Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[C:40]1[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=4)[C:32]([O:34]C)=[O:33])[CH:22]=3)[O:17]2)[CH2:13][CH2:12]1)=[O:10])[CH3:4]>CO.C1COCC1>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[C:40]1[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=4)[C:32]([OH:34])=[O:33])[CH:22]=3)[O:17]2)[CH2:13][CH2:12]1)=[O:10])[CH3:4]
Reactant: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)OC)c4)ccc2O3)cc(OC)c1-c1cnn(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OC)c1-c1cnn(C)c1
Temperature: 25 °C

Procedure:
Aqueous 1 N sodium hydroxide solution (0.75 mL) was added to a solution of Methyl 5-{1′-[3-ethoxy-5-methoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate in MeOH (2 ml) and THF (2 ml) and stirred at room temperature for over night. The organic solvent was evaporated and diluted with water. Aqueous 1N HCl aq. (1 ml) was added thereto at room temperature, and the resulted solid was collected and recrystallized from MeOH to afford the intended compound as a colorless solid. 1H-NMR (DMSO-d6) δ: 9.08 (1.0H, d, J=2.2 Hz), 9.02 (1.0H, d, J=1.7 Hz), 8.41 (1.0H, dd, J=2.2, 1.7 Hz), 8.07-8.03 (3.0H, m), 7.88 (1.0H, d, J=0.5 Hz), 7.27-7.24 (1.0H, m), 6.72-6.70 (2.0H, m), 4.33-4.19 (1.0H, br m), 4.09 (2.0H, q, J=7.0 Hz), 3.85 (3.0H, s), 3.83 (3.0H, s), 3.67-3.11 (3.0H, br m), 2.94 (2.0H, s), 2.12-1.89 (2.0H, br m), 1.84-1.77 (2.0H, m), 1.37 (3.0H, t, J=7.0 Hz). MS [M+H]+=597.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS([C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[NH:19][CH:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2[nH]ccc2[N+](=O)[O-])o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furyl-methylthio)ethylamine (3 g, 0.014 mol) and 2-methylsulphinyl-3-nitropyrrole (2 g, 0.011 mol) in ethanol (50 ml) was refluxed for 7 days, and it was then evaporated to dryness. The residue was purified by elution from a column of silica gel with ethyl acetate-petroleum ether (b.p. 60-80°)(4:1) to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)-ethylamino]-3-nitropyrrole, m.p. 67--67°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.[CH:15](O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Step 2 A solution of tert-butyl 5-bromothiazol-2-ylcarbamate (3 g, 10.7 mmol), isopropanol (6.40 g, 107.4 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in THF (30 mL) was treated with diethyl azodicarboxylate (3.74 g, 21.5 mmol) dropwise at 0° C. and was stirred overnight while warming slowly to rt. The mixture was concentrated and the residue was dissolved in DCM (20 mL), filtered to remove undissolved solid and concentrated. The residue was purified by column chromatography (eluting with hexane) to give tert-butyl 5-bromothiazol-2-yl(isopropyl)carbamate as a light yellow oil (3.10 g, 90%). 1H NMR (400 MHz, chloroform-d) δ 7.34 (s, 1H) 5.29 (m, 1H) 1.59 (s, 9H) 1.45 (d, 6.8 Hz, 6H). Mass spectrum m/z 265, 267 (M+H—C4H9)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][N:7]=1)=[O:5].[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH:17](Br)[CH3:18]>C1COCC1.O.C(=O)=O>[Br:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:5])[CH2:18][CH2:17][CH:16]([O:20][CH3:21])[O:15][CH3:14])[CH:11]=1
Reactant: CON(C)C(=O)c1cc(Br)ccn1
Reactant: COC(OC)C(C)Br
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC(=O)c1cc(Br)ccn1)OC
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To a solution of (1) (8.86 g, 36.2 mmole) in 250 mL of anhydrous THF in a 3-neck flamed dried round bottom flask at −70° C. (acetone-dry ice bath) is slowly added the Grignard reagent prepared from bromopropionaldehyde dimethyl acetal (16.5 g, 90.4 mmol) and Mg turnings (4.39 g, 181 mmol) in anhydrous THF (250 mL), maintaining internal temperature around −68° C. to −70° C. After stirring at −70° C. for 2 hours, the reaction mixture is diluted with 200 mL of water with the dry ice bath removed. The mixture is poured into a separatory funnel, and the mixture is extracted 3 times with ethyl acetate (150 mL). The organic layers are combined and dried over Na2SO4 and the solvent evaporated leaving a thick yellow oil (11 g, 100% crude yield, MS ES+258.02).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](OC(C)(C)C)(N(C)C)[N:26]([CH3:28])[CH3:27]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:24])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][N:26]([CH3:28])[CH3:27])[CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C(Cc1ccccc1)c1c[nH]c(C(=O)NCc2ccccc2)c1
Solvent: C1CCOC1
Product: CN(C)C=C(C(=O)c1c[nH]c(C(=O)NCc2ccccc2)c1)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of compound 2 (1 equivalent) in THF, at ambient temperature, was added (Me2N)2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product 3 was utilized without purification. 1H NMR (CDCl3) δ 4.4 (s, 2H), 4.8 (s, NH), 6.8-7.4 (m, 13H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:9])[CH2:4][CH2:3]1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[CH2:3][CH2:4]1)=[O:9]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: N[C@H]1CC[C@H](C(=O)c2nc3ccccc3s2)CC1
Product: O=C(c1nc2ccccc2s1)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1

Procedure:
The title compound was prepared according to the same protocol as for example 1, step 1.c, using however (trans-4-amino-cyclohexyl)-benzothiazol-2-yl-methanone (0.3 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol). 93 mg (68%) of a beige solid were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[N:5]=[C:4]([CH3:14])[N:3]=1.[C:15](O)(=O)[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>P(Cl)(Cl)(Cl)=O>[CH2:10]([N:9]([CH2:12][CH3:13])[C:6]1[N:5]=[C:4]([CH3:14])[N:3]=[C:2]2[C:7]=1[NH:8][C:15]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[N:1]2)[CH3:11]
Reactant: CCN(CC)c1nc(C)nc(N)c1N
Reactant: O=C(O)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1nc(C)nc2nc(-c3ccncc3)[nH]c12
Yield: 31.8 %

Procedure:
A homogeneous mixture obtained by grinding 5 g of 4,5-diamino-6-diethylamino-2-methylpyrimidine and 3.4 g of isonicotinic acid in a mortar is added to 110 ml of phosphorus oxychloride under stirring, and refluxed with heating for 3 hours. The reaction solution is concentrated and 180 ml of water is added to the residual oil. The aqueous solution is neutralized with an ammonia solution and the crystals precipitated are filtered and purified by column chromatography on silica gel with a mixture of chloroform and methanol (10:1) as an eluent. Recrystallization from methanol gives 2.3 g of 6-diethylamino-2-methyl-8-(4-pyridyl)purine, melting at 228°-230° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]([F:28])([F:27])[F:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:22])([CH3:21])[CH2:13][C:14](=[O:20])[N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[CH3:23])[CH:7]=1.[CH2:29]([OH:32])[C:30]#[CH:31]>>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([CH3:23])=[C:8]([C:6]3[CH:7]=[C:2]([C:31]#[C:30][CH2:29][OH:32])[CH:3]=[CH:4][C:5]=3[O:24][C:25]([F:27])([F:28])[F:26])[CH:17]=2)[C:12]([CH3:21])([CH3:22])[CH2:13][C:14]1=[O:20])[CH3:19]
Reactant: C#CCO
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(Br)ccc3OC(F)(F)F)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C#CCO)ccc3OC(F)(F)F)cc21

Procedure:
Compound 57A was prepared from Compound 9B using a procedure similar to that described for Example 56A except that propargyl alcohol was used as the coupling partner. MS (electrospray): mass calculated for C24H24F3NO3, 431.45; m/z found 432.2, [M+H]+.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:11]([F:21])[CH2:10]1)=O)(C)(C)C>CCOCC.C(Cl)Cl>[F:21][CH:11]1[CH:12]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOCC2)C(F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: FC1CNCCC1N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.0 N HCl in Et2O (15 mL) was added to a solution of 3-Fluoro-4-morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 4.44 mmol) in DCM (2 mL) and the resulting suspension was stirred at room temperature 4 days. The precipitate was filtered off and tritured with Et2O (2×5 mL) Na2CO3 saturated solution (10 mL) was added and the resulting solution was concentrated under reduced pressure. EtOH (15 mL) was added and precipitate was filtered off.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH3:29])[CH:18]=2)O1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:29][C:19]1[CH:18]=[C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ncccc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1

Procedure:
Pd(dppf)Cl2 (0.089 g) was added to a mixture of 4-bromo-2-methylbiphenyl (1.5 g), potassium acetate (1.787 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.312 g) in DME (25 mL) and DMSO (1.25 mL). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give crude 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (173 mg) was added to a suspension of 3-bromopyridin-2-amine (865 mg), the prepared 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane and sodium carbonate decahydrate (2861 mg) in DME (30 mL) and water (6 mL) and the mixture was stirred at 80° C. under nitrogen for 6 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (1.25 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[O:6][CH:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:8][CH2:7][CH:5]2[CH2:4][CH2:3][C@@H:2]([CH3:1])[O:6]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: C[C@@H]1CCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC[C@@H](C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of Example 64A (4.0 g, 25.8 mmol) in dichloromethane (100 mL) were added triethylamine (10.8 mL, 77.0 mmol) and p-toluenesulfonyl chloride (4.9 g, 25.8 mmol). The reaction mixture was stirred at room temperature overnight and then washed with water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-25% ethyl acetate in hexanes) to provide 3.5 g (50%) of the title compound. MS (DCI+) m/z 288 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>O>[CH2:24]([C:23]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:26])[CH3:25]
Reactant: CCC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and propionyl chloride (101.7 mg, 1.10 mmol) followed by stirring at 60° C. for 16 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 117 mg (45%).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[Cl:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[C:17]([CH3:25])=[C:16]([CH3:26])[C:15]=1[CH:27]=[CH:28][C:29](=[O:31])[CH3:30].O>CO>[Cl:13][C:14]1[C:22]2[O:21][C:20]([CH3:23])([CH3:24])[CH2:19][C:18]=2[C:17]([CH3:25])=[C:16]([CH3:26])[C:15]=1[CH:27]1[CH2:3][C:4](=[O:5])[CH:30]=[C:29]([OH:31])[CH2:28]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)OC(C)(C)C2
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(Cl)c2c1CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of sodium in 30 ml of absolute methanol was added 6.5 ml of diethyl malonate and 10 g of the 4-(7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzofuran-6-yl)-3-buten-2-one in 20 ml of absolute methanol, and refluxed for 4 hours. The reaction mixture was added 100 ml of water and concentrated under reduced pressure and then added 17 g of 20% aqueous solution of sodium hydroxide. After refluxing 1 hour, the reaction mixture was cooled to room temperature and washed with benzene. Concentrated hydrochloric acid was added dropwise into the aqueous layer until the bubble of carbon dioxide ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 11.8 g of 5-(7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: Cc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one was obtained (93%): 1H NMR (300 MHz, CDCl3) 7.34-7.27 (m, 11H), 7.06-7.02 (m, 3H), 6.76 (s, 1H), 6.72 (s, 1H), 6.55-6.50 (m, 1H), 5.05 (s, 1H), 2.17 (s, 3H), 2.12 (s, 3H); MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[I:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([I:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(I)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(I)c3)c2cn1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (72 mg, 0.37 mmol) and 3-iodoaniline (1.25 g, 5.71 mmol) is stirred at 160° C. for 30 min. The resulting product is chromatographed over silica gel (5-7% MeOH/CH2Cl2) to give 7-amino-4-(3-iodoanilino)pyrido[4,3-d]pyrimidine (83 mg, 61%) as a light brown rosettes. 1H NMR (DMSO) δ 9.84 (1H, brs), 9.34 (1H, s), 8.44 (1H, s), 8.30 (1H, brs), 7.90 (1H, dd, J=7.9, 0.8 Hz), 7.47 (1H, d, J=7.7 Hz), 7.18 (1H, t, J=8.0 Hz), 6.66 (2H, brs), 6.46 (1H, s).
Reaction SMILES: CCCCCC.C([Li])CCC.C[CH2:13][O:14]CC.[Si:17]([O:24][CH2:25][C:26]1[C:35]2[C:30](=[C:31]([CH3:36])[CH:32]=[CH:33][CH:34]=2)[C:29]([O:37][CH2:38][O:39][CH3:40])=[CH:28][CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Si:17]([O:24][CH2:25][C:26]1[C:35]2[C:30](=[C:31]([CH3:36])[CH:32]=[CH:33][CH:34]=2)[C:29]([O:37][CH2:38][O:39][CH3:40])=[C:28]([CH:13]=[O:14])[CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCOc1c(C=O)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Reaction time: 1 h

Procedure:
52 ml of a hexane solution of 1.6M n-butyl lithium was dropped in an absolute ether (110 ml) solution of 19 g of 1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methylnaphthalene and agitated for 1 hour. After ice cooling, 8.5 ml of N,N-dimethylformamide was dropped in the reaction solution and the ice bath was removed, followed by agitation for 1 hour until room temperature was reached. Iced water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography (2% ethyl acetate/hexane) to obtain 14.1 g of the captioned compound as a brown oily substance.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Sodium hydroxide (30 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D47) (195 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E21) (78 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.62 (2H, t), 3.06 (2H, t), 4.99 (1H, m), 6.98 (1H, dd), 7.26 (1H, d), 7.55 (1H, d), 7.90 (1H, dd), 8.47 (1H, dd), 8.70 (1H, d), 11.12 (1H, s), 12.15 (1H, br s). δF (DMSO-d6, 376 MHz): −118.0. MS (ES): C23H19FN4O4 requires 434; found 435.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@H:10]2[O:22][C@@H:21]([CH2:23][O:24]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[N:6]=1)=O.[NH3:28]>>[C@@H:10]1([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:28])=[O:2])=[N:6]2)[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]1[OH:12]
Reactant: N
Reactant: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate (62 g, 161 mmol) was placed in a steel bomb and treated with freshly prepared methanolic ammonia (350 ml, prepared by passing dry HCL gas into dry methanol at 0° C. until saturation) at 0° C. The steel bomb was closed and stirred at room temperature for 18 h. The steel bomb was then cooled to 0° C., opened and the content evaporated to dryness. The residue was treated with dry ethanol (100 ml) and evaporated to dryness. The residue obtained was triturated with acetone to give a solid, which was filtered and washed with acetone. The solid was dried overnight at room temperature and dissolved in a hot EtOH (600 ml) and water (10 ml) mixture. The volume of the EtOH solution was reduced to 150 ml by heating and stirring on a hot plate. The hot EtOH solution on cooling provided colorless crystals, which were filtered, washed with acetone and dried under vacuum. Further concentration of the filtrate gave additional material. The total yield was 35 g (89%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=2[CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Cc1cccc(NCc2ncc[nH]2)c1C
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2cccc(C)c2C)[C@@H]1O
Yield: 36.9 %

Procedure:
The title compound (253 mg, 37%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (400 mg, 1.42 mmol) and 2,3-dimethylphenyl-1H-imidazol-2-ylmethylamine (287 mg, 1.42 mmol), according to the same procedure used for the preparation of example 1 above.