Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH2:54][C@@H:55]([CH3:74])[CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:73])([O:70]CC)[O:67]CC>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:54][C@@H:55]([CH3:74])[CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:67])([OH:73])[OH:70]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOC[C@H](C)N)OCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)COCCOCCOCCP(=O)(O)O)OCCCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 20, step 5) and (S)-diethyl (2-(2-(2-(2-aminopropoxy)ethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 28, step 2) by following the procedure described for example 28, step 3-5.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:22][CH:21]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:43]2[CH:44]=[CH:45][C:46]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]3)=[CH:47][CH:48]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#CCN1CCC(CO)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(CO)CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, (1-propargylpiperidin-4-yl)methanol (122 mg, 0.8 mmol) and diisopropylamine (370 mg, 0.56 mmol) were added to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (220 mg, 0.4 mmol; prepared as described in example 7) in tetrahydrofuran (15 mL). Subsequently, bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.075 mmol) were added; the reaction mixture was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a paddle of silica gel. The paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 95:5) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>C(#N)C.C(OCC)(=O)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[NH:11]1[C:12]2[C:8](=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([C:17]4[CH:18]=[CH:19][C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=4)[CH2:27][CH2:28]3)[CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1ccc2cc(C3CCN(CCCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-4-(4-indolyloxy)butane (prepared from 4-hydroxy-1H-indole and 1-bromo-4-chlorobutane), 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled and diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 48% overall yield as a tan solid. mp 113°-115° C. FDMS m/e=398 (M+ of free base).
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]([C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1)#[CH:25]>CCCCCCC.C(Cl)Cl>[C:26]1([C:24]#[C:25][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#CC1=CCCCC1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)cc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (110 mg, 84%); 1H NMR δ (CDCl3): 7.78 (d, J=8.09 Hz, 2H), 7.42-7.33 (t, J=8.11 Hz, 2H), 7.32 (m, 1H), 6.62 (s, 1H), 6.31-6.27 (m, 1H), 3.94 (s, 3H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 246.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[S:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=O.[CH2:31]([Mg]Br)[CH3:32]>CCCCCC.C(OCC)(=O)C>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:8]2[C:7]3[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:4]([CH3:30])=[C:3]([CH2:1][CH2:31][CH3:32])[C:11]=3[S:10][CH2:9]2)=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Reactant: CC[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Yield: 22 %

Procedure:
Using N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide obtained in Example 163 and ethylmagnesium bromide, the title compound was synthesized in the same manner as in Example 164. Yield: 22%. Melting point: 159-160° C. (hexane-ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][C:30]1[N:29]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: OCCc1nc2ccccc2[nH]1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(1H-benzo[d]imidazol-2-yl)ethanol were reacted to give 218. LCMS m/z: 535.3 (MH+)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>CN(C)C=O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
Under an argon atmosphere, 2-fluorobenzaldehyde (5 g) was dissolved in 15 ml of dimethylformamide and potassium carbonate (8.35 g) was added. Ethyl 4-mercaptobutyrate (8.6 ml) was added at room temperature and was stirred at room temperature for 14 hours. After the addition of 100 ml of ethyl acetate, the mixture was washed with 50 ml of water twice, 50 ml of a 0.5N hydrochloric acid, and 50 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=4/1) purification. The resulting effective fractions were concentrated to yield ethyl 4-(2-formylphenylthio)butyrate (6.86 g, Yield 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNS(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC(=O)OC(C)(C)C)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
The compound (817.3 mg) obtained in Example 102-2 was dissolved in anhydrous methanol (24.5 ml) and added with 1-methyl-2-imidazolealdehyde (309.4 mg) and sodium cyanoborohydride (235.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 24 hours. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (910.0 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[C:15]1[CH:19]=[C:18]([S:20][CH3:21])[NH:17][N:16]=1.[F:22][C:23](I)([F:25])[F:24].O>CN(C)C=O>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([Cl:3])[C:5]=1[C:15]1[CH:19]=[C:18]([S:20][CH3:21])[N:17]([C:23]([F:25])([F:24])[F:22])[N:16]=1
Reactant: FC(F)(F)I
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(F)(F)F
Temperature: 25 °C

Procedure:
Sodium hydride was added dropwise to a suspension of 0.5 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5(methylsulfenyl)pyrazole (compound 16) in 5 ml of anhydrous N,N-dimethylformamide at 0° C., and the mixture was stirred at room temperature. An excess of trifluoromethyl iodide was introduced into the reaction mixture, and the resulting mixture was stirred for 3 hours with the reactor closed. The reaction mixture was poured into water, followed by extraction with ether, washing with brine and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: chloroform/hexane=1/20), giving 0.2 g of the desired product in the form of light brown oil (yield 33.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:36])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]F)=[CH:25][CH:24]=3)[C:12]2=[O:35])=[CH:4][CH:3]=1.[CH3:37][NH:38][CH2:39][CH2:40][S:41]([OH:44])(=[O:43])=[O:42].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:36])[CH2:9][CH2:10][CH:11]2[C:12](=[O:35])[N:13]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:38]([CH3:37])[CH2:39][CH2:40][S:41]([OH:44])(=[O:43])=[O:42])=[CH:27][CH:28]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCCCCF)cc2)cc1
Reactant: CNCCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCCCCN(C)CCS(=O)(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute methanol. 120 mg of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate were then added. The mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated using a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying gave the product (50 mg) as an oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:29])[C:27]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:24]2[CH:23]=[C:22]([F:21])[C:27]([F:28])=[C:26]([F:29])[CH:25]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
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: CCO
Solvent: Cc1ccccc1
Product: Nc1nc(-c2cc(F)c(F)c(F)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 6.5 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,4,5-trifluorophenylboronic acid (107 mg, 0.609 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (30 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 50 g, 18-32%, gradient 2.5-15% ethanol in DCM, residue dry loaded, product eluted in 15% ethanol) and by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 50% acetonitrile) afforded (2R,3R,4S,5R)-2-{6-amino-2-(3,4,5-trifluorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl) tetrahydrofuran-3,4-diol 12 as a white solid (13.2 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>O1CCOCC1>[CH2:15]([NH:20][C:8]([C:5]1[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCN
Reactant: O=C(O)c1ccc(Cl)nn1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCCCNC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a flask containing 6-chloropyridazine-3-carboxylic acid (375 mg, 2.37 mmol) in dioxane (5 mL) was added thionyl chloride (420 mg, 0.26 mL, 3.56 mmol). The brown mixture was refluxed for 6 hours under nitrogen with stirring. After cooling to ambient temperature, the solvent was removed by rotary evaporator. The gummy black material was diluted with dioxane (5 mL) and the resulting solution was cooled in an ice-water bath. To the cooled solution was added amyl amine (410 mg, 0.55 mL, 4.74 mmol). The resulting black reaction solution was stirred at ambient temperature for 16 hours under nitrogen. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (25 mL). The solution was washed with water (2×10 mL) and the organic layer was dried over MgSO4, filtered-off the solid and concentrated to afford a gummy material which was purified by column chromatography eluted with dichloromethane to yield 310 mg (57%) of the product as a colourless solid. m.p. 98-101° C. 1H NMR (300 MHz, CDCl3) δ 8.28, 8.05, 7.68, 3.51, 169-1.63, 0.90. MS (ES+) m/z 228 (M+1).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1Br.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>CCOCC>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 330 ml) was added dropwise with stirring to a solution of 2,6-dichloro-4-trifluoromethylbromobenzene (163.3 g) in ether while maintaining the temperature below -70° C. The mixture was stirred for 1 hour at -78° C. then ethyl chloroformate (61.7 g) was added while maintaining the temperature below -70° C. The mixture was stirred at room temperature overnight. It was cooled to 0° C. and a saturated aqueous solution of ammonium chloride was added. The layers were separated and the organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give ethyl 2,6-dichloro-4-trifluoromethylbenzoate (123.9 g) as a colourless liquid bp 90°-96° C. at 5 mmHg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.Cl>CO>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of serine methyl ester hydrochloride (0.12 g, 0.78 mmol) in 1.6 ml of dry MeOH, at room temperature, under argon, were added successively triethylamine (10% solution, 0.16 ml) and (BOC)2O (0.19 g, 1.1 eq.) and the solution was stirred for 60 minutes. It was then poured in cold 2% HCl and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, the solids were filtered and the solvents evaporated to give 0.17 g (100%) of the titled compound as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([C:8]([N:10]2[C@@H:14]3[CH2:15][CH2:16][C@H:11]2[C@H:12]([NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH2:13]3)=[O:9])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][CH:36]=[CH:37][N:38]=1)CCC>COCCOC.[Cu]I.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>[F:1][C:2]1[C:3]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[C:4]([C:8]([N:10]2[C@@H:14]3[CH2:15][CH2:16][C@H:11]2[C@H:12]([NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH2:13]3)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(F)c1I)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(c1cccc(F)c1-c1ncco1)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Temperature: 145 °C
Yield: 70.8 %

Procedure:
In a microwave vial was dissolved the title compound of Example 277 (30 mg, 0.06 mmol) and 2-(tributylstannyl)oxazole (15 μL, 0.07 mmol) in DME (1 mL). The solution was degassed with N2 for 5 minutes then CuI (1 mg, 0.0045 mmol) and Pd(PPh3)4 (5 mg, 0.0045 mmol) were added. The reaction was purged with N2 and heated at 145° C. for 3 h. The reaction was cooled to rt, filtered through a pad of celite and purified via prep HPLC to give the title compound (19 mg, 72%). MS (ESI) mass calcd. for: C21H17F4N5O2, 447.1; m/z found 448.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) 8.49 (s, 1H), 8.36 (s, 0.8H), 7.85 (s, 0.8H), 7.76 (s, 0.4H), 7.62-7.45 (m, 1H), 7.43-7.33 (m, 1H), 7.32-7.23 (m, 2H), 7.23-7.09 (m, 1H), 4.91-4.85 (m, 0.4H), 4.78 (d, J=5.4 Hz, 0.6H), 4.42 (td, J=8.6, 2.8 Hz, 0.6H), 4.28 (td, J=8.2, 3.6 Hz, 0.4H), 4.00-3.95 (m, 0.6H), 3.89 (d, J=4.4 Hz, 0.4H), 2.23-1.44 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C1(C=CC(O)=CC=1)O>>[CH3:10][C:6]1[CH:5]=[C:3]([NH:4][CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[C:2]([CH3:1])=[CH:8][C:7]=1[I:9]
Reactant: Cc1cc(I)c(C)cc1N
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [OH-]
Product: COC(=O)CCNc1cc(C)c(I)cc1C

Procedure:
15.0 g (0.061 mol) of 2,5-dimethyl-4-iodo-aniline, 55 ml of (0.611 mol) of methyl acrylate, 6 ml of benzyltrimethyl ammonium hydroxide and 0.3 g (3 mmol) of hydroquinone are refluxed for 11 days. Then the excess acrylate is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride.
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].C(N(CC)CC)C.ClC(OCC)=O.[C:25]1([CH2:31][O:32][C:33]2[C:34]([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:53]=3)=[C:35]([CH2:47][CH2:48][NH2:49])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([CH2:31][O:32][C:33]2[C:34]([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH2:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH:53]=3)=[C:35]([CH2:47][CH2:48][NH:49][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCC(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of monomethyladipate (0.74 ml) and triethylamine (0.69 ml) in dry dichloromethane (50 ml) was stirred at 0° during the dropwise addition of a solution of ethyl chloroformate (0.48 ml) in dry dichloromethane (20 ml). The mixture was stirred under an atmosphere of nitrogen at 0° for 30 minutes and a solution of 3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]benzeneethanamine (2.70 g) in dry dichloromethane (50 ml) was then added. The mixture was stirred at 20° for 18 hours.