction time: 24 h
Yield: 57.8 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (30.0 g, 128 mmols), 2-thiohydantoin (14.8 g, 128 mmols), and sodium acetate (36 g) in acetic acid (200 ml) is stirred under nitrogen and heated to reflux. After 24 hours the mixture is allowed to cool, and is stirred into water (2 L). After an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-imidazolidinone (24.6 g), mp 278°-279° C. (dec).
Reaction SMILES: Cl[C:2]1[C:3](C=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[NH2:15]O.[CH:17]([O-:19])=O.[Na+]>C(O)=O>[C:3]([C:2]1[C:17](=[O:19])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:15]
Reactant: O=Cc1nc2ccccc2cc1Cl
Reactant: NO
Reactant: O=C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cc2ccccc2[nH]c1=O

Procedure:
Where the starting material above is a 2-chloro-3-cyanoquinoline, this can be prepared by starting from an appropriate substituted acetanilide. This is heated with phosphoryl chloride and dimethylformamide to give the corresponding 2-chloro-3-quinolinecarboxaldehyde. The process involved is discussed in detail by meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1, 1981, 1520. The chloroquinolinecarboxaldehyde is then reacted with hydroxylamine hydrochloride, formic acid and sodium formate with heating to give the corresponding 3-cyano-2(1H)-quinolinone. This is then heated with an excess of phosphoryl chloride to give the desired 2-chloro-3-cyanoquinoline.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([O:34]CC)=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)OCC)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenate (1.00 g, 2 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N sodium hydroxide (4 mL). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.92 g, 97.9%) as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1>CO.O>[NH:25]1[CH:24]=[C:23]([NH:22][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=2)[CH:27]=[N:26]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Solvent: O
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cn[nH]c2)ncc1Cl
Yield: 52 %

Procedure:
A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (0.10 g, 0.31 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.17 g, 0.93 mmol) was heated in MeOH:water (10:1, 5 mL) at 90° C. for 18 hours. The solvents were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM). The purified fractions were combined, the solvent was removed in vacuo and the solid was sonicated in cyclohexane and filtered. The residue was dried in vacuo to give the title compound 35 as a light yellow solid (0.060 g, 52%). 1H NMR (300 MHz, d6-DMSO) δ 1.34 (d, J=7.04 Hz, 3H), 2.92-3.11 (m, 4H), 3.86 (q, J=7.04 Hz, 1H), 6.85 (brs, 1H), 7.13-7.25 (m, 4H), 7.36-7.44 (m, 1H), 7.57-87 (m, 2H), 8.37 (s, 1H), 9.63 (s, 1H). LCMS-C: rt 4.72 min; m/z 371 [M+H]+.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH2:38]([O:45][C:46]([NH:48][C@H:49]([C:77](ON1C(=O)CCC1=O)=[O:78])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:76])[CH2:56][CH2:57][CH2:58][CH2:59][C:60]([NH:62][CH2:63][CH2:64][O:65][C@@H:66]1[O:74][C@@H:73]([CH3:75])[C@@H:71]([OH:72])[C@@H:69]([OH:70])[C@@H:67]1[OH:68])=[O:61])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:45][C:46]([NH:48][C@H:49]([C:77]([NH:19][CH2:18][CH2:17][O:16][C@H:15]1[O:20][C@H:21]([CH2:24][O:25][C@H:26]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]2[OH:28])[C@@H:22]([OH:23])[C@H:13]([O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C@@H:14]1[OH:37])=[O:78])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:76])[CH2:56][CH2:57][CH2:58][CH2:59][C:60]([NH:62][CH2:63][CH2:64][O:65][C@@H:66]1[O:74][C@@H:73]([CH3:75])[C@@H:71]([OH:72])[C@@H:69]([OH:70])[C@@H:67]1[OH:68])=[O:61])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 40 mL vial, 2-aminoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranoside (883 mg, 1.612 mmol) was dissolved in DMF (10 mL). To the above solution at 0° C. was added a solution of 2,5-dioxopyrrolidin-1-yl N2-[(benzyloxy)carbonyl]-N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysinate (700 mg, 1.008 mmol) in DMF (10 mL) dropwise. After stirring at rt for 18 hr, the mixture was concentrated. The residue was purified by HPLC (waters Delta Pak C4 300 A, 15 um, 50×250 mm column, flow rate 85 ml/min, gradient 8-30% ACN/water in 25 min) to give the title compound. UPLC Method B: m/e=1127.335 [M+1]; Rt=2.83 min.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N+:20]([O-])=O)[C:11]=1[OH:23]>C(O)C.O>[NH2:20][C:12]1[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=[C:10]([Cl:9])[C:11]=1[OH:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)cc(Cl)c1O
Reaction time: 2 h

Procedure:
Solid sodium dithionite (10 g) was added in portions to a stirred solution of 2-chloro-6-nitro-4-trifluoromethylphenol (4.5 g) in a mixture of ethanol (20 ml) and water (30 ml). The solution was stirred for 2 hours, left overnight, filtered, and evaporated. The residue was mixed with toluene and the toluene removed under reduced pressure. The residue was extracted with boiling chloroform (3×100 ml) and the chloroform extracts evaporated to give a yellow oil identified as the required substituted phenol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(-c2nnn[nH]2)cc1
Product: CCOC(=O)Cn1nnnc1-c1ccc(O)cc1

Procedure:
Feed materials: 5-(4-hydroxyphenyl)tetrazole and ethyl bromoacetate.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:19]=[N:18][C:17]3[C:16](=[O:20])[N:15]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[C:14]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)=[N:13][C:12]2=3)[CH:6]=1)C.[Li+].[OH-]>C1COCC1.CO.O.O>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=[CH:33][C:28]([C:14]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:16](=[O:20])[C:17]3[N:18]=[CH:19][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:40])=[O:3])[C:12]=3[N:13]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A solution of 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid ethyl ester (200 mg, 0.37 mmol) in THF/MeOH/H2O 3:2:1 (5 mL) was cooled to 0° C. and treated with 3 N aqueous LiOH (183 μL, 0.55 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 4 h. The reaction was diluted with H2O, extracted with Et2O, and acidified with 1N aqueous HCl. The resulting white precipitate was collected by suction filtration to provide 3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid (155 mg, 82%) as a white solid. HPLC-MS calculated for C30H19ClN4O3 (M+H+): 519.1. Found: 519.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[O:25])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Reaction time: 1 h

Procedure:
After dissolving 0.53 g of 2-amino-4-(4-aminophenoxy)pyridine in a mixture of 20 ml of tetrahydrofuran and 10 ml of dimethylformamide, 0.36 ml of p-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=20:1, followed by 10:1). The solvent was distilled off under reduced pressure to obtain 610 mg of the target substance as a white powder.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.Cl.[CH3:21][CH2:22][O:23]CC>CN(C)C(=O)C>[Br:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:22](=[O:23])[CH3:21])[N:14]=1
Reactant: CCOCC
Reactant: Brc1cccc(Br)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: CC(=O)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
12.5 mL of a solution of n-BuLi 1.6 M in hexane (20 mmol) are added at −78° C. to a solution of 4.70 g 2,6-dibromopyridine 20 (20 mmol) in 100 mL anhydrous ether. The reaction medium is left in the cold for 30 min. 2 mL N,N-dimethylacetamide are added cold (−78° C.) for 1 h, then allowed to reach the ambient temperature. The reaction medium is neutralized with 25 mL of an aqueous HCl 1M solution. The aqueous phase is extracted with Et2O (3×20 mL). The combined organic phases are washed with brine (3×20 mL), dried on MgSO4, filtered, then evaporated under vacuum. The raw product is recrystallized in an Et2O/n-C5H12 (1/2) mixture. 1.18 g of an orange solid is obtained, i.e. a 28% yield.