Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: C=CCOC(=O)Cl
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Solvent: c1ccncc1
Product: C=CCOC(=O)OC1CCN(CCC)C(=O)N1c1nnc(SC)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and allyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-allyloxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]=O.O>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:14][C:10]1[S:9][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1nccs1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CNCc2nccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A stirred solution of N-benzylamine (0.56 mL, 5.1 mmol) and 2-thiazolecarboxaldehyde (0.55 g, 4.9 mmol) in toluene was heated to reflux for 2 hours with azeotropic removal of water. The solution was cooled to room temperature and concentrated to an oil. This oil was dissolved in 15 mL of ethanol and treated with excess NaBH4 and the mixture stirred overnight. Acetone was added and the mixture stirred 30 minutes and concentrated to a soild mass. This mass was partitioned between 2N aqueous NaOH and 2 portions of ethyl ether. The combined ethereal extracts were washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide 0.59 g (57%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 0.24 ml of triethylamine and 0.12 ml of methanesulfonyl chloride were added and the mixture was stirred overnight at room temperature. Next, 0.24 ml of triethylamine and 0.12 ml of methanesulfonyl chloride were added to the reaction solution and stirring was continued at room temperature for 2 hours. The reaction solution was filtered with silica gel and NH silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (447 mg, 90% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][C@H:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][C:26](=[C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[C:30]1([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:12]([C@@H:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:28][CH2:27]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)[C@@H]1CSC(c2cccnc2)N1
Reactant: NCCCCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Product: O=C(NCCCCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)[C@@H]1CSC(c2cccnc2)N1
Yield: 46 %

Procedure:
The title compound was prepared in a yield of 46% in a similar manner to that described in Example 17' by reacting 2-(3-pyridyl) thiazolidine-4(R)-carboxylic acid and 1-(7-aminoheptyl)-4-(diphenylmethylen) piperidine (prepared as described in Preparation 43').
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1)(=O)C.[Li+].[OH-].C1COCC1>CO>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1
Reactant: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)c3ccc(S(=O)(=O)C(C)C)cc3)CC1)c1ccc(C#N)n1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2c(C#N)ccc23)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
(1-Cyano-1′-(4-(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methyl acetate (16.2 mg, 0.0297 mmol) was treated with 1M LiOH (1 mL), THF (5 mL) and MeOH (1 mL). The mixture was stirred at room temperature over night. The volatiles were removed and the residue was neutralized with 1N HCl. The mixture was extracted with CH2Cl2 (2×). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7′-(hydroxymethyl)-1-(4-isopropylsulfonylbenzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (11.3 mg, 75%). ESI-MS m/z calc. 505.58. found 506.5 (M+1)+; Retention time 1.49 minutes (3 min run). NMR (400 MHz, DMSO) δ 7.93 (dd, J=8.2, 6.5 Hz, 3H), 7.73 (d, J=8.3 Hz, 2H), 7.32 (d, J=4.0 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.45 (d, J=4.1 Hz, 1H), 5.39-5.30 (m, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H), 2.20-2.12 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t, J=5.9 Hz, 1H), 1.57 (dd, J=12.5, 6.2 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O>C1COCC1>[OH:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:24](=[O:23])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1

Procedure:
(S)-3-Amino-4-(4-(trifluoromethyl)phenyl)butan-1-ol was dissolved in 5 mL THF and 4 mL K2CO3 (1M, aq.) and BOC2O were added. The reaction was stirred over night and acidified (about pH 2). The reaction was extracted with EtOAc (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as a white solid and used without further purification. LCMS (API-ES) m/z (%): 333.1 (100%, M++H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[Cl:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(F)cc2Cl)c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
In a pressure-vessel, a stirring mixture of 2-bromo-4-tert-butylbenzoic acid (1.00 g, 3.89 mmol) and 2-chloro-4-fluorophenol (860 mg, 620 μL, 5.87 mmol) in toluene (20 mL) was added Cs2CO3 (2.53 g, 7.78 mmol) followed by copper(I) triflate benzene complex (98 mg, 0.19 mmol). The sealed vessel was heated to 120° C. for 16 h. After cooling to room temperature, the reaction mixture was partitioned between 50 mL EtOAc and 50 mL H2O. The aqueous layer was acidified using 2.0 N HCl(aq) and re-extracted with EtOAc. The combined organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-3% MeOH/CH2Cl2 to give the product, 4-tert-butyl-2-(2-chloro-4-fluorophenoxy)benzoic acid as a white solid (907 mg, 2.81 mmol) in 72% yield. LC/MS: m/z 323.2 (M+H) at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH:12]1([C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH2:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[CH:12]1([C:15]([CH:17]2[CH2:19][CH2:18]2)([OH:16])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:14][CH2:13]1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(C1CC1)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(O)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsilylacetylene (5 mL, 35.4 mmol) in THF (100 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (22.1 mL, 35.4 mmol) was added dropwise. The solution was stirred for 30 min before dicyclopropyl ketone (4.06 mL, 35.4 mmol) was added. The temperature was then slowly raised to room temperature and the reaction was stirred overnight. The reaction was then poured into a saturated ammonium chloride solution and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 4.14 (s, 1H), 1.22-1.10 (m, 2H), 0.65-0.55 (m, 2H), 0.50-0.30 (m, 6H), 0.14 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][NH:32][CH2:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([N:32]([CH3:31])[C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added N-methylethanamine (0.025 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (18 mg, 17% yield). m.p.=91.9° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.07 Hz, 3 H) 1.24 (br. s., 3 H) 1.85-2.04 (m, 3 H) 2.13-2.21 (m, 1 H) 2.43-2.48 (m, 3 H) 2.90 (s, 3 H) 3.14-3.22 (m, 4 H) 3.34-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.02 (m, 1 H) 6.92 (d, J=8.84 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.25 (d, J=8.59 Hz, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: CC1C=C(C)NC(=O)C=1C[NH:11][C:12](=[O:33])[C:13]1[CH:18]=[C:17](N2CCCCC2)[N:16]=[C:15](C2C=CC(C=O)=CC=2)[CH:14]=1.CNC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:12]([NH2:11])(=[O:33])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 314.8 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-formylphenyl)-6-(piperidin-1-yl)isonicotinamide (0.2 g, 0.45 mmol) in methanol (12 mL), dimethyl amine (2.6 mL, 4.5 mmol, 2M solution in THF) and acetic acid (0.02 g, 0.45 mmol) were added and reaction mass stirred at rt for 90 min. Then reaction mass was cooled to 0° C. and sodium cyanoborohydride (0.056 g, 0.9 mmol) was added. Reaction stirred at 0° C. for 2 h and then stirred at rt for overnight. On completion, solvent was removed under reduced pressure, residue treated with water and extracted with ethyl acetate. Combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel obtaining N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((dimethylamino)methyl)phenyl)-6-piperidin-1-yl)isonicotinamide as light green solid (0.173 g, 79%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[CH:17][C:10]=23)O1.Br[C:39]1[CH:40]=[C:41]([C:45]([CH3:50])([CH2:48][CH3:49])[C:46]#[N:47])[CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:50][C:45]([C:41]1[CH:40]=[CH:39][CH:44]=[C:43]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:16]=[CH:17][C:10]=23)[CH:42]=1)([CH2:48][CH3:49])[C:46]#[N:47]
Reactant: CCC(C)(C#N)c1cccc(Br)c1
Reactant: CC1(C)OB(c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
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: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)(C#N)c1cccc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine (307 mg, 0.630 mmol), 2-(3-bromophenyl)-2-methylbutanenitrile (150 mg, 0.630 mmol) and 2 M aqueous solution of sodium carbonate (0.945 ml, 1.89 mmol) in dioxane (4 ml) was degassed by vacuum/nitrogen cycles (×5). Bis(tri-tert-butylphosphine)palladium(0) (16.10 mg, 0.032 mmol) was added and the resultant mixture was degassed by vacuum/nitrogen cycles (×5) and stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a sticky white solid (0.240 mg, 80% purity, 59% yield).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4])[NH2:2].C(N(CC)CC)C.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1>[CH3:12][O:11]/[N:10]=[C:8]1\[CH2:9][C@@H:5]([C:3]2[O:4][C:27](=[O:28])[NH:2][N:1]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]\1
Reactant: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO/N=C1\C[C@@H](c2n[nH]c(=O)o2)N(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (Intermediate 9, 1.84 mmoles; 500 mg) and triethylamine (2.76 mmoles; 27 mg) in THF (25 mL) at 0° C. was added 1,1′-carbonyldiimidazole (2.76 mmoles, 448 mg). The stirring was continued for 5 hours. Another portion of triethylamine and 1,1′-carbonyldiimidazole were added and stirring was continued at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and washed with NH4Clsat., and 10% NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated to dryness to give the desired N-protected intermediate, tert-butyl (2S,4E)-4-(methoxyimino)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate, as a white foam (460 mg, 84%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9](=[O:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH3:20])[CH3:7]>>[CH2:6]([O:8][C:9](=[O:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][C:13]=1[CH2:18][CH2:19][CH3:20])[CH3:7]
Reactant: CCCc1ccccc1OCC(=O)OCC
Reactant: O=S(=O)(O)Cl
Product: CCCc1cc(S(=O)(=O)Cl)ccc1OCC(=O)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Chlorosulfonic acid (36.59 mL, 550.5 mmol) was cooled to 0° C. under argon atmosphere. The cooled chlorosulfonic acid was added dropwise to compound 4.2 (24.5 g, 110.1 mmol) using a dropping funnel. The reaction was stirred at 0° C. for 30 min. and at room temperature for 4 h. The reaction mixture was poured into ice-water and stirred slowly at 0° C. for 20 min. The precipitated crystals were collected and dried in vacuo using oven at 40° C. to give 4.3 (30.8 g) as pale-yellow crystals. 1H NMR (300 MHz) (CDCl3) δ 7.90-7.79 (2H, m); 6.81 (1H, d, J=8.4 Hz); 4.75 (2H, s); 4.28 (2H, q, J=7.1 Hz); 2.79-2.67 (2H, m); 1.77-1.60 (2H, m); 1.30 (3H, t, J=7.1 Hz); 0.97 (3H, t, J=7.3 Hz).
Reaction SMILES: OC1CCNCC1.[NH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C([O:30][C@@H:31]1[C@H:35]([O:36]C(=O)C2C=CC=CC=2)[C@@H:34]([CH2:45][O:46]C(=O)C2C=CC=CC=2)[O:33][C@H:32]1[N:55]1[CH:63]=[N:62][C:61]2[C:56]1=[N:57][C:58]([Cl:65])=[N:59][C:60]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:65][C:58]1[N:59]=[C:60]([NH:8][N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[C:61]2[N:62]=[CH:63][N:55]([C:56]=2[N:57]=1)[C@@H:32]1[O:33][C@H:34]([CH2:45][OH:46])[C@@H:35]([OH:36])[C@H:31]1[OH:30]
Reactant: NN1CCC(Oc2ccccc2)CC1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Agent: OC1CCNCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Oc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 56.1 %

Procedure:
This compound was prepared from 4-hydroxypiperidine using the methodology described in Example 16. 1-Amino-4-phenoxypiperidine (0.96 g, 5.0 mmol) was reacted with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 4 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenoxy-1-piperidinyl)adenosine 1.07 g, 57%) as a foam, 1H NMR (DMSO-d6) δ3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.43-4.54 (2H, m, H-2' and --C--H), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 6.90-7.33 (5H, 2m, Ar-H), 8.42 (1H, s, H-8), 9.49 (1H, s, N-H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([OH:30])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1.S(Cl)(Cl)=O.[CH3:36]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([O:30][CH3:36])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1
Reactant: O=C(O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reaction time: 8 h
Yield: 23 %

Procedure:
A 100-mL of flask was charged with 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1.02 g, 2.4 mmol) dissolved in MeOH (15 mL). Then thionyl chloride (418 mg, 3.5 mmol) was added dropwise slowly at 0° C. under N2 protection. The mixture was stirred overnight under reflux. The mixture was concentrated to give the crude product, which was purified by chromatography to give the pure product (230 mg, 23%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[Br:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Brc1ccncc1-c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(-c3cnccc3Br)cc12
Temperature: 25 °C

Procedure:
In a 100-ml round-bottom flask is placed 2.8 mL of dimethylformamide (2.74 g, 3.74 mmol). The flask and the content was cooled in an ice-salt bath for about 0.5 hour and 0.86 mL (1.44 g, 94 mmol) of freshly distilled phosphorusoxychloride is subsequently added with stirring to the dimethylformamide dropwise. Then a solution of 2 (1.00 g, 3.66 mmol) in 1 mL of dimethylformamide is added to the above solution slowly. After the addition, the temperature of the solution is brought to 40° C. and allowed to stir for an hour. At this time, 1 N NaOH (10 mL) was added to the reaction mixture dropwise. The resulting mixture is heated rapidly to the boiling point and allowed to cool to room temperature. The resulting precipitate is collected on a filter and the solid was further washed with water. Compound 3 obtained from this procedure was pure enough for the next reaction.
Reaction SMILES: C(O[C:4](=[O:16])[CH:5]([N:11]=[CH:12][N:13](C)C)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:17]N>C(O)C>[CH2:9]([O:8][C:6]([CH:5]1[C:4](=[O:16])[NH:17][N:13]=[CH:12][NH:11]1)=[O:7])[CH3:10]
Reactant: NN
Reactant: CCOC(=O)C(N=CN(C)C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1NC=NNC1=O
Temperature: 60 °C
Yield: 44.9 %

Procedure:
2-(Dimethylamino-methyleneamino)-malonic acid diethyl ester (1 g, 4.34 mmol) was dissolved in ethanol (6.5 ml) and the mixture was heated to 60° C. Hydrazine (1M solution in THF, 5.5 ml, 5.52 mmol) was added dropwise during a period of 30 min and the mixture was heated to reflux for another 30 min. The reaction mixture was then cooled to 0° C. for 1 h and the precipitate that formed was filtered off. The filtrate was evaporated and ethyl acetate/methanol 4:1 (16 ml) was added to the oily residue. The suspension that formed was again filtered and the filtrate was evaporated. The remaining residue was triturated with ethyl acetate (9 ml) and the light brown solid was filtered off. The filtrate was again evaporated, the remaining solid triturated with a small amount of ethyl acetate and the resulting light brown solid was filtered off and combined with the first batch to give the title compound (333 mg, 1.95 mmol, 45%). MS: m/e=172.1 [M+H+].