Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH2:2][CH3:3]>CO.[BH4-].[K+]>[OH:9][CH:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:14])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CCCN1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 66 %

Procedure:
3-Hydroxy-2-propyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 1.5 g of N-propylphthalimide in 25 cm3 of methanol and 0.48 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 35° C. and the residue is cooled to 0° C. The precipitate obtained is filtered off and then washed with cold water. The solid is taken up in dichloromethane and the solvent is then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 1.0 g of 3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one is thus obtained in the form of a beige-colored powder. (Rf=0.6, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=C[CH:8]=2)[CH:3]=[CH:2]1.C1(CC([NH2:19])=O)C=CC=CC=1.CC(C)([O-])C.[K+].N.N1C2C(=CC=CC=2)C=N1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C([N+]([O-])=O)=CC=CN=1.[N+](C1C=NC=CC=1Cl)([O-])=O.C([Mg]Br)=C>O.O1CCOCC1.O1CCCC1.CCOCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:19][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)Cc1ccccc1
Agent: C=C[Mg]Br
Agent: CC(C)(C)[O-]
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: c1cc2cc[nH]c2cn1

Procedure:
An indole glyoxyl ester is reacted with a phenyl acetamide derivative in a one-pot reaction in an inert solvent in the presence of a strong base. Preferably an ether is used as an inert solvent, such as tetrahydrofurane or dioxane. As a base potassium tert.-butoxide can for example be used. The water formed during the reaction is removed, for example by using a molecular sieve. The phenyl acetamides used as starting material are readily available from the corresponding acetic acids which are converted to the acid chloride and hydrolyzed with ammonia. The indole glyoxyl esters (R=methyl, ethyl) can be synthesized by Friedel-Crafts-type acylation of the corresponding indole derivative with methyl or ethyl oxalyl chloride, cf. Tetrahedron 1999, 55 (43), 12577-12594. The corresponding azaindole glyoxyl esters can be prepared according to the method reported in J. Org. Chem. 2002, 67: 6226-6227 or by Friedel-Crafts acylation in the presence of aluminum chloride, cf. Organic Letters (2000) vol. 2, no. 10, 1485-1487. The 4- and 6-azaindole starting compounds can be prepared by reacting 2-chloro-3-nitropyridine or 3-nitro-4-chloropyridine with vinyl magnesium bromide to give the 7-chloro-substituted 4- or 6-azaindole. The chloro substituent is then removed by catalytic hydrogenation. Said reactions are carried out as described in J. Org. Chem. 67: 2345-2347 (2002) and J. Heterocycl. Chem. 29: 359-363 (1992). The 4-aza-indole starting compound can also be synthesized according to the procedures disclosed in Org. Biomol. Chem. 3, 20, 3701-3706 (2005).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18].N1C=CC=CC=1.O1CCOCC1>C(OCC)(=O)C>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:19])=[O:18]
Reactant: CC(C)(C)CO
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
Neopentyl alcohol (0.75 g, 8.50 mmol) was added to a solution of commercially available 2-methyl-5-nitro-benzenesulfonyl chloride (1.00 g, 4.20 mmol), pyridine (1.72 mL, 21.2 mmol and anhydrous dioxane (40 mL). A water cooled condenser was attached and the material was heated to reflux. After stirring for two days the mixture was cooled to room temperature and diluted with ethyl acetate (350 mL). The organic layer was washed with water, then 1 N HCl solution, and finally brine. After drying with MgSO4 the solution was concentrated to afford 690 mg of the title compound as a yellow solid.(55%): 1HNMR (DMSO-6) δ8.57 (d, J=2 Hz, 1H), 8.51 (dd, J=8 Hz, 2 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 3.78 (s, 2H), 2.70 (s, 3H), 0.88 (s, 9H); MS (EI): [M+] 287; Anal. Calc. for C12H17NO5S: C, 50.16; H, 5.96; N, 4.88. Found: C, 49.83; H, 5.69; N, 4.90.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:26]2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:6]=1.SCC(O)=O.C1CCN2C(=NCCC2)CC1.CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:26]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(CN(C2CCN(c3nc4ccc(Cl)cc4s3)C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C(O)CS
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]-(2-nitrobenzensulphonyl)amino]methyl]phenyl]acetic acid methyl ester (412 mg), mercaptoacetic acid (95 mL), 1,8-diazabicyclo[5,4,0]-7-undecene (4 mL) and dimethylformamide (4 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (204 mg). Yield: 71%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11]>C1C=CC=CC=1>[C:2]1([NH:1][C:10](=[O:11])[C:9]([CH3:14])([CH3:13])[CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1ccccc1
Yield: 60 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were aniline (24.18 g, 0.260 mole) and trimethylacetoyl chloride (15.06 g, 0.125 mole), the reaction was carried out in benzene and produced 13.24 g of crystals of the desired product (60% yield), mp 132°-132.5° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.568-7.078 ppm (m, 5H; aryl H); 1.310 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[O:21]1[CH:26]2[CH:22]1[CH2:23][O:24][CH2:25]2.C(N(CC)CC)C>ClCCl>[OH:21][C@@H:22]1[CH2:23][O:24][CH2:25][C@H:26]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC(OCCO)CC1
Reactant: C1OCC2OC12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(OCCO[C@@H]2COC[C@H]2O)CC1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (6.70 g, 24.0 mmol) produced in Reference Example 1 (1b) and 3,4-epoxytetrahydrofuran (1.03 g, 12.0 mmol) were dissolved in dichloromethane (5.0 mL). To the resulting mixture, a boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added at room temperature, followed by stirring for 16 hours. More boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added, followed by further stirring for two hours. Triethylamine (1.82 g, 18.0 mmol) was then added, and the resulting reaction liquid was directly purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, ethyl acetate:methanol, 100:0-95:5, V/V) to give the desired title compound (2.14 g, yield 49%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([CH:13]=[CH2:14])[N:6]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([CH2:13][CH3:14])[N:6]=1)=[O:4]
Reactant: C=Cc1nc(OC)cc(C(=O)OC)n1
Agent: [Pd]
Solvent: CO
Product: CCc1nc(OC)cc(C(=O)OC)n1
Reaction time: 4 h

Procedure:
6-Methoxy-2-vinyl-pyrimidine-4-carboxylic acid methyl ester (130 mg) was combined with MeOH (5 ml) to give a light yellow solution. Pd/C 10% (13 mg) was added and the reaction mixture was hydrogenated with a balloon at RT for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give title compound as an off white solid. MS (ISP) 197.1 ([M+H]
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25]C(OC(C)(C)C)=O)[CH:20]=1)[CH2:5][P:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:8])=[O:7].[OH-].[Na+]>CO.C1COCC1.O>[NH2:25][C:21]1[CH:20]=[C:19]([CH:4]([CH2:5][P:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:8])=[O:7])[C:3]([OH:33])=[O:2])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C(CP(=O)(O)CCCCc1ccccc1)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Reaction time: 0.75 h

Procedure:
2-(3-(t-Butoxycarbonylamino)phenyl)-3-((4-phenylbutyl)(hydroxy)-phosphinoyl)propanoic acid methyl ester (845 mg, 1.8 mmol) was stirred in 1 M NaOH (5.3 mL, 5.3 mmol) in methanol/THF/H2O for 1.5 hours. The product was concentrated in vacuo. The residue was dissolved in 10 mL methylene chloride and TFA (10 mL) was added. After 45 minutes, the reaction mixture was concentrated to provide 2-(3-aminophenyl)-3-((4-phenylbutyl)(hydroxy)phosphinoyl)propanoic acid, NMR (DMSO-d6) 1.30-1.45 (m, 8), 1.80 (m, 1), 2.35 (m, 1), 3.62 (m, 1), 6.58-6.65 (m, 3), 7.05 (m, 1), 7.15 (m, 3), 7.23 (m, 2) ppm; as a crude product. Pure product was obtained by preparative reversed-phase HPLC.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]=[C:7]=[O:8])(=[O:3])[CH3:2].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])(=[O:3])[CH3:2]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(=O)CCN=C=O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)CCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 5 h

Procedure:
To the above solution of 2-acetylethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (15 ml.) at 80° C. and stirred for further 5 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-acetylethyl)carbamoyl]-5-fluorouracil (439 mg.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[CH:23]([O-])([O-])OCC>C(O)(=O)C>[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C@H:13]2[CH2:12][C@H:11]([NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:14]2)[CH:23]=1
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: c1ccc2sc(N[C@H]3C[C@H](n4cnc5cccnc54)C3)nc2c1
Temperature: 90 °C

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (intermediate from step 3 in example 1, 0.100 g, 0.321 mmol) was dissolved in acetic acid (10 mL) and treated with ethyl orthoformate (2.0 ml, 12.02 mmol). The solution was heated at 90° C. for 20 minutes and the solution evaporated to dryness under reduced pressure. Purification using the silica chromatography (0-10% methanol in dichloromethane gradient) gave the desired N-(trans-3-(3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.061 g, 0.190 mmol, 59.1% yield) as an off-white solid. M+1: 322.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.82 (ddd, J=13.89, 8.51, 4.01 Hz, 2 H) 3.20-3.32 (m, 2 H) 4.61 (tt, J=7.73, 4.01 Hz, 1 H) 5.37 (quin, J=7.68 Hz, 1 H) 7.06-7.15 (m, 1 H) 7.23-7.34 (m, 2 H) 7.61 (d, J=8.02 Hz, 1 H) 7.58 (d, J=8.22 Hz, 1 H) 8.10 (dd, J=8.12, 1.27 Hz, 1 H) 8.19 (s, 1 H) 8.41 (dd, J=4.69, 1.37 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: Cn1ccc(CCl)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccn(C)c(=O)c6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 4-(chloromethyl)-1-methylpyridin-2(1H)-one (47.3 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 49.6 mg; LC (method 23): tR=1.96 min; Mass spectrum (ESI+): m/z=584 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[C:31]([F:42])[C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:33]([OH:35])[CH:34]=1>>[F:42][C:31]1[CH:30]=[C:29]([NH:28][C:2]2[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]3=[C:4]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[N:3]=2)[CH:34]=[C:33]([OH:35])[C:32]=1[N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: Nc1cc(O)c(N2CCOCC2)c(F)c1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3cc(O)c(N4CCOCC4)c(F)c3)nc3c2cnn3C2CCCCO2)c1

Procedure:
N-(3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide can then be reacted with 5-amino-3-fluoro-2-morpholinophenol under palladium catalyzed aminolysis conditions to yield N-(3-(6-((3-fluoro-5-hydroxy-4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide, which can be deprotected under mild acidic conditions to provide N-(3-(6-((3-fluoro-5-hydroxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].C[Si](Cl)(C)C.[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:41](=[O:42])[NH:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(=O)Nc2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 14 %

Procedure:
A solution of 8a (0.06 g, 0.14 mmol), trimethylsilyl chloride (0.01 mL, 0.08 mmol) and phenylisocyanate (0.1 mL, 0.92 mmol) in CH2Cl2 was stirred at room temperature for 5 days. The reaction mixture was then washed with saturated NaHCO3 (10 mL) and H2O (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a crude oil. The oil was purified by column chromatography (eluent: ethyl acetate/n-hexanes) to afford 22 (0.01 g, 14%) as a clear oil: 1H NMR (CDCl3): δ 1.15 (s, 3H); 1.48 (s, 3H); 1.52-1.72 (m, 3H); 1.82 (dd, 1H, 2.7, 10.2 1H); 2.03-2.20 (m, 1H); 2.22 (s, 1H); 2.24-2.48 (m, 2H); 2.54 (dd, Ja=5.1, Jb=13.5, 1H); 2.80 (dd, Ja=3.6, Jb=13.2, 1H); 3.75 (s, 3H); 5.21 (dd, Ja=7.8, Jb=12.3, 1H); 5.54 (dd, J=11.7, 1H); 6.40 (m, 1H), 6.69 (br s, 1H); 6.87 (br s, 1H); 7.12 (m, 2H); 7.28-7.45 (m, 5H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][C@@H:5]2[O:6][C:7]3[C:12]([CH2:13][CH2:14][P:15](=[O:20])([O:18][CH3:19])[O:16][CH3:17])=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:4]2[C@H:3]1[CH2:22][OH:23].C(N(CC)CC)C.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51](OC(=O)C)(=[O:53])[CH3:52].Cl.CO.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[C:51]([O:1][C@@H:2]1[CH2:21][C@@H:5]2[O:6][C:7]3[C:12]([CH2:13][CH2:14][P:15](=[O:20])([O:18][CH3:19])[O:16][CH3:17])=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:4]2[C@H:3]1[CH2:22][OH:23])(=[O:53])[CH3:52]
Reactant: COP(=O)(CCc1cccc2c1O[C@H]1C[C@@H](O)[C@H](CO)[C@@H]21)OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COP(=O)(CCc1cccc2c1O[C@H]1C[C@@H](OC(C)=O)[C@H](CO)[C@@H]21)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A solution of dimethyl 2-{(1S,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-hydroxymethyl-1H-cyclopenta[b]benzofuran-5-yl}ethylphosphonate (12) 1000 mg (2.921 mmol) and triethylamine 3.26 ml (23.368 mol) in anhydrous DMF (20 ml) was cooled to 0° C. under argon atmosphere, and a solution of triphenylmethyl chloride in DMF (5 ml×2) was added to the solution, followed by stirring at room temperature for 2 hours, and then at 60° C. overnight. The reaction mixture was again cooled to 0° C., and triethylamine 1.63 ml (11.684 mmol), N,N-dimethylamindpyridine 713.7 mg (5.842 mmol), and acetic anhydride 0.551 ml (5.842 mmol) were added to the reaction mixture. After the temperature was increased to 60° C., the mixture was stirred for 1 hour. After the mixture was allowed to cool to room temperature, ice-cold ion exchanged water 40 ml was added to the mixture, and the mixture was extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with water (50 ml×2) and brine (50 ml), dried, concentrated, and then dried in vacuo. The thus-obtained yellow oil was dissolved in methanol 30 ml, and hydrogen chloride-methanol (1.387M) 6.32 ml (8.764 mmol) was added to the resultant solution, followed by stirring at room temperature for 2 hours. After sodium bicarbonate was added little by little to neutralize the mixture, the resultant suspension was filtered with Celite, and the filtrate was concentrated. After the precipitate was again filtered off with Celite, the filtrate was concentrated. The residue was subjected to column chromatography (Silica gel FL-60D produced by Fuji Silicia Co.; chloroform:methanol 95:5) to recover dimethyl 2-{(1S,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-hydroxymethyl-1H-cyclopenta[b]benzofuran-5-yl}ethylphosphonate (12) used as the starting material (270.6 mg, 27%). The crude product of the titled compound was again purified by column chromatography (DIOL column produced by Yamazen Co.; ethyl acetate) to obtain the titled compound 667.9 mg (1.738 mmol) as a pale yellow oil (yield 60%). The structure of this compound was determined by the following data.
Reaction SMILES: [NH2:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([N:14]([CH3:16])[CH3:15])([CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:4].[CH3:23][C:24]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:3]([CH3:4])([CH2:5][O:6][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9])[CH:2]([NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:24]=1[CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CN(C)C(C)(CO[Si](C)(C)C(C)(C)C)C(N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(c2ccccc2)C(C)(CO[Si](C)(C)C(C)(C)C)N(C)C)c1C
Yield: 30 %

Procedure:
The title compound (64 mg; 30%) was prepared from [2-amino-1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-methyl-2-phenylethyl]dimethylamine D48 (150 mg; 0.46 mmol), 2,3-dimethylbenzoic acid (75 mg; 0.5 mmol), PL-dicyclohexylcarbodiimide (385 mg; 0.5 mmol; Polymer Labs 1.3 mmol/g), 1-hydroxybenzotriazole (77 mg; 0.5 mmol) in DCM (5 ml) in a similar manner to that described in E1. Mass spectrum (Electrospray LC/MS): Found 455 (MH+), C27H42N2O2Si requires 454. Ret. time 2.57 and 2.61 min.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[CH:9]=[C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=O)[NH:12][C:13]=3[CH:14]=[CH:15][C:6]2=[N:5][N:4]=1)[CH3:2].O=P(Cl)(Cl)[Cl:25]>C(#N)C>[Cl:25][C:11]1[N:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]=[C:6]1[CH:15]=[CH:14]2
Reactant: CCc1nnc2ccc3[nH]c(=O)c(-c4ccccc4)cc3n12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nnc2ccc3nc(Cl)c(-c4ccccc4)cc3n12
Temperature: 150 °C

Procedure:
A mixture of 1-ethyl-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (7-4) (70 mg, 0.241 mmol) and POCl3 (3.0 mL, 32.2 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 150° C. for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with CHCl3, washed with sat. NaHCO3 solution, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 7-chloro-1-ethyl-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridine (7-5) as pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C@@H:6]([NH:13]C(=O)C)[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])C.[ClH:18]>>[ClH:18].[NH2:13][C@@H:6]([C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C[C@@H](NC(C)=O)[C@H](C)[C@H](C)CC
Agent: Cl
Product: CC[C@@H](C)[C@@H](C)[C@H](N)CC(=O)O
Yield: 89 %

Procedure:
(3R,4R,5R)-3-Acetylamino-4,5-dimethyl-heptanoic acid ethyl ester (13.63 g, 56.0 mmol) was heated under reflux with 200 mL of 1M hydrochloric acid for 72 hours. The solution was cooled and extracted 2× with 50 mL aliquots of MTBE. The aqueous phase was evaporated to a semisolid. Acetonitrile (4×100 mL) was added and evaporated to give 10.75 g (89% yield) of the titled compound as a white crystalline solid: 1H NMR (CD3OD, 399.77 MHz) 0.87 (t, J=7.3 Hz, 3H), 0.94 (t, J=6.6 Hz, 6H), 1.02–1.15 (m, 1H), 1.37–1.53 (m, 2H), 1.58–1.68 (m, 1H), 2.64 (dd, J=17.5, 7.4 Hz, 1H), 2.73 (dd, J+17.5, 4.8 Hz, 1H), 3.54–3.61 (m, 1H). Low resolution mass spec: nominal m/e calc'd for C9H20ClNO2 (M+H)+: 174. Found: m/e 174.