Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:2]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2c(C#N)cccc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-Cyanoindole (2.5 g) was dissolved in DMF (7.5 ml). Cs2CO3 (11.46 g) was added followed by ethyl 3-bromopropionate (3.38 ml). This mixture was heated to 80° C. for 40 minutes. A further portion of DMF (5 ml) was added and heating at 80° C. continued for 1 hour. The reaction mixture was evaporated then dissolved in H2O (200 ml) and extracted with EtOAc (200 ml). This was evaporated to give a yellow oil (3.5 g) which was purified on a 40+M Biotage cartridge, eluting with a 25-75% mixture of Et2O in hexane. This gave the title compound (3.44 g) as a pale yellow oil. δH (CDCl3, 400 MHz): 1.19 (3H, t), 2.82 (2H, t), 4.12 (2H, q), 4.50 (2H, t), 6.71 (1H, d), 7.23-7.28 (1H, m), 7.33 (1H, d), 7.47 (1H, d), 7.60 (1H, dd). MS (ES): C14H14N2O2 requires 242; found 243 (MH+).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>O>[Na+:5].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 461.5 %

Procedure:
To a solution of sodium sulfite (14.3 g, 113 mmol) in water (60 mL) was added 4-methylbenzyl chloride (15.0 mL, 1 13 mmol). The mixture was stirred under reflux for 12 hours, and cooled to rt. The precipitate was collected by filtration, and washed with water and ether to give 4-methylphenylmethanesulfonic acid sodium salt (12.5 g, 60 mmol, 53%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH2:13]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.ClCCl>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[CH:24][CH:25]=2)=[N:4][C:3]=1[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1nc(-c2ccc(C(=O)OCc3ccccc3)cc2)cnc1N
Temperature: 85 °C
Yield: 49.7 %

Procedure:
To a stirred mixture of 3-amino-6-bromo-N-methyl-2-pyrazinecarboxamide (0.577 g, 2.5 mmol), 4-benzyloxycarbonylphenylboronic acid (0.768 g, 3.0 mmol), triethylamine (1.01 g, 10 mmol) in 10 mL of DMF was added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1), (20.4 mg, 0.025 mmol). The stirred mixture was warmed to 80-90° C. for 12 h and then concentrated on a rotary evaporator under reduced pressure. The residue was dissolved in 50 mL of EtOAc, washed with brine (30 mL). The organic layer was filtered through celite, and then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica EtOAc) gave a solid (450 mg, 59.7% yield). 1H NMR (400 MHz; DMSO-d6): 8.91 (s, 1H); 8.84 (br s, 1H); 8.33 (d, 2H); 8.02 (d, 2H); 7.30-7.48 (m, 5H); 5.38 (s, 2H); 2.86 (s, 3M); MS (EI) for C20H15N4O3: 363 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C@@H](C3C=CC=CC=3)C)[CH2:14]2)=[CH:9][CH:8]=1)=[O:5].C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[CH3:1][N:2]([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CN(C)C)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of N2,N2-dimethyl-N1-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)glycinamide (0.91 g, 2.5 mmol) and ammonium formate (0.79 g, 12.5 mmol) in mixture of tetrahydrofuran (20 ml), methanol (40 ml) and water (7 ml) was added 10% palladium on carbon (wet, 300 mg) and stirred at 95° C. for 3 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give N2,N2-dimethyl-N1-(4-((2S)-morpholin-2-yl)phenyl)glycinamide (0.63 g, 96%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[S:16]([O-:19])(=O)=[O:17])[CH2:3][CH2:2]1.[Na+].P(Cl)(Cl)([Cl:23])=O>C(#N)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[S:16]([Cl:23])(=[O:19])=[O:17])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)Cl)c1
Temperature: 0 °C

Procedure:
31 g (0.1 mol) of sodium 2-morpholino-5-nitrobenzenesulfonate obtained in Step (a) above and 60 ml (0.67 mol) of phosphorus oxychloride were added to 300 ml of acetonitrile and the mixture was refluxed by heating for 2 hours. After cooling, the reaction mixture was added to 600 ml of ice water. The crystals thus-precipitated were collected by filtration. Yield: 18.5 g (60%).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[CH:13]=[CH:12][C@@H:11]1[O:17]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[OH:16][CH2:15][C@@H:14]1[C@@H:10]([OH:9])[C@@H:11]([OH:17])[CH:12]=[CH:13]1
Reactant: O=C(O[C@@H]1[C@@H](CO)C=C[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1C=C[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a stirred solution of (1R,2S,5R)-5-(hydroxymethyl)cyclopent-3-ene-1,2-diyl dibenzoate (7) (7.5 g, 22.1 mmol) in methanol at room temperature under N2 atmosphere was added drop wise sodium methoxide (25% by wt in methanol) (14.3 mL, 77.66 mmol) over a period of 20 minutes. The mixture was stirred at room temperature for 2 hr and quenched drop wise with 1N HCl solution to the pH neutral. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (5% MeOH/DCM) to give triol 8 (2 g, 71%) as an oil; [α]24D+254.04° (c 1.0, MeOH); 1H NMR (500 MHz, CD3OD) δ 2.78 (d, J=5.0 Hz, 1H), 3.73 (dd, J=5.0, 11.0 Hz, 1H), 3.55 (dd, J=6.5, 10.5 Hz, 1H), 3.93 (t, 1H), 4.50 (t, 1H), 5.88-5.87 (m, 1H), 5.97 (d, J=6.0 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 53.7, 62.2, 73.2, 74.5, 132.0, 135.0; HR-MS Calcd. For (C6H10O3−H)+ 129.0630. found 129.0553.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1
Reactant: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OC)C1c1ccc(C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
A solution of 3-ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate (2 g, 6.05 mmol) in dichloromethane (DCM) (30 ml) was treated with DDQ (1.374 g, 6.05 mmol) and stirred at rt for 1.5 hours. The reaction was filtered through a pad of celite and washed with DCM. The filtrate was diluted with sat. NaHCO3, extracted with DCM, washed with brine, dried with Na2SO4, filtered, and concentrated to afford 3-ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (1.9145 g, 5.83 mmol, 96% yield) as brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (d, J=7.8 Hz, 2 H), 7.08-7.00 (m, 2 H), 6.05 (br. s., 2 H), 3.86 (q, J=7.2 Hz, 2 H), 3.45 (s, 3 H), 2.43 (s, 3 H), 2.37 (s, 3 H), 0.69 (t, J=7.2 Hz, 3 H); LCMS (m/z) ES+=329 (M+1).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li+].CCC[CH2-].C(#N)C.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>C1COCC1.O>[NH2:20][C:19]([C:18]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=1[Cl:16])=[CH:2][C:1]#[N:4]
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: CC(C)NC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C(N)c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
90 g (889.46 mmol) of diisopropylamine are introduced into 1660 ml of THF at −70° C. in a three-necked flask with mechanical stirrer under argon. 124.66 ml of N-butyllithium solution (2.5M in hexane, 758.66 mmol) are added dropwise at a rate such that the temperature does not rise above −60° C. The mixture is stirred for 10 min and then a solution of 32.22 g (784.82 mmol) of acetonitrile in 340 ml of THF is slowly added dropwise, and the suspension is stirred for 30 min. Then a solution of 90 g (523.21 mmol) of 2,4-dichlorobenzonitrile in 340 ml of THF is added dropwise, and the mixture is stirred at −70° C. for 20 min. It is allowed slowly to reach RT and is stirred at RT for a further 16 h. 600 ml of water are added, most of the THF is distilled off, and water and dichloromethane are added. The organic phase is washed with sat. aqueous sodium chloride solution. Removal of the solvent results in dark crystals which are purified by stirring with diethyl ether. 76.5 g (69% of theory) of the product are obtained as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[BH4-].[Na+].Cl>CO.O>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
tert-Butyl 3-oxopyrrolidine-1-carboxylate (3.00 g, 16.20 mmol) was dissolved in dry MeOH (60 mL) and cooled in an ice-water bath. Sodium borohydride (0.61 g, 16.20 mmol) was added carefully and the reaction mixture was stirred at 0° C. for 15 mins. The reaction mixture was diluted with water and pH was set to −9 with HCl (1% aqueous solution). The aqueous layer was extracted with EtOAc and the organic layers were combined, dried with MgSO4, filtered and evaporated to give the title compound (3.00 g, 98.9%). 1H NMR (500 MHz, CDCl3): δ 1.42 (s, 9H), 1.85-1.96 (m, 2H), 3.26-3.33 (m, 2H), 3.38-3.47 (m, 3H), 4.38-4.40 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 28.72, 33.95, 43.99, 54.38, 70.60, 79.57, 155.07.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O.CNN>C(Cl)Cl>[NH2:10][O:9][CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C1CCCN1CCON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: ClCCl
Product: NOCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(2-(2-Oxo-pyrrolidin-1-yl)-ethoxy)-isoindol-1,3-dione (590 mg, 2.15 mmol) and methylhydrazine (119 mg, 2.58 mmol) were mixed in methylene chloride, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel chromatography to give 1-(2-aminooxy-ethyl)-pyrrolidin-2-one (the title compound, 298 mg).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:23][OH:24].CCN(C(C)C)C(C)C>>[OH:24][CH2:23][CH2:22][CH:21]([NH:20][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(CCO)c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CCO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 3-amino-3-phenyl-propan-1-ol and DIEA to give 2-(3-hydroxy-1-phenyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [OH:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(C(C)C)CC)(C)C.[Cl:37][CH2:38][C:39](Cl)=[O:40].C(OCC)(=O)C>O1CCCC1>[Cl:37][CH2:38][C:39]([N:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH:3]1[C:2]([OH:1])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(O)(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)C(C(O)(c2ccccc2)c2ccccc2)C1
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[hydroxy(diphenyl)methyl]-1-piperazine carboxylate (0.50 g, 1.4 mmol) in tetrahydrofuran (5 mL) were sequentially added diisopropylethylamine (2 mL) and chloroacetyl chloride (0.46 g, 4.1 mmol) with ice cooling, and the mixture was stirred for 4 hours while elevating the temperature to room temperature. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (0.28 g, yield 46%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1O
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(F)cc1OCCOC1CCCCO1
Yield: 58.7 %

Procedure:
A mixture of 0.374 g (2 mmole) of 5-fluoro-2-methoxy-4-nitro-phenol, 0.439 g (2.10 mmole) of 2-(2-bromo-ethoxy)-tetrahydro-pyran, 0.828 g (6.0 mmole) of potassium carbonate and 5 mL of dimethylformamide was heated at 80 degrees for 4 hours. The cooled mixture was poured into 50 mL of dilute ammonium chloride solution and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 20:80-30:70) to give 0.370 g of 2-[2-(5-fluoro-2-methoxy-4-nitro-phenoxy)-ethoxy]-tetrahydro-pyran (IV.44) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[C:17]([C:25]#[N:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>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.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([C:25]#[N:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1cc(Br)cc2ccccc12
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C#N)c3ccccc3c2)cc1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 40.4 %

Procedure:
4-Methoxycarbonylphenylboronic acid (0.039 g), 3-bromonaphthalene-1-carbonitrile (0.05 g), tetrakis(triphenylphosphine)palladium (0.012 g) and cesium carbonate (0.11 g) were suspended in a mixed solvent of N,N-dimethylformamide (3 mL) and water (1 mL), and the resulting mixture was stirred at 150° C. for 40 minutes using microwave reactor (Biotage). The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 4-(4-cyanonaphthalene-2-yl)benzoic acid methyl ester (0.025 g).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15](=[O:36])[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15](=[O:36])[CH2:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[O:25])[CH2:22][CH2:23]2)[N:10]=[N:9]1
Reactant: O=C(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCc1cn(Cc2ccccc2)nn1
Reactant: [H][H]
Solvent: CCO
Product: O=C(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCc1c[nH]nn1

Procedure:
3,5-dichlorobenzyl 4-(3-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-3-oxopropyl)piperidine-1-carboxylate (51 mg, 0.096 mmol) was dissolved in ethanol (4 ml). The solution was then submitted to continuous flow hydrogenation using H-cube hydrogenation apparatus, at 70° C. and 30 bar hydrogen pressure. After 90 mins the solution was concentrated and the residue purified using preparative LC-MS. Product fractions were collected, concentrated under reduced pressure, diluted with ethyl acetate, and extracted with water. The organics were separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])(C(C)(C)C)(C)C>ClCCl>[OH:15][CH2:16][C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:59])([OH:60])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)CO)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-(tert-butyldimethylsilyloxy)acetate (Compound 22) (70.0 mg, 87 μmol) in dichloromethane (2 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-hydroxyacetate (HOGly-pdCpA) (Compound 20) (14.0 mg, 23%).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (84 mg, 77%), MS (ISP) m/z=437.3 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3,3,3-trifluoro-propionic acid.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.ClCCl>>[CH2:7]([O:8][CH2:1][CH:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2)[CH2:6][CH3:5]
Reactant: C=C1C(=O)C2CCN1CC2
Solvent: ClCCl
Product: CCCOCC1C(=O)C2CCN1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone (100 mg) in dry dichloromethane (5 ml) propanol (1 equiv., 0.04 ml) was added in presence of molecular sieves (4 Å). The reaction mixture was stirred at RT for overnight. The reaction mixture was filtered and the filtrate was concentrate to get crude product, which was purified (70 mg, 50%) by column chromatography on silica gel using 0.5% methanol in chloroform as eluent.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.ClC1C=C(C2[NH:28][C:29](=[S:39])NC=2C2C=CC(F)=CC=2)C=CN=1>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[NH:28][C:29](=[S:39])[NH:2][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(F)c1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Agent: Cl
Product: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(F)c2)cc1

Procedure:
24b was prepared from 23b (6.1 g; 20 mmol) using the method described in the synthesis of 24a.