Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50](O)=[O:51]>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]#[N:15])([NH:16][C:50]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([CH3:44])[CH:53]=2)=[O:51])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cncc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.485 g, 2.15 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (11 mL) and N-ethyl diisopropylamine (0.44 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.047 g, 2.37 mmol, 1.1 equiv; BOP reagent) 5-methyl-nicotinic acid (0.295 g, 2.15 mmol, 1.0 equiv) and the reaction mixture stirred at 40° C. during a weekend. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.48 g (65%) of the title compound as off-white foam. MS (ISP): 345.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:39]2[CH2:40][CH2:41][CH:36]([CH3:35])[CH:37]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CC1CCNCC1NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (153 mg, 0.69 mmol) in DMF (5 mL) was added HOBt (141 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), tert-butyl 4-methylpiperidin-3-ylcarbamate (150 mg, 0.69 mmol), and DIEA (0.18 mL, 1.3 mmol) at 0° C. Then the reaction mixture was stirred at rt for 5 h, partitioned between EtOAc and water. The organic phase was separated and washed with brine, and concentrated in vacuo to yield the crude product, which was purified by column chromatography using 0-2% MeOH: DCM solvent mixture to yield the titled intermediate (160 mg, 54%) as a thick liquid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 4.65-4.56 (m, 1H), 4.35-4.16 (m, 2H), 3.25-2.89 (m, 2H), 2.85-2.69 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.45 (m, 1H), 1.22 and 1.14 (2s, 9H), 1.05 and 0.95 (2d, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=416.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:10]2=[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:13][N:9]2[CH2:8][CH2:7][NH:6]1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:10]3[N:5]([C:3](=[O:4])[CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[NH:6][CH2:7][CH2:8][N:9]3[N:13]=2)=[CH:15][CH:16]=1
Reactant: O=C(CCl)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reactant: C1COCCN1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CN1CCOCC1)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A mixture of 2-chloroacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (80 mg, 0.215 mmol), morpholine (37 mg, 0.430 mmol), and triethylamine (22 mg, 0.215 mmol) in 1,2-dichloroethane (2 ml) was stirred for 24 hours at ambient temperature. After dilution of dichloromethane, the mixture was washed with an aqueous saturated sodium bicarbonate solution, and brine. The organic phase was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:ethyl acetate ethyl acetate/methanol; 20/1), and the obtained oil was crystallized from diisopropyl ether to give 7-(4-fluorophenyl)-2-morpholinoacetyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (50 mg).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:26])=[C:5]([CH:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]([O:11]C)=[C:7]([CH3:10])[C:8]=1[CH3:9].[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[CH3:26][C:4]1[C:3](=[O:2])[C:8]([CH3:9])=[C:7]([CH3:10])[C:6](=[O:11])[C:5]=1[CH:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC(c1cccnc1)c1c(C)c(OC)c(C)c(C)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccnc1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To a solution of 1.1 g (3.09 mmol) of 1-(3,6-dimethoxy-2,4,5-trimethylphenyl)-1-(3-pyridyl)heptane in 20 ml of acetonitrile-water (1:1), the solution of 4.5 g (8.2 mmol) of cerium ammonium nitrate (CAN) in 15 ml of acetonitrile-water was added dropwise with stirring at 0° C. and stirred for 30 minutes after the completion of addition. The reaction product was isolated by a routine method, to give 635 mg (63%) of 1-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-1-(3-pyridyl)heptane. The physical data are shown in Table 2-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Yield: 66.2 %

Procedure:
A solution of tert-butyl (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate (120 mg, 0.22 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 64 mg (65%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55-1.86 (m, 4 H) 2.01-2.14 (m, 1 H) 2.66-2.85 (m, 2 H) 2.87-3.04 (m, 1 H) 3.32 (dd, J=11.77, 2.35 Hz, 1 H) 4.39 (br. s., 1 H) 6.20 (d, J=5.84 Hz, 1 H) 7.12-7.66 (m, 8 H) 8.47 (s, 1 H), [M+H]+ 439.6.
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1>C(COC)OC>[CH3:14][C:12]1[CH:13]=[C:8]([Sn:3]([CH3:5])([CH3:4])[CH3:2])[CH:9]=[C:10]([CH3:15])[N:11]=1
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: C[Sn](C)(C)Cl
Agent: [Na]
Solvent: COCCOC
Product: Cc1cc([Sn](C)(C)C)cc(C)n1
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
To a mixture of 100 g sodium (30% dispersion in toluene) and 400 ml dimethoxyethane (DME) cooled in an ice-salt bath and under nitrogen was added a solution of 121 g trimethyltin chloride in 50 ml DME over a 2 hour period while keeping the temperature below 5° C. The mixture was stirred at 0°-5° C. for 2.5 hours and then 70 g 4-chloro-2,6-dimethylpyridine in 50 ml DME was added over a 1.5 hour period while keeping the temperature at 0°-10° C. The reaction mixture was stirred at the latter temperature for 1 hour and then allowed to stand at room temperature overnight. The mixture was filtered and concentrated, and the residue treated with ether and again filtered and concentrated. The resulting orange liquid was distilled, collecting the material boiling at 130° C. (20 mm.) to give 80 g 2,6-dimethyl-4-(trimethylstannyl)pyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[N:4][CH:3]=1.O.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)([CH3:16])[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:8]([C:6]1[N:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:12]([CH3:16])([CH3:11])[C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:3]=[N:4][CH:5]=1)#[N:9]
Reactant: CC(C)(C(=O)O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: N#Cc1cncc(Cl)n1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Temperature: 80 °C
Yield: 70.2 %

Procedure:
6-Chloropyrazine-2-carbonitrile (example 20b) (890 mg, 6.4 mmol) was dissolved in DME (24 mL) and water (6 mL) followed by 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (1.86 g, 6.4 mmol) and K2CO3 (1.76 g, 12.7 mmol). The mixture was degassed using an argon stream, Pd(PPh3)4 (369 mg, 0.32 mmol) was added and the mixture was heated (80° C.) overnight. The solvents were removed under reduced pressure and a residue was suspended in 1M aq. NaOH (10 mL) and washed with EtOAc. The aqueous phase was then acidified to pH 4-5 using 6N aq. HCl and extracted with EtOAc (3×60 mL). The organic extracts were combined, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (5% MeOH in DCM) to give 1.2 g (70%) of the pure intermediate 2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid. 1H NMR (400 MHz, dMSO): δ 1.50 (s, 6H), 1.69 (m, 1H), 7.54-7.56 (d, 2H), 8.13-8.15 (d, 2H), 9.17 (s, 1H), 9.56 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=[C:2]([O:1][CH2:23][CH2:22][O:21][CH3:20])[C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 95 %

Procedure:
34 g (148 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of anhydrous DMF. 7.2 g (178 mmol) of 60% sodium hydride are then added portionwise, and the reaction medium is stirred for 1 hour. 16.5 mL (178 mmol) of 2-methoxyethyl chloride are added dropwise, and the medium is stirred at room temperature for 2 hours and then hydrolysed and extracted with ethyl ether. The organic phase is washed with 1N sodium hydroxide solution and then three times with water. The residue obtained is purified by chromatography (eluent: heptane). A yellow oil is obtained (m=42.7 g; yield=95%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][C@@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[CH2:17][CH2:16][C@@:15]3([CH3:23])[C@H:8]4[CH2:9][CH2:10][C@@H:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3α-Hydroxy-5α-pregnan-20-one (5.12 g) in pyridine (40 mL) was treated with toluene-p-sulphonyl chloride (5.6 g) , and the reaction mixture was stirred at room temperature for 18.0 h. This solution was poured into dilute (5%) hydrochloric acid (200 mL) and washed three times with chloroform (150 mL portions). The combined organic phase was extracted with more 5% hydrochloric acid and water, dried over magnesium sulfate and evaporated to an oil which on standing crystallized and gave 3α-toluene-p-sulphonyloxy-5α-pregnan-20-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinic acid (16) (5 g, 23.8 mmol) in methanol (50 ml) was added thionyl chloride in dropwise (5.66 g, 47.62 mmol) at 0° C. and 2 drops of DMF [vigourous bubbling was observed]. The mixture was stirred at room temperature for 3 h. To this methanol was added and stirred the reaction mixture for 2 h at RT. The reaction mixture is concentrated under reduced pressure to and the mixture was poured in to ice cold water (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure to yield methyl 2,6-dichloro-5-fluoronicotinate (17) (5 g, 93.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][Zn+])=[CH:30][CH:29]=1.O1CCCC1>CCOC(C)=O.[Cl-].[NH4+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][C:2]2[CH:3]=[C:4]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Bis(tri-t-butylphosphine)palladium(0) (4.38 mg, 0.00857 mmol) and 4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (0.075 g, 0.17 mmol) were combined in a dry round bottomed flask fitted with a stirbar and sealed with a septum. The flask was evacuated/refilled with nitrogen three times then a solution of 4-chlorobenzylzinc chloride in tetrahydrofuran (0.50M, 0.720 mL, 0.360 mmol) was added dropwise via a syringe. A nitrogen line was attached and the reaction was stirred at rt for 30 minutes, then at 60° C. for ˜2 hours. The reaction was cooled to rt, diluted with EtOAc and saturated ammonium chloride solution, then the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice more with EtOAc. The organics were combined, washed with bicarbonate solution, then brine, then dried over sodium sulfate. The mixture was filtered then evaporated in vacuo and the residue was purified by column chromatography on silica, elution 100% hexane to 100% EtOAc to afford the title compound as a light yellow oil. Yield 63 mg (76% yield). LCMS: (FA) ES+, 483, 485.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6](CC2C=CC(OC)=CC=2)[C:5]([C:18](=[O:32])[CH:19]([C:25]2(O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([CH3:33])[CH:3]=1.FC(F)(F)C(O)=O>ClCCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:5](=[C:4]([CH3:33])[CH:3]=1)[C:18](=[O:32])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]12[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C(=O)c1c(C)cc(Br)c(=O)n1Cc1ccc(OC)cc1)C1(O)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)C1C(=O)c2c(C)cc(Br)c(=O)n2C12CCCCC2

Procedure:
To a solution of ethyl 3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-(1-hydroxycyclohexyl)-3-oxopropanoate (5, 1.0 mmol, 1.0 eq) in 1,2-dichloroethane (15 mL), add trifluoroacetic acid (10 mmol, 10 eq) and heat the reaction at 60° C. for 16 h. After completion, remove the solvent and quench the reaction with ammonia and extract with dichloromethane. Remove the solvent under reduced pressure and purify the crude using silica gel column chromatography to afford ethyl 6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate (6).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[CH:34]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:35]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH:34]=[CH2:35])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[CH3:14])=[CH:5]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Agent: [Pd+2]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Temperature: 25 °C

Procedure:
To a stirred mixture of (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (2.58 g, 5.4 mmol, 1 eq), Pd(OAc)2 (363 mg, 1.62 mmol, 0.3 eq) and PPh3 (846 mg, 3.24 mol, 0.6 eq) in THF (50 mL) at RT, tributyl(vinyl)tin (1.97 g, 5.94 mmol, 1.1 eq) was added and the resulting mixture was stirred at reflux overnight. The mixture was allowed to cool to RT and filtered through silica gel (10 g). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[CH2:19][CH:20]=[CH2:21].CC1(C)N([O])C(C)(C)CCC1.F[B-](F)(F)F.CC#N.[OH2:44]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:44])[CH2:7][O:6]1)=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Reactant: O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reaction time: 2 h

Procedure:
A solution of the ester (0.21 g, 0.63 mmol, prepared as described in Step A), in 10 ml of CH3CN--H2O(9:1, v/v) was added dropwise to a stirred solution of TEMPO-BF4 in 10 ml CH3CN--H2O (9:1, v/v). Stirring was continued for 2 h and the reaction mixture was concentrated in vacuo. The residue was partitioned between Et2O and H2O. The organic phase was washed with brine and dried (Na2 SO4). Removal of solvent provides a yellow oil which was purified by flash chromatography (silica gel, hexane-EtOAc 2:1) to give 0.18 g of product as an off white solid.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].[SH:10][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17](=[O:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:19]([CH2:18][C:17]([NH:16][C@H:12]1[C@@H:11]([S:10][CH2:2][C:3]([CH:5]2[CH2:9][CH2:8][CH2:7][O:6]2)=[O:4])[NH:14][C:13]1=[O:15])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1S
Reactant: O=C(CCl)C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)C1CCCO1
Yield: 59 %

Procedure:
(RS)-2-Chloroacetyltetrahydrofuran (2.46 g, 16.5 mmol), (3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-one (4.157 g, 16.5 mmol) and potassium carbonate (2.227 g 16.5 mmol) in DMF (10 ml) were stirred for 2 h, diluted with ethyl acetate, washed twice with water and with brine, dried concentrated and flash chromatographed eluting with 40, 30, 20, 10 and 0% hexane in ethyl acetate to give the title compound as a foam (3.547 g, 59%); νmax (CH2Cl2) 3405, 1785, 1693, 1520, 1496 and 1240 cm-1 ; δ(CDCl3, 250 MHz) 1.9-2.3 (4 H, m), 3.42 and 3.62, 3.46 and 3.56 (together 2 H, 2 ABq, J15.8 Hz, 15.4 Hz), 3.85-4.0 (2 H, m), 4.4-4.5 (1 H, m), 4.58 (2 H, s), 5.01, 5.04 (together 1 H, 2 d, J4.7 Hz), 5.59 (1 H, dd, J 8.8, 4.5 Hz) 6.62, 6.68 (together 1 H, 2 s), 6.9-7.4 (5 H, m) and 7.45, 7.47 (together 1 H, 2 d, J8.8 Hz). [Mass spectrum: M+ (364)].
Reaction SMILES: Cl.[CH2:2]=[C:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.O.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]1([S:19][CH2:2][CH:3]2[C:8](=[O:9])[CH:7]3[CH2:10][CH2:11][N:4]2[CH2:5][CH2:6]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: C=C1C(=O)C2CCN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: O=C1C2CCN(CC2)C1CSc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone hydrochloride (1 g, 0.0057 mol) in water (10 ml) triethylamine (1.73 g, 0.0171 mol), tetra-n-butyl ammonium bromide (180 mg, 0.00057 mol) and thiophenol (0.63 g, 0.0057 mol) were added and the reaction mixture was allowed to stir at 80° C. for 18 h. The completion of reaction was monitored by tlc. The reaction mixture was quenched with ice-cold water (20 ml), extracted with dichloromethane (4×50 ml), organic layers were washed with brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified (550 mg) by column chromatography on silica gel using chloroform as eluent.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[NH2:21][CH2:22][CH2:23][P:24](=[O:27])([O-:26])[O-:25].[OH-].[Na+]>C(O)C.O>[P:24]([CH2:23][CH2:22][NH:21][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6])([OH:27])([OH:26])=[O:25]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncnc2c1nc(NCCP(=O)(O)O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 110 °C

Procedure:
A mixture of 8-bromoadenosine (1 mmol), aminoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at 110° C. under nitrogen. After 24 h the cooled reaction mixture was purified through preparative HPLC to give 8-(2-phosphonoethylamino)-adenosine (4.1). mp 175° C.;