Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:22](Cl)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH:23]=[CH2:22]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: C=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.4 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (2.55 g) in DMF (25 ml) and the mixture stirred for 20 minutes at room temperature. Allyl chloride (0.756 g) was added dropwise and stirring continued for 20 hours. Ice-water (75 ml) was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was triturated with hexane and filtered to give 4-[4-(4-pyridyl)piperazin-1-yl]phenol allyl ether (2.5 g) as a solid; NMR(d6DMSO) δ8.18(2H,dd), 6.8-7.0(6H,m), 5.92-6.13(1H,m), 5.2-5.45(2H,m), 4.5(2H,m), 3.45(4H,m), 3.11(4H,m).
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37][CH2:38]Br.C(Cl)Cl>C(C(C)=O)C>[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:38][CH2:37][O:36][CH3:35])=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COCCBr
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)CCCC(C)C)nn23)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 30 mg) and potassium carbonate (108 mg) were suspended in methyl ethyl ketone (3 ml). Thereafter, 2-methoxyethyl bromide (327 mg) was added to the obtained suspension, and the obtained mixture was stirred at 80° C. for 10 hours. Thereafter, the reaction solution was cooled to a room temperature, and methylene chloride (5 ml) was then added thereto. The obtained mixture was washed with an aqueous 1 M hydrochloric acid solution (5 ml×3), an aqueous saturated sodium bicarbonate solution (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (14 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[CH2:14]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1,4-dioxa-spiro[4.5]decan-8-ol (11.0 g, 70 mmol) in dry tetrahydrofuran (50 ml) is added dropwise to a stirred suspension of 60% sodium hydride disperse in mineral oil (2.80 g, 70 mmol) in dry tetrahydrofuran (50 ml). Once the addition is complete the reaction mixture is stirred for 2 hours at room temperature. A solution of benzyl bromide (13.2 g, 77 mmol) in dry tetrahydrofuran (50 ml) is added dropwise over a period of 20 minutes and stirred at room temp overnight. The reaction mixture is poured into water (200 ml), neutralised with 0.5 N aqueous hydrochloric acid and extracted with methylene chloride (2×100 ml). The combined organic layer was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is absorbed onto silica gel and purified on flash chromatography to give 8-benzyloxy-1,4-dioxa-spiro[4.5]decane (16 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:6]=[CH:5][N:4]=1.S(Cl)([Cl:23])=O.[OH-].[Na+]>ClCCl>[Cl:23][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc(-c2cc(CO)ncn2)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(-c2cc(CCl)ncn2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
4-Hydroxymethyl-6-(3,4,5-trimethoxyphenyl)-pyrimidine (339 mg) was dissolved in dichloromethane (20 mL), and to the solution thionyl chloride (0.15 mL) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. An aqueous solution of sodium hydroxide was added to the reaction mixture to neutralize it, and extraction was conducted with methylene chloride. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[NH:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]1[CH:26]=O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9](=[CH:26][C:18]2[NH:17][C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=2)[C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1
Reactant: O=Cc1cc2c([nH]1)CCCC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1cc2c([nH]1)CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].O[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 506 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (2 g, 6.79 mmol) prepared in Preparation Example 2 was dissolved in THF/benzene (270 mL/90 mL) solution, and 2-hydroxyethylmorpholine (5.83 g, 44.45 mmol) and triphenylphosphine (11.66 g, 44.45 mmol) were added thereto and kept at 0° C. Diisopropyl azodicarboxylate (8.99 g, 44.45 mmol) was added dropwise to the mixture, followed by stirring for 2 hrs at room temperature. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 14 g of the titled compound (yield: 93%) as a red solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=2)[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:25]=2[C:38]([OH:40])=O)=[CH:19][CH:18]=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH2:55].O>C(Cl)Cl>[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH:55][C:38]([C:25]1[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:27]2[C:32]([C:24]=1[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:40]
Reactant: CN(C)CCN
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)O)n(CCN(C)C)c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)NCCN(C)C)n(CCN(C)C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.48 g, 7.71 mmol) was added to a solution of 3-{bis[4-(methoxymethoxy)phenyl]methyl}-1-(2-dimethylaminoethyl)indole-2-carboxylic acid (2.0 g, 3.86 mmol) obtained in Example 48 and N,N-dimethylethylenediamine (0.64 ml, 5.78 mmol) in 30 ml of methylene chloride, followed by stirring at room temperature for 4.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.48 g (quantitative) of the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=O.O.[NH2:19]N>CCO>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:19]1
Reactant: COC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2cc[nH]n2)cc1
Temperature: 50 °C

Procedure:
To a solution of crude (E)-methyl 4-(3-(dimethylamino)acryloyl)benzoate (28.1 mmol) in EtOH (100 mL) was added hydrazine monohydrate (1.50 mL, 30.9 mmol) and the reaction was heated at 50° C. for 24 hours. The reaction temperature was then increased to 60° C. for 24 hours. Additional hydrazine monohydrate (1.5 mL) was added, and the reaction was heated at 60° C. for an additional 6 hours. The reaction was cooled, concentrated, and dried in a vacuum oven at 45° C. overnight to yield methyl 4-(1H-pyrazol-3-yl)benzoate as an orange solid (8.15 g, quantitative): mp 106° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.15-8.05 (m, 2H), 7.91-7.83 (m, 2H), 7.65 (d, J=2.4 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 3.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.91, 136.89, 131.83, 130.13, 129.37, 125.50, 103.35, 52.14, 22.46; EIMS m/z 202.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: NC1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: NC1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.113 g) and 4-piperidinamine (0.152 mL) to afford the title compound (0.109 g).
Reaction SMILES: Cl[C:2]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:12]([Br:13])=[CH:11][C:10]([C:14]([F:26])([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[Br:27])=[O:5].[F-:35].[K+]>CS(C)=O>[Br:27][C:8]1[CH:9]=[C:10]([C:14]([F:26])([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:12]([Br:13])[C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:28]=[CH:29][CH:30]=[C:31]([N+:32]([O-:34])=[O:33])[C:2]=1[F:35]
Reactant: [F-]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1F
Temperature: 145 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To 108 ml of DMSO were added 5.44 g (8.34 mmol) of 2-chloro-N-(2,6-dibromo-4-(perfluorobutan-2-yl)phenyl)-3-nitrobenzamide and 4.90 g (84.3 mmol) of potassium fluoride (spray-dried product), followed by stirring at 145° C. for 2 hours. The reaction solution was poured into ice-water to precipitate the crystal, and the obtained crystals were filtered and washed with hexane. The obtained crystals were purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=5:1) to prepare 2.42 g (yield 46%) of a target compound.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34]([CH3:44])([C:40]([O:42][CH3:43])=[O:41])[CH2:35]2.N1C=CC=CC=1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][C:34]([CH3:44])([C:40]([O:42][CH3:43])=[O:41])[CH2:35]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(C)Cc2cccc(N)c2C1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C1(C)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1

Procedure:
A solution of 200 mg (0.97 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2, Example 77A), 459 mg (1.2 mmol) of methyl 4-amino-2-methyl-2,3-dihydro-1H-indene-2-carboxylate (Example 95A), 556 mg (1.46 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and 5 ml of pyridine in 20 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and after filtration the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC. This gave 448 mg (0.77 mmol, 79% of theory) of a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[C:9]=2[OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[K+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]([OH:17])=[O:12])[C:9]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.3 %

Procedure:
According to the general method of Sharma et al., 2000, Synth. Commun., 30:397-405, a stirred solution of the 3-(phenylmethyl)salicylaldehyde (1.27 g, 6 mmol) in ethanol (16 ml) was treated dropwise with a solution of silver nitrate (2.0 g, 12 mmol) in water (16 ml). A solution of potassium hydroxide (2.69 g, 48 mmol) was then added dropwise over 40 minutes. The solution was allowed to stir at RT for 6 h. The mixture was filtered through a pad of celite, and the filter pad washed with water (2×10 ml). The filtrate was washed with diethyl ether (2×15 ml) and then acidified with 1N HCl. The milky suspension was extracted with diethyl ether (2×30 ml), and the combined extracts were dried (Na2SO4) and the solvent removed to yield 3-(phenylmethyl)salicylic acid as a tan solid (0.47 g, 34%). 1H-NMR (CDCl3, 400 MHz): δ 4.02 (s, 2H), 6.84 (t, 1H, J=8 Hz), 7.19-7.32 (m, 6H), 7.79 (d, 1H, J=8 Hz), 10.74 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([Cl:58])=[N:11][C:12]=3[NH:16][C@@H:17]2[CH2:21][CH2:20][N:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[CH:27][N:28]4[C@@H:31]4[CH2:35][C@H:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:33]([OH:41])[C@H:32]4[OH:42])=[C:24]([NH:43][CH2:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:23]=3)[CH2:18]2)[C@H:4]([OH:59])[C@@H:3]1[OH:60].CO.[C:63](Cl)(=[O:66])[CH2:64][CH3:65]>C1COCC1>[Cl:58][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[CH:15][N:7]2[C@@H:5]2[CH2:6][C@H:2]([NH:1][C:63](=[O:66])[CH2:64][CH3:65])[C@@H:3]([OH:60])[C@H:4]2[OH:59])=[C:12]([NH:16][C@@H:17]2[CH2:21][CH2:20][N:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[CH:27][N:28]4[C@@H:31]4[CH2:35][C@H:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:33]([OH:41])[C@H:32]4[OH:42])=[C:24]([NH:43][CH2:44][CH:45]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:23]=3)[CH2:18]2)[N:11]=1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](N)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](NC(=O)CC)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{(1S,2R,3S,4R)-4-[2-{(R)-3-[9-((1R,2S,3R,4S)-4-Amino-2,3-dihydroxy-cyclopentyl)-2-chloro-9H-purin-6-ylamino]-pyrrolidin-1-yl}-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (32 mg, 0.038 mmol) and TEA (0.016 mL, 0.113 mmol) are suspended in THF (0.5 mL). MeOH (0.5 mL) is added to aid solubility. Propionic acid chloride (0.0035 mL, 0.040 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is reduced in vacuo and purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA) to yield the title compound (MH+ 894/895).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:54][NH2:55]>C1COCC1>[CH3:54][NH:55][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([O:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([NH:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)=[O:29])[CH2:14][CH2:15]2)=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Reactant: CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(O[C@H]2CC[C@H](NC(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1728 (0.22 g, 0.5 mmol), EDC HCl (0.12 g, 0.63 mmol), HOBT (0.09 g, 0.63 mmol), TEA (0.17 mL, 0.63 mmol) in THF (10 mL) was added 2M MeNH2 in THF (1.25 mL, 2.5 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature overnight. The solvent was removed in vacuo and then purified by recrystallization with EtOAc/Hexanes gave the title compound, 0.16 g (71%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.28 (q, J=4 Hz, 1H), 7.77 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 6.99 (d, J=9 Hz, 2H), 6.21 (d, J=8 Hz, 1H), 4.49-4.36 (m, 1H), 3.62-3.45 (m, 1H), 2.75 (d, J=4 Hz, 3H), 2.11-1.87 (m, 4H), 1.57-1.25 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:28][CH3:29])[CH2:11][N:12]1[C:17](=[O:18])[C:16]([C:19](O)=[O:20])=[CH:15][N:14]=[C:13]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(=O)OCC(C)C.[NH2:38][OH:39]>O1CCCC1>[OH:39][NH:38][C:19]([C:16]1[C:17](=[O:18])[N:12]([CH2:11][CH:10]([O:28][CH3:29])[O:9][CH3:8])[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][CH:15]=1)=[O:20]
Reactant: NO
Reactant: COC(Cn1c(-c2ccccc2)ncc(C(=O)O)c1=O)OC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(Cn1c(-c2ccccc2)ncc(C(=O)NO)c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Triethylamine (49.4 ml) was added to a solution of 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxylic acid (97.3 g) in tetrahydrofuran (800 ml) in an ice bath in an argon atmosphere, and isobutyl chlorocarbonate (45.6 ml) was added dropwise thereto at 5° C. or lower, followed by stirring at the same temperature for 1 hour. To the reaction mixture was added a 50% hydroxylamine aqueous solution (422 ml), followed by stirring for 20 minutes. The reaction mixture was separated to layers. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated saline (200 ml), and concentrated. To the residue was added toluene (200 ml), followed by concentration. The resulting crude crystals were washed with isopropyl ether (1000 ml) by heating under reflux for 10 minutes, cooled to room temperature, and crystals were collected by filtration. The collected crystals were dried in vacuo at room temperature overnight to obtain the title compound (93.3 g; yield: 91%) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OC(C)C)c1
Temperature: 65 °C
Yield: 74.5 %

Procedure:
To a flask containing methyl 3-bromo-5-hydroxybenzoate (2.1 g, 8.9 mmol) in anhydrous DMF (10 mL) was added K2CO3 (2.47 g, 17.9 mmol) and 2-iodopropane (1.07 mL, 10.7 mmol). The reaction mixture was heated at 65° C. overnight then diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 1.81 g (75%) of methyl 3-bromo-5-isopropoxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C11H13BrO3: 273.12; no observed m/z ion, tR=4.17 min.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)c1C
Yield: 43.5 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (100 mg) to give 80 mg (43%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=[CH:5][CH:4]=1.[ClH:15].Cl.[CH2:17]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:11].[ClH:15].[CH2:17]([N:26]1[CH2:31][CH2:30][N:29]([CH2:10][C:9]([NH:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:12])[CH2:28][CH2:27]1)[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: COc1ccc(CNC(=O)CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CN2CCN(CC(=O)c3ccccc3)CC2)cc1

Procedure:
A mixture of N-(4-methoxybenzyl)-2-chloroacetamide (3.65 mmol), N-phenacyl piperazine dihydrochloride (3.97 mmol) and K2CO3 (10.5 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-30)(61%), M+ 381.