Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.[CH2:23]([O:25][C:26]([C:28]1[C:29]2[CH:30]=[CH:31][NH:32][C:33]=2[CH:34]=[CH:35][CH:36]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cu](I)I>[CH2:23]([O:25][C:26]([C:28]1[C:29]2[CH:30]=[CH:31][N:32]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]4[CH2:12][CH2:11][CH2:10][N:9]4[C@@H:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH3:14])[CH:7]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc2[nH]ccc12
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cccc2c1ccn2-c1cncc([C@@H]2CCCN2[C@H](C)c2ccc(OC)cc2)c1
Temperature: 190 °C
Yield: 42.6 %

Procedure:
A mixture of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4.0 g, 11 mmol), 1H-indole-4-carboxylic acid ethyl ester (6.3 g, 33 mmol), K2CO3 (2.3 g, 16.6 mmol), copper iodide (0.42 g, 2.2 mmol) in NMP (22 mL) was heated in a microwave tube at 190° C. for 30 minutes. The resulting mixture was cooled to room temperature filtered through celite and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography (30% ethyl acetate/heptane) to give the titled compound as a yellow solid (2.2 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([OH:10])=O)[N:3]=1.S(Cl)([Cl:13])=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([Cl:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cncc(Cl)n1
Solvent: CC#N
Product: O=C(Cl)c1cncc(Cl)n1

Procedure:
A mixture of 2-chloro-6-carboxy-pyrazine (1000 mg, 6.3 mmol) in ACN (20 mL) was treated with thionyl chloride (800 uL). The resulting mixture, which became homogeneous upon heating, was refluxed for 2 h. The solvent was removed under reduced pressure which gave an oil. The crude product was used in the next step.
Reaction SMILES: [S:1]([C:5]1[C:6](=[O:25])[C:7]2[N:8]3[C:16]([N:17]=[C:18]4[C:24]=2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19]4)=[C:15]1[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]1)=[CH:9]3)([OH:4])(=[O:3])=[O:2].S(C1C=C(C(O)=O)C(=CC=1)C(O)=O)(O)(=O)=O.C1C=C(N)C2C(N)=CC=CC=2C=1.P(Cl)(Cl)([Cl:56])=O>CN1CCCC1=O.C1(C)C(C)=CC=CC=1>[C:6]1(=[O:25])[C:7]2=[C:24]3[C:18](=[N:17][C:16]4[N:8]2[CH:9]=[C:10]2[C:15]=4[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:19]=[CH:20][CH:21]=[C:22]3[CH:23]=[CH:5]1.[S:1]([Cl:56])([OH:4])(=[O:3])=[O:2]
Reactant: O=c1c(S(=O)(=O)O)cc2cccc3nc4c5ccccc5cn4c1c23
Reactant: O=P(Cl)(Cl)Cl
Agent: Nc1cccc2cccc(N)c12
Agent: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: O=S(=O)(O)Cl
Product: O=c1ccc2cccc3nc4c5ccccc5cn4c1c23
Temperature: 80 °C
Yield: 91.4 %

Procedure:
11.5 g of sulphophthaloperinone, prepared from 4-sulphophthalic acid and 1,8-naphthylenediamine in N-methylpyrrolidone, are suspended in 100 ml of xylene. 9.2 g of phosphorus oxychloride are added and the mixture is heated to 80° C for 6 - 7 hours, whilst stirring. 25 - 30 ml of xylene are then distilled off under reduced pressure and after cooling the reaction product which has precipitated is filtered off and the residue is rinsed with petroleum ether. 11.6 g of phthaloperinone-sulphochloride are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[C:20]([NH2:22])=[O:21].[C:28](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:27][O:26][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:25]=1)[C:20]([NH:22][CH2:28][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[O:21]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1cc(OC)cc(C(N)=O)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)cc(C(=O)NCN2CCN(c3ccccn3)CC2)c1
Temperature: 25 °C
Yield: 108 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 3,5-dimethoxybenzamide (91 mg, 0.5 mmol, Lancaster), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 38.5 mg (72%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.59 (t, J=4 Hz, 4H), 3.48 (t, J=4 Hz, 4H), 3.78 (s, 6H), 4.20 (d, J=5 Hz, 1H), 6.62 (m, 2H), 6.81 (d, J=6 Hz, 1H), 7.03 (s, 2H), 7.50 (t, J=6 Hz, 1H), 8.10 (d, J=5 Hz, 1H), 8.78 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 355 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH2:21]([C:23]1[C:24](=[O:30])[NH:25][C:26](=[S:29])[NH:27][CH:28]=1)[CH3:22].CCN(C(C)C)C(C)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:29][C:26]3[NH:27][CH:28]=[C:23]([CH2:21][CH3:22])[C:24](=[O:30])[N:25]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CCc1c[nH]c(=S)[nH]c1=O
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
A mixture of 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (65 mg, 0.202 mmol), 5-ethyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (47.4 mg, 0.304 mmol) and DIPEA (0.163 mL, 0.933 mmol) in DCE (3.0 mL) was sealed in a vessel and stirred at room temperature for 5 min, then was heated with a microwave condition at 80° C. for 30 min. After cooling, the reaction was quenched with water, extracted with EA, the combined organic layers were dried with sodium sulfate, concentrated, and purified via MDAP to afford the title compound (41 mg, 45.9% yield). LCMS: rt=3.94 min, [M+H+]=441
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH3:24])#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=2[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(C(=O)OCC)cc1C
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), ethyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (1) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.
Reaction SMILES: Cl.[CH:2]12[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.C(N(CC)CC)C.O.[F:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:20][NH:21][C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:25]=[C:24](S(C)=O)[N:23]=1>C(Cl)Cl>[CH:2]12[CH2:7][CH:6]1[CH2:5][N:4]([C:24]1[N:23]=[C:22]([NH:21][CH2:20][C:19]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:17]([F:16])[CH:18]=3)[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:25]=1)[CH2:3]2
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(F)c1
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc(N2CC3CC3C2)nc1NCc1ccc(OC)c(F)c1
Reaction time: 18 h

Procedure:
In DCM (50 mL) was dissolved the above product ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxylate. To the solution were added 3-azabicyclo[3.1.0]hexan hydrochloride salt (0.8 g, 6.67 mmol) and triethylamine (4 mL, 28.8 mmol). The reaction was conducted at ambient temperature for 18 h, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation to give ethyl 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylate as a faint yellow oil (3.1 g). The product was used in the subsequent procedure without further purification.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:23]([CH2:31][CH2:32]OS(C)(=O)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH:15]=1>CN(C)C=O>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:32][CH2:31][CH:23]([CH:22]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 20.9 %

Procedure:
Potassium phthalimide (0.33 g, 2.2 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide (6 mL) at room temperature under nitrogen. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The layers were separated and the organic phase evaporated to dryness. The residue was chromatographed on silica gel (50% ethyl acetate: cyclohexane) to give the title compound (0.26 g, 21%) as a yellow oil which was a mixture of diastereoisomers. LC/MS: 4.29 min; z/e 687, calcd (M+18) 687. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55-7.20(4H), 6.90-6.75 (4H), 4.55-4.30 (2H), 3.80 (3H), 3.75 (1H), 3.65 (2H), 2.80-2.45 (3H), 2.10-1.50 (4H), 1.40 (9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.N.C1COCC1.C[N:49](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:28])[NH2:49])([CH2:25][CH3:26])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(N)=O
Reaction time: 4 h
Yield: 70 %

Procedure:
At the room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.167 mmol), NH3 in THF (8.5 mg, 0.5 mmol), HATU (100 mg, 0.25 mmol) and DMAP (60 mg, 0.50 mmol) in DMF (3 mL) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (70 mg).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]1([NH:12][C:13](=[O:24])[CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][CH2:14][C:13]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:24])=[S:4]
Reactant: NNC(N)=S
Reactant: O=C(CCC(=O)c1ccccc1)NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCC(=O)NC1CCCCC1)c1ccccc1
Yield: 69.2 %

Procedure:
Thiosemicarbazide (1.75 g, 19.2 mmol) was added to a solution of N-cyclohexyl-4-oxo-4-phenyl-butyramide (3.30 g, 11.7 mmol), prepared in the previous step, in 40 ml of methanol plus 3.2 ml of 1 N HCl plus 3.2 ml of water and the reaction stirred at room temperature for 21 hours. The solid formed was removed by filtration and dried to give 2.69 g of a white solid. The filtrate was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1.10 g of a white foam. The initial solid filtered from the reaction was dissolved in methylene chloride, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a white foam. Both materials were combined and crystallized from methylene chloride-ethyl acetate to give the title compound (3.31 g, 69%) as a white solid, mp 89-92° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCCCCCCCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.498 g, 1.7 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Nonanoyl chloride (1.26 mL, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in 25 mL ethyl acetate and undissolved salts were removed by filtration. After evaporation of the ethyl acetate, the residue was dissolved in methanol and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and chromatographed on a Chromatotron (4 mm silica gel plate) in a mixture of hexane:acetone (80:20). Two separate subsequent runs on the Chromatotron (4 mm silica gel plate) with a mixture of chloroform:acetone (95:5) and a mixture of hexane:acetone (85:15) followed by lyophilization afforded 0.236 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-[(nonanoyloxy)methyl]-tetrahydro-2-furyl)-9H-purine as an oil (32% yield).
Reaction SMILES: CC(C)=[O:3].C1OC1CCCCCCC.[CH2:15]1[O:25][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:15]([OH:25])[CH:16]([OH:3])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCC1CO1
Reactant: CC(C)=O
Agent: CCCCCCCC1CO1
Product: CCCCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to 1 mole of a mixture of 1-nonene oxide and 1-decene oxide at room temperature. After 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and a mixture of 1,2-nonanediol and 1,2-decanediol is obtained by distilling under vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:24]I.[Cl-].[NH4+]>C(OCC)C.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([I:24])=[CH:11][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
A solution of 13.7 g of 5-[(tert-butoxycarbonyl)amino]-2-(isopropoxy)pyridine (54.3 mmol) and 18.1 mL of N,N,N′-tetramethylethylenediamine (120 mmol) in 200 mL of anhydrous diethyl ether was cooled to −78° C. and treated with n-BuLi (2.5 M in hexanes, 48 mL, 120 mmol) under an inert atmosphere. The mixture was placed in a −8° C. bath for 1 hour and allowed to slowly warm to room temperature. After 40 minutes, the flask was cooled to −8° C. and stirred for 4 hours. The mixture was then cooled to −78° C., treated with a solution of iodine (19.0 g, 75 mmol) in 100 mL of anhydrous THF, and the resulting mixture was stirred for 16 hours while allowing the bath to warm to 11° C. The reaction mixture was poured into a rapidly stirring aqueous saturated ammonium chloride solution (200 mL) and diluted with 100 mL of water and 300 mL of diethyl ether. The phases were separated and the aqueous layer was extracted with 200 mL of diethyl ether. The combined organic layers were washed with two 200 mL portions of sodium thiosulfate (10% aqueous solution), dried over sodium sulfate, decanted, and concentrated in vacuo. Chromatography on SiO2 (10% to 50% ethyl acetate in hexanes, gradient) gave the title product as an oil, which solidified on standing (13 g, 63% yield).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[C:5]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH3:24]N(C)CCN(C)C.C([Li])CCC.CCCCCC.CI>C1COCC1>[CH3:16][CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:13][C:5]1[C:6]2[C:7]([CH3:12])([CH3:11])[CH2:8][O:9][C:10]=2[C:2]([CH3:24])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)[Si](Oc1ccc(Br)c2c1C(C)(C)CO2)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c2c1OCC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
[(7-bromo-3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane (Intermediate 25, 7.1 g, 17.72 mmol) was dissolved in anhydrous THF (72 mL) and cooled to 0° C. Tetramethylethylenediamine (8.0 mL, 53.16 mmol) was added and the yellow solution was stirred at 0° C. for 10 min. A solution of 1.6 M butyllithium in hexane (22.5 mL, 35.4 mmol) was added drop wise over 10 minutes and then stirred at 0° C. for 15 min. Methyl iodide (11 mL, 177.2 mmol) was added drop wise over 6 min. The white solid was removed by filtration and the wet cake was washed in with THF. The combined organic layers were evaporated to dryness. The residue was dissolved in ethyl acetate and washed twice with aqueous NaHCO3 and once with water. The organic solution was dried on anhydrous Na2SO4 and evaporated to dryness. to give brown oil. The residue was purified by flash chromatography on silica gel using cyclohexane to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (3.6 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N)cc(Cl)n1
Yield: 81.2 %

Procedure:
A solution of 2,6-dichloropyridin-4-amine 41.6.A (available from Aldrich) (3.10 g, 19.0 mmol) in 20% NaOMe/MeOH (15 mL) was refluxed for 72 hr. The reaction mixture was diluted with H2O (40 mL) and extracted with 30% iPrOH/CHCl3 (3×30 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL) and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution gave title product 41.6.B as white solid (2.45 g, 81.2%).
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].N1C=CC=CC=1.CC1C=CC(S(OCCCCC#C)(=O)=O)=CC=1.[O:42]=[CH:43][C:44]1[CH:52]=[CH:51][C:49](O)=[C:46]([O:47][CH3:48])[CH:45]=1>C(Cl)Cl>[CH2:12]([O:18][C:49]1[CH:51]=[CH:52][C:44]([CH:43]=[O:42])=[CH:45][C:46]=1[O:47][CH3:48])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]
Reactant: C#CCCCCO
Reactant: COc1cc(C=O)ccc1O
Agent: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCCCCOc1ccc(C=O)cc1OC
Yield: 61.5 %

Procedure:
4-Methylbenzenesulfonyl chloride (2.9 g, 15 mmol), 5-hexyn-1-ol (1.1 mL, 10 mmol) and pyridine (1.6 mL, 20 mmol) in CH2Cl2 (10 mL) were treated according to Procedure 4 giving hex-5-ynyl 4-methylbenzenesulfonate (2.1 g, 83%) as a colourless oil. Vanillin (0.84 g, 5.6 mmol) was alkylated with hex-5-ynyl 4-methylbenzenesulfonate (2.1 g, 8.3 mmol) according to Procedure 4 and the crude product was recystallised from EtOAc/petrol to provide 4-(hex-5-ynyloxy)-3-methoxybenzaldehyde (0.80 g, 62%) as a colourless crystalline solid; mp 67-68° C.; δH (400 MHz, CDCl3) 1.74 (p, J=7.0 Hz, 2H, CH2), 1.97 (t, J=2.8 Hz, 1H, C≡CH), 2.02 (p, J=7.0 Hz, 2H, CH2), 2.30 (td, J=7.0, 2.8 Hz, 2H, CH2C≡CH), 3.92 (s, 3H, OCH3), 4.14 (t, J=7.0 Hz, 2H, OCH2), 6.97 (d, J5,6=8.0 Hz, 1H, H5), 7.41 (s, 1H, H2), 7.43 (d, J5,6=8.0 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 18.1, 24.9, 27.9, 56.0, 68.5, 68.8, 83.9, 109.3, 111.4, 126.7, 130.0, 149.9, 154.0, 190.9; vmax 1029, 1269, 1584, 1681, 2956, 3246 cm−1.