Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 13.7 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 3-methoxyphenylboronic acid 49 mg, sodium carbonate 57 mg and polymer-carried bis(acetato)triphenylphosphine palladium (II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. To the obtained residue were added 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL and ethanol 6.0 mL, and it was stirred at room temperature for 1 hour. 0.5 mol/L Hydrochloric acid was added to the reaction mixture, solid matter was filtrated to give 2-(4-fluoroanilino)-4-(3-methoxyphenyl)benzoic acid 10 mg of pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53](=[NH:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[NH2:67][C:68]1[CH:77]=[CH:76][C:75]([C:78]([C:80]2[N:84]3[CH:85]=[CH:86][CH:87]=[CH:88][C:83]3=[C:82](Br)[N:81]=2)=[O:79])=[CH:74][C:69]=1[C:70]([O:72][CH3:73])=[O:71]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:67][C:68]1[CH:77]=[CH:76][C:75]([C:78]([C:80]2[N:84]3[CH:85]=[CH:86][CH:87]=[CH:88][C:83]3=[C:82]([N:66]=[C:53]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[N:81]=2)=[O:79])=[CH:74][C:69]=1[C:70]([O:72][CH3:73])=[O:71]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2nc(N=C(c3ccccc3)c3ccccc3)c3ccccn23)ccc1N
Temperature: 110 °C

Procedure:
3.83 g (11.75 mmol) of caesium carbonate, 0.73 g (1.18 mmol) of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [Binap], 4.93 ml (29.4 mmol) of benzophenoneimine and 0.54 mg (0.59 mmol) of tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] are added to the solution of 2.20 g (5.88 mmol) of methyl 2-amino-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate (described in Patent Application WO2006097625) in 35 ml of anhydrous N,N-dimethylformamide under argon, and the mixture is then heated at 110° C. for 3 hours. The reaction medium is then filtered and then diluted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride. It is dried over sodium sulphate, filtered and concentrated to dryness so as to obtain a red solid. After purification by flash chromatography on silica gel (toluene/ethyl acetate/triethylamine gradient=98/1/1 to 90/9/1), 1.18 g (42%) of an orangey-red powder are obtained.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Si:22]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C1COCC1>[C:25]([Si:22]([CH3:24])([CH3:23])[O:29][CH2:30][CH2:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:2])=[CH:35][CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a cold suspension of methyl triphenyl phosphonium iodide (2.88 g, 7.13 mmol) in THF (20 mL) was added KOBt (0.88 g, 7.84 mmol) slowly. The reaction mixture was warmed to RT and stirred for about 1 h. A solution of 4-(2-(tert-butyldimethylsilyloxy)ethoxy)benzaldehyde (1.0 g, 3.56 mmol) in THF (15 mL) was added slowly to the above reaction mixture and stirred for about another 3 h. The reaction was quenched with water and extracted with diethyl ether (3×75 mL). The combined organic extracts were washed with brine (1×75 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography using 10% EtOAc-hexane as the eluent. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford tert-buyldimethyl (2-(4-vinylphenoxy)ethoxy)silane 0.65 g, (65%), 1H NMR (400 MHz, CDCl3): δ 7.350-7.342 (d, J=3.2 Hz, 2H), 6.882-6.875 (d, J=2.8 Hz, 2H), 6.857-6.692 (m, 1H), 5.625-5.581 (d, J=17.6 Hz, 1H), 5.132-5.104 (d, J=11.2 Hz, 1H), 4.052-3.954 (m, 4H), 0.909 (s, 9H), 0.1 (s, 6H), MS m/z: 279.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1>N1C=CC=CC=1.ClCCl>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:11]([CH:8]1[CH2:10][CH2:9]1)=[O:12]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cnccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cnccn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g (105 mmol) of 2-aminopyrazine in 100 mL of pyridine was added dropwise a solution of 10.99 g (9.56 mL, 105 mmol) of cyclopropanecarbonyl chloride in 100 mL of dichloromethane. The resultant yellow solution was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and a small amount of water and washed sequentially with 1 M aqueous cuprous sulfate solution and water. The water layer was extracted with three portions of ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, eluting sequentially with 50%, 80% and 100% ethyl acetate/hexane) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([NH2:23])=O)[NH:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](=[S:33])[NH2:23])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(c1c(Cl)ccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1c(Cl)ccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.70 g), Lawesson's reagent (0.77 g) and tetrahydrofuran (20 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.60 g, yield 84%) as yellow crystals. melting point 200-201° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:32]([CH3:34])[CH3:33])[CH:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.Cl>[Si:25]([O:24][CH:19]([C:20]([F:23])([F:21])[F:22])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][N:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=[C:2]([NH:1][C:44]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[C:3]1=[O:35])[CH:32]([CH3:33])[CH3:34])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)NCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 18 h
Yield: 78 %

Procedure:
R=benzylaminocarbonyl: To a solution of 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (300 mg) in dry tetrahydrofuran (10 mL) was added benzyl isocyanate (86 mg). After 20 h triethyl amine (65 mg) and benzyl isocyanate (43 mg) were added. After another 18 h the reaction mixture was diluted with ethyl acetate and 10% hydrochloric acid. The organic portion was separated, washed with 10% hydrochloric acid and brine, and evaporated to give a crude oil. The reaction was found to be incomplete. To a solution of the recovered oil in dry tetrahydrofuran (6 mL) was added triethyl amine (80 mg) and benzyl isocyanate (86 mg). The solution was heated under reflux for 6 h and stirred 18 h. The reaction mixture was diluted with ethyl acetate; washed with saturated aqueous sodium bicarbonate, 10% hydrochloric acid and brine; dried; evaporated; and dried under vacuum to give a crude solid. Purification by chromatography, eluting with ethanol:ethyl acetate:dichloromethane (0.25:3:96.75 ), gave N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-[2-oxo-6-phenyl-3-(3-benzylureido)-1,2-dihydro-1-pyridyl]acetamide (295 mg); TLC: Rf =0.20, ethanol:ethyl acetate:dichloromethane (0.5:4:95.5); MS: m/z=645(M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18]O)[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:21]([O:20][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C@@H:6]([CH2:18][N:46]2[C:42](=[O:52])[C:43]3=[CH:51][CH:50]=[CH:49][CH:48]=[C:44]3[C:45]2=[O:47])[CH2:5]1)[CH3:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72485.8 %

Procedure:
A solution of 4,4-Diethoxy-1-((S)1-phenyl-ethyl)-(R)-2-hydroxymethyl-piperidine (65.35 g, 0.213 mmol), triphenylphosphine (61.3 g, 0.234 mol) and phthalimide (34.4 g, 0.234 mol), in tetrahydrofuran (700 ml) cooled to 0° C. was added diethyl azodicarboxylate over the course of 1.5 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the solvent was removed in vacuo. The residue was dissolved in hot heptane-toluene (3:2) (650 ml) before it was cooled on an ice bath. The precipitate consisting of triphenyl phosphine oxide was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene-ethyl acetate-heptane (3:1:3) as eluent. The solvent was evaporated in vacuo whereupon a viscous oil was obtained. Upon addition of light petrol ether the product crystallized to give 67.4 g (73%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:9]([Si:6]([CH2:7][CH3:8])([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[Si:4]([CH2:15][CH3:16])([CH2:17][CH3:18])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Reactant: [Li][Si](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC[Si](CC)([Si](C)(C)c1ccccc1)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 68 mg (0.20 mmol) of octaethylcyclotetrasilane was added 0.72 ml (0.20 mmol) of a tetrahydrofuran solution (0.26M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to afford a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 31 mg (0.05 mmol) of 2,2,3,3,4,4,5,5-octaethyl-1,1,6,6-tetramethyl-1,6-diphenylhexasilane (1) obtained in Example 1 was treated with 15 mg (0.10 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to give 1,6-bis(trifluoromethanesulfonyloxy) hexasilanes. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C. and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column (hexane) chromatography to afford 43 mg (61% yield) of hexadecasilane (6).
Reaction SMILES: Cl[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:11][C:10]3[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=3[N:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
8-Chlorotheophylline (3.5 g) and piperazine-1-carboxylic acid tert-butyl ester (11.69 g) were mixed, and stirred at 110° C. overnight. Then, the reaction mixture was diluted with ethyl acetate and water, insoluble white solid was collected by filtration, and washed with ethyl acetate to give 3.65 g of the title compound.
Reaction SMILES: [N:1]1([CH:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-:26].O[CH2:28][CH2:29][CH2:30][P+:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br-:26].[N:1]1([CH:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:28][CH2:29][CH2:30][P+:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCCC(CCCCCCCCCCCC(=O)O)n1ccnc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: [Br-]
Solvent: ClCCl
Product: CCCCCC(CCCCCCCCCCCC(=O)OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)n1ccnc1
Yield: 78.5 %

Procedure:
A stirred solution of 13-(1H-imidazol-1-yl)octadecanoic acid (365 mg, 1.041 mmol), (3-hydroxypropyl)triphenylphosphonium bromide (418 mg, 1.041 mmol) and DMAP (catalytic amount) in DCM (10 ml), was cooled to 0° C., to which was then added DCC (215 mg, 1.041 mmol) under N2 gas, and stirring continued overnight at room temperature. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel column (5% MeOH in DCM) to give TPP-13-ISA as a gummy semi-solid (600 mg, 78%)
Reaction SMILES: [CH3:1][CH:2]1[S:26][C:5]2[C:6]([CH3:25])([CH3:24])[O:7][C:8]3[CH:13]=[C:12]([CH:14]([CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:15])[CH:11]=[C:10]([OH:23])[C:9]=3[C:4]=2[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:42].[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH2:51][C:52](O)=[O:53])[CH2:45][CH2:44]1>C(Cl)Cl>[ClH:42].[CH3:1][CH:2]1[S:26][C:5]2[C:6]([CH3:25])([CH3:24])[O:7][C:8]3[CH:13]=[C:12]([CH:14]([CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:15])[CH:11]=[C:10]([O:23][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][N:46]4[CH2:45][CH2:44][O:43][CH2:48][CH2:47]4)[C:9]=3[C:4]=2[CH2:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)S1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CC(C)S1
Temperature: 25 °C

Procedure:
1,2-Dihydro-2,4,4-trimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno-[2,3-c][1]benzopyran, dicyclohexylcarbodiimide and γ-morpholinobutyric acid hydrochloride are combined in methylene chloride and stirred at room temperature. The insoluble dicyclohexylurea is removed by filtration and the methylene chloride is removed on a rotary evaporator. The residue is crystallized from ether to give 1,2-dihydro-2,4,4-trimethyl-9-[4-(morpholino)butyryloxy]-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran hydrochloride.
Reaction SMILES: [N:1]1([C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[NH:8][CH:9]=[N:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)NC(=O)N([C@@H:23]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@@H:24]2[OH:31])C=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>>[C@@H:23]1([N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][CH:13]=[N:14][C:6]=3[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@@H:24]1[OH:31]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: c1nc(N2CCCC2)c2[nH]cnc2n1
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Product: OC[C@H]1O[C@@H](n2cnc3c(N4CCCC4)ncnc32)[C@@H](O)[C@@H]1O
Temperature: 35 °C
Yield: 68.6 %

Procedure:
6-Pyrrolidinopurine (Sigma Chemical Co., St. Louis, Mo.) (2.6 mmoles), 0.5 g, and uracil arabinoside (5.29 mmoles, 1.29 g) were suspended in 100 ml of a 10 mM potassium phosphate 0.04% potassium azide solution with a pH of 7.4. Purified uridine phosphorylase (6000 I.U.) and purine nucleoside phosphorylase (8400 I.U.) (Krenitsky, T. A., et al. Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 35° C. Twenty days later the reaction was filtered and the filtrate chromatographed on a column containing Dowex-1-hydroxide resin (2.5×8 cm). The product was eluted from the column with 90% methanol/water (v/v). Fractions containing product were combined and the solvent removed under vacuum. The residue was dissolved in 50 ml of 30% n-propanol and water (v/v) and chromatographed on a BioRad P-2 column (5×90 cm). The product was eluted with 30% n-propanol/water (v/v). Product-containing fractions were combined and the solvent was removed under vacuum yielding 0.573 g of 9-β-D-arabinofuranosyl-6-pyrrolidino-9H-purine. NMR and mass spectrometry were consistent with the structure. Anal. Calcd. for C14H19N5O4 : Calcd: C, 52.33; H, 5.96 N, 21.79. Found: C, 52.60; H, 6.09; N, 21.51.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([OH:29])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:29][C:24]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[N:23]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1cc(C)nc(O)n1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2nc(C)cc(C)n2)c(Cl)c1=O
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (Intermediate 79 step 1, 15.4 g, 48 mmol) in N,N-dimethylformamide (150 mL) was treated with 4,6-dimethyl-pyrimidin-2-ol (5.98 g, 48 mmol) and potassium carbonate (8 g, 58 mmol). The reaction was heated at reflux for 12 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography (5/1 petroleum ether/ethyl acetat) afforded 2-[5-chloro-4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (7.47 g, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.CCCCC>[C:13]1([S:19]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]3[CH:10]=[CH:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Yield: 72.5 %

Procedure:
4-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 1 Eq.) was dissolved in dry THF and cooled in an ice-bath. NaH (60% dispersion in mineral oil, 305 mg, 1.2 Eq.) was added portionwise. The resultant mixture was stirred at 0° C. for 45 minutes and benzene sulfonyl chloride (1.076 g, 1.2 Eq.) was added slowly dropwise. The resultant mixture was stirred at 0° C. for a further 75 minutes and then the solvent was removed in vacuo. The residue was partitioned in EtOAc/sat. NH4Cl and extracted with EtOAc (3×50 mL). The combined organics were washed with sat. aq. Na2CO3 (1×20 mL), brine (1×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (20% EtOAc/80% hexanes), followed by recrystallization from EtOAc/hexanes. The product was filtered and then washed with pentane obtaining the title compound as a white powder (1.24 g, 73% yield); 1H NMR (DMSO D6) 6.8 (1H, d), 7.6-7.66 (3H, m), 7.72-7.76 (1H, m), 8.0 (1H, d), 8.1 (2H, m), 8.24-8.26 (1H, m); LC/MS M+1; (obs.) 339.1; LC/MS M−1 (obs.) 337.1.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([O:10]CC)=[O:9])[O:6][CH2:5][CH2:4][O:3]1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH2:7][C:8]([OH:10])=[O:9])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CCOC(=O)CC1(C)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(CC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 2-methyldioxolan-2-ylacetate (2.0 g) in methanol (69 ml) was added 1N sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature overnight. Then, the mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. To the mixture was added ethyl acetate, and the mixture was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-methyldioxolan-2-ylacetic acid (1.63 g) as colorless