Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[N:1]1[C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]=2[C:10]1=[O:15]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(O)cc1F
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(O)cc1F

Procedure:
The filtrate from Step A was mixed with 9.74 g (0.0640 mole) of 3,4,5,6-tetrahydrophthalic anhydride, and the mixture was heated at reflux for approximately 64 hours. At the end of this period, the dark brown solution was poured over ice and extracted in succession with ethyl acetate and diethyl ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and filtered. The sol-vents were evaporated under reduced pressure from the filtrate, leaving a dark brown oil as residue. This was placed on a silica gel column and eluted with methylene chloride/ethyl acetate (95/5). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 14.71 g of N-(2-fluoro-4-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide was recovered as an orange solid, m.p. 132°-136° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:13]O)[CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[Cl:16][CH2:17][C:18]([OH:20])=[O:19].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[Cl:16][CH2:17][C:18]([O:20][CH:3]([N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])[C:2]([CH3:15])([CH3:13])[CH3:1])=[O:19]
Reactant: CC1=C(C)C(=O)N(CC(C)(C)CO)C1=O
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(C(OC(=O)CCl)C(C)(C)C)C1=O
Yield: 84.1 %

Procedure:
A mixture of 105.6 g (0.5 mole) of N-(2,2-dimethyl-3-hydroxypropyl)dimethylmaleimide, 56.7 g (0.6 mole) of chloroacetic acid, 5.9 g of concentrated sulfuric acid and 400 ml of toluene are heated as described in Example 1 until the formation of water (9 ml) has ceased. The reaction solution is worked up as in Example 1, affording 121 g of a colourless liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([OH:11])=O)[CH2:6][CH2:5]1.C(Cl)(=O)[C:13]([Cl:15])=O>ClCCl.CN(C)C=O>[Cl:15][CH2:13][C:9]([CH:7]1[CH2:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8]1)=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCC1CCC(C(=O)O)O1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC1CCC(C(=O)CCl)O1
Temperature: 0 °C

Procedure:
A solution of (2RS,5SR)-5-methoxymethyltetrahydrofuran-2-carboxylic acid (3.1g) in dichloromethane (50ml) was treated with oxalyl chloride (2.68ml) and dimethylformamide (1 drop). The mixture was stirred for 1h and heated to reflux for 10 mins. The solvent was evaporated and then dichloromethane was evaporated from the residue twice. The product was dissolved in dichloromethane (100ml) and the solution cooled in an ice bath. Diazomethane was then passed into the solution as described in Example 14(a). When the addition was complete the mixture was stirred at 0° C. for 0.5h and then hydrogen chloride gas was passed into the solution until all the diazoketone had been consumed. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.44g) was isolated by column chromatography using gradient elution (silica gel, 4:1 going to 1:1 hexane : ethyl acetate); vmax (film) 1740cm-1 ; δH (CDCl3) 1.6-2.35 (4H,m), 3.30-3.75 (2H,m), 3.37 (3H,s) and 4.05-4.75 (4H,m).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][NH:13][CH3:14]>O>[CH3:12][N:13]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])[CH3:14]
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CNC
Solvent: O
Product: CN(C)CC(=O)Nc1ccccc1
Yield: 97 %

Procedure:
A mixture of chloroacetanilide (10.0 g, 59 mmol) in dimethylamine, 40% wt in water (100 ml) was refluxed for 4 hours. The cooled reaction mixture was partitioned between dichloromethane (100 ml) and 1M NaOH aqueous solution (100 ml). The aqueous layer was extracted twice more with dichloromethane (2×100 ml), the combined organic layers were concentrated in vacuo to a volume of approximately 100 ml and washed with water (2×100 ml) in order to remove the remaining dimethylamine. The organic layer was collected, dried over sodium sulfate and the solvent evaporated in vacuo to provide 10.2 g (97% yield) of the pure dimethylaminoacetanilide. 1H NMR (CDCl3, 200 MHz) δ: 9.1 (br. s, NH, 1H), 7.6-7.0 (m, Ar, 5H) 3.1 (s, CH2, 2H), 2.4 (s CH3, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.[NH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O>>[NH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([O:11][CH2:4][CH2:3][O:2][CH3:1])=[O:10]
Reactant: COCCO
Reactant: NC(CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COCCOC(=O)CC(N)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 6.00 mL (76.3 mmol) of 2-methoxyethanol were added 2.00 g (12.1 mmol) of 3-amino-3-phenylpropionic acid (racemic mixture) synthesized in Reference example 1 and 1.78 g (18.2 mmol) of conc. sulfuric acid, and the mixture was reacted under stirring at 60° C. for 4 hours. After completion of the reaction, the resulting reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the reaction mixture to adjust a pH thereof to 8.5. Then, 10 mL of ethyl acetate and 4 mL of water were added to the mixture to carry out extraction, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.22 g (Isolation yield based on 3-amino-3-phenylpropionic acid (racemic mixture): 82.2%) of 2-methoxyethyl 3-amino-3-phenylpropionate (racemic mixture) as colorless liquid.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][OH:8])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2].[CH2:20](Cl)Cl>B(F)(F)F.CCOCC>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][O:8][CH3:20])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CO
Reactant: ClCCl
Agent: FB(F)F
Solvent: CCOCC
Product: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1COC

Procedure:
To (±)-cis-3-Ethyl-4-hydroxymethyl-N-toluensulfonyl-2-azetidinone (18 mg) in CH2Cl2 at 0° to 5° C. was added boron trifluoride etherate solution (1 drop) and then diazomethane-ether solution dropwise (4 ml). The reaction mixture was purified by preparative TLC on a silica gel plate (1500μ) and developed with CH2Cl2 to afford the titled compound. NMR(CDCl3): δ1.04(3H, t), 1.54-1.92(2H, m) 2.45(3H, s), 3.16(1H, m), 3.26(3H, s), 3.70(2H, m ), 4.18(1H, m), 7.34(2H, d), 7.88(2H, d).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(N)cc2ccoc12
Yield: 99.7 %

Procedure:
A mixture of 2,2,2trifluoro-N-(7-methyl-benzofuran-5-yl)-acetamide (580 mg) and potassium carbonate (1.64 g) in methanol (25 ml) and water (2.5 ml) was heated at reflux for 2.5 hours. The residue was extracted with dichloromethane (3×25 ml) and the combined, dried (MgSO4) organic phase was evaporated in vacuo to give the title compound as a colourless oil (350 mg).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:10]([F:20])[CH:9]=1)[CH2:4][CH3:5])[CH3:2].Br[CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:27]([NH:26][C:24]([CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:21])=[CH:9][C:10]=2[F:20])[CH2:15][CH2:16]1)=[O:25])[CH3:28]
Reactant: CCNC(=O)C(Br)c1ccccc1
Reactant: CCC(CC)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(C(=O)NC(CC)CC)cc2F)CC1
Reaction time: 16 h
Yield: 33 %

Procedure:
A mixture of N-(1-ethyl-propyl)-3-fluoro-4-piperazin-1-yl-benzamide (12 mg, 0.04 mmol), 2-bromo-N-ethyl-2-phenyl-acetamide (12 mg, 0.05 mmol), and K2CO3 (8 mg, 0.05 mmol) in DMF (2 mL) was stirred for 16 h. The mixture was poured into water and extracted with DCM. The organic layer was dried (MgSO4) and purified by PTLC to give a white solid (6 mg, 34%). MS (ESI): mass calcd. for C26H35FN4O2, 454.58. m/z found, 455.5 [M+H]+. 1H NMR (CDCl3): 7.47-7.42 (m, 2H), 7.34-7.30 (m, 5H), 7.05-7.02 (m, 1H), 6.90 (t, J=8.4, 1H), 5.67 (d, J=8.9, 1H), 3.99-3.94 (m, 1H), 3.89 (s, 1H), 3.37-3.31 (m, 2H), 3.19-3.17 (m, 4H), 2.64-2.55 (m, 4H), 1.66-1.59 (m, 5H), 1.49-1.42 (m, 2H), 1.16 (t, J=7.2, 3H), 0.93 (t, J=7.4, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL), added with anhydrous trifluoromethane sulfonic acid (0.758 ml, 3 eq.), and stirred at room temperature for 30 minutes. The reaction solution was poured into water and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 641 mg, 81%).
Reaction SMILES: [Br:1]Br.[CH:3]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:12]=2)=[CH:9][N:8]=[C:7]1[CH3:28])([CH3:5])[CH3:4]>C(O)(=O)C>[Br:1][C:16]1[C:11]([C:10]2[N:6]([CH:3]([CH3:5])[CH3:4])[C:7]([CH3:28])=[N:8][CH:9]=2)=[N:12][C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)n1C(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ncc(-c2nc(Nc3ccc(S(C)(=O)=O)cc3)ncc2Br)n1C(C)C
Temperature: 60 °C
Yield: 111 %

Procedure:
Bromine (50 μl, 0.94 mmol) was added to a solution of 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-mesylanilino)pyrimidine (Example 69; 350 mg, 0.94 mmol) in glacial acetic acid (3.5 ml). The mixture was heated at 60° C. for 140 minutes and the volatiles were then removed by evaporation. The residue was azeotroped with water to give a gum, which was then triturated with EtOAc to give a solid (470 mg). This crude product was purified by chromatography on silica gel eluting with DCM/MeOH (98:2 increasing in polarity to 95:5). The purified product was triturated with EtOAc to give the title compound (125 mg, 30%) as a solid. NMR: 1.39 (d, 6H), 2.48 (s, 3H), 3.12 (s, 3H), 4.68 (sept, 1H), 7.20 (s, 1H), 7.81 (d, 2H), 7.92 (d, 2H), 8.79 (s, 1H), 10.28 (br s, 1H); m/z 450.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[S:4].[Cl:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:19][CH2:18][Cl:17])=[CH:12][CH:11]=1)=[S:4]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: CNC(=S)N1CCSC1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)N1CCSC1c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.4 %

Procedure:
A mixture of 5 g of N-methyl-2-(4-hydroxyphenyl)thiazolidine-3-carbothioamide, 4.6 g of 1-chloro-2-tosyloxyethane, 4 g of potassium carbonate and 20 ml of dimethylformamide is stirred at room temperature for 2 days and further stirred at 50° C. for 20 hours. The mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous 10% sodium hydroxide solution and water, and dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:chloroform=2:8), and the resultant product is recrystallized from ethanol. 3.07 g of N-methyl-2-[4-(2-chloroethyloxy)phenyl]thiazolidine-3-carbothioamide are obtained. Yield: 51.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])#[N:17].C(N(CC)CC)C>CC(C)=O>[C:16]([CH:18]([CH2:22][CH3:23])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20])#[N:17]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CCC(C#N)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(C#N)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 15.8 g (0.12 mole) of 2-cyanobutyryl chloride and 10.1 g (0.1 mole) of triethylamine in 200 ml of absolute acetone for 3 hours at room temperature. 100 g of ice were added, after which the crystals were filtered off under suction, and the product was recrystallized from dimethylformamide/water and dried at 50° C. under greatly reduced pressure. 14.9 g (50%) of 6-[p-(2-cyanobutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 225°-227° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([S:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1.ClCCl.P(Br)(Br)[Br:25]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][Br:25])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([S:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CSc1nc(-c2ccc(F)cc2)c(CO)c(C(C)C)n1
Solvent: ClCCl
Solvent: O
Product: CSc1nc(-c2ccc(F)cc2)c(CBr)c(C(C)C)n1
Yield: 90.1 %

Procedure:
14.6 g (50 mmol) of compound (9) and 200 ml of dichloromethane were added into a 500 mL three-neck round bottomed flask, equipped with a mechanical stirrer and a dropping funnel, followed by addition of 67 g (0.1 mol) of phosphorus tribromide dropwise at room temperature. After TLC assay showed that the starting compound (9) was depleted, 100 mL of water was added, and the organic layer was collected. The organic phase was then washed with 5% aqueous NaHCO3 solution, dried over anhydrous calcium chloride, and evaporated under reduced pressure to remove the solvent, obtaining 16 g raw product of compound (7), which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH:15]([CH3:17])[O:14][CH:13]([CH3:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:20]=[C:21](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:18][CH:13]1[O:14][CH:15]([CH3:17])[CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:21](=[O:20])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1CN(c2ccc(N)c(C(=O)O)c2)CC(C)O1
Solvent: O
Solvent: C1COCCO1
Product: CC1CN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC(C)O1

Procedure:
To the mixture of 8.9 g of 2-amino-5-(2,6-dimethylmorpholin-4-yl)benzoic acid in 60 ml of dioxane, under stirring and external cold water cooling 10 ml of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 ml of ether. The product is stirred for 5 minutes in the mixture of 50 ml of methanol and 5 ml of triethylamine, then filtered off and washed with 30 ml of methanol. After drying 7 g of the title product is obtained (MH+: 277).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CO.[C].[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[NH:3][CH:2]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH3:11]
Reactant: COC(=O)c1c(Cl)[nH]c(-c2ccccc2F)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c[nH]c(-c2ccccc2F)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
To a solution of methyl 2-chloro-5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate (10.2 g) in methanol (200 mL) was added 10% palladium carbon (50% containing water, 1.28 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 20 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound as white crystals (yield 6.70 g, 76%).
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:38][OH:39].C[O-].[Na+]>C(O)(=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:39][CH3:38])[N:21]=1
Reactant: CO
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98 %

Procedure:
To a 250 mL dry round-bottomed flask was charged (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (6a, 7.50 g, 14.26 mmol) Anhydrous methanol (30 mL) was added and a white suspension was formed. At 50° C., a solution of sodium methoxide in methanol (25%, 19.7 mL, 64.17 mmol) was added via a dry syringe under a nitrogen atmosphere. A white cloudy reaction mixture was formed. After 3.5 h at 50° C., the reaction was complete with no starting material left as shown by TLC test. The mixture was cooled down to room temperature and neutralized by addition of glacial acetic acid (3 mL). A white solid was filtered out and washed with methanol (3×5 mL). The filtrate was mixed with 20 g of silica gel and concentrated to dryness. The mixture was loaded in line with a silica gel cartridge and separated via column chromatography using a gradient of methanol in dichloromethane 0 to 15% MeOH. The product eluted out at 12% methanol in dichloromethane. The product containing fractions were combined, concentrated under reduced pressure and dried under vacuum (0.2 mmHg, 50° C., 24 h) to a white powder solid (4.45 g, 98% yield), mp 199-202° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36](O)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36]([NH:20][CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(CC1CCCC1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 19 from α-cyclopentylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:30])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reaction time: 72 h
Yield: 46.3 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.10 g, 0.34 mmol), o-toluoyl chloride (0.062 mL, 0.43 mmol), and triethylamine (0.06 mL, 0.43 mmol) in methylene chloride (7 mL) was stirred under argon for three days. The reaction mixture was diluted with methylene chloride, washed with 1N hydrochloric acid (2×50 mL), brine (2×40 mL), dried (magnesium sulfate) and concentrated to give an off-white solid. Recrystallization from methylene chloride/hexanes gave the above-named compound (0.065 g). m.p. 175° C. NMR (CDCl3, 400 MHz): δ 7.83 (d, 2H), 7.64 (br s, 1H), 7.53 (m, 3H), 7.43 (m, 1H), 7.31 (m, 2H), 7.10 (s, 1H), 2.56 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a solution of triphenylphosphine (37.2 g, 142 mmol) in dry THF (160 mL) was added CCl4 (50 mL). The reaction mixture was stirred for 10 minutes and (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (20.0 g, 70.8 mmol) was introduced as a solid at room temperature under nitrogen. The resulting solution was refluxed for 2 hours. THF was distilled off under reduced pressure, and the remaining material diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained crude product was purified over silica gel column chromatography (100-200 mesh, 5% ethyl acetate in hexanes) to yield compound 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (19.3 g, 90.6%) as a white solid.