Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[N:18]=[C:17]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:29]([O:32][Si](CC)(CC)CC)([CH3:31])[CH3:30])=[C:27]([F:28])[C:22]3=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[C:27]([F:28])[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2c1F
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: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccn2c(-c3ccnc(-c4ccc(F)c(F)c4)n3)cnc2c1F
Reaction time: 48 h

Procedure:
3,4-Difluorophenylboronic acid (90 mg, 0.57 mmol), 3-(2-chloropyrimidin-4-yl)-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (120 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.015 mmol), THF (1.4 ml) and aqueous Na2CO3 solution (2M; 0.44 ml) were combined and heated to reflux for 18 h. On cooling, the mixture was partitioned between 2M NaOH solution (2 ml) and CH2Cl2 (3 ml) and the phases separated using a phase-separation cartridge. The organic fraction was purified by column chromatography (silica, 90% EtOAc/isohexane), then the silyl protection removed by treatment with an ethanolic solution of 37% hydrochloric acid (5 drops in 2 ml of ethanol). After 48 h, the solution was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over MgSO4, filtered, concentrated and the residue purified by column chromatography (silica, EtOAc) affording the title compound as a white amorphous solid (158 mg): δH (360 MHz, CDCl3) 1.76 (6H, s), 7.00-7.20 (2H, m), 7.40-7.70 (2H, m), 8.20-8.40 (1H, m), 8.36 (1H, s), 8.80 (1H, m), 9.90-9.92 (1H, m); m/z (ES+) 385 (100%, [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][NH2:30])=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[NH:18][C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:30][N:29]=2)=[CH:22][CH:21]=1
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nnc(Cc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (200 mg, 0.76 mmol) and (4-fluoro-phenyl)-acetic acid hydrazide (141 mg, 0.76 mmol). Obtained as a greyish solid (21 mg, 7%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=O)=O)[CH3:3].[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21])[CH3:18]>C(N(CC)CC)C>[CH2:17]([N:19]([CH2:23][CH3:24])[C:20]([N:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9](=[O:10])[N:4]([CH:2]([CH3:3])[CH3:1])[S:5]1)=[O:21])[CH3:18]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N1SN(C(C)C)C(=O)c2ccccc21
Yield: 80.8 %

Procedure:
In a similar manner 12 g of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide was caused to react with 7.28 g of diethylcarbamoyl chloride in the presence of 14 ml of triethylamine. The crude product was crystallized from methanol to afford 12.4 g of N,N-diethyl-3,4-dihydro-3-(1-methylethyl)-4-oxo-1H-2,1,3-benzothiadiazine-1-carboxamide, m.p. 103°-104.5° C.
Reaction SMILES: C([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=C.BrCOC>C(Cl)Cl.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:4]1([C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH:3]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccccc1C(c1ccccc1)(c1ccccc1)c1ccccc1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: COCBr
Agent: [Br-]
Solvent: ClCCl
Product: Oc1ccccc1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
The 2-(vinyltrityl)phenol (1.0 equiv.) is dissolved in CH2Cl2/50% KOH/H2O. Benzyltriethyl ammonium bromide is added as a phase transfer agent (0.1 equiv.). To this two phase mixture is added bromomethylmethylether (MOMBr). The reaction is allowed to stir for 30 minutes. The organic phase is separated, washed with water and brine before being dried with MgSO4. Solvent is removed to yield the MOM-protected 2-triphenylmethylphenol in near quantitative yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(#N)C.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]2
Reactant: COC(=O)CBr
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CN1CCc2cc(OC)c(OC)cc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3 g, 13.06 mmol) was suspended in acetonitrile (40 ml); potassium carbonate (3.61 g, 26.1 mmol) and methyl 2-bromoacetate (3.00 g, 19.59 mmol) were added; and the reaction mixture was stirred under microwave irradiation at 100° C. for 1 hour. Then the mixture was diluted with ethyl acetate and washed with water, brine and dried over Na2SO4. The organic layer was evaporated and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH:TEA 100:1:1) affording the title compound (2.6 g, 9.81 mmol, 75% yield). MS/ESI+ 266.1 [MH]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][NH2:25]>C(O)C.CN(C)C(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CN
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CNCCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
In analogy to the method described in example 17.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5) was treated with methylamine in ethanol and N,N-dimethylacetamide to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine as colorless oil, MS: 405 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[CH2:28]([NH2:31])[CH2:29][NH2:30]>CS(C)=O>[F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:30][CH2:29][CH2:28][NH2:31])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: NCCN
Reactant: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: CS(C)=O
Product: NCCNc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reaction time: 22 h

Procedure:
100 mg (0.25 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are dissolved in 1 ml of dimethyl sulfoxide, and 0.2 ml of ethylenediamine is added. After stirring for 22 h at 100°, the reaction mixture is concentrated and chromatographed (methylene chloride:methanol:concentrated ammonia solution=90:10:1). N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine is obtained; FAB-MS: 423 (M+ +H), Rf =0.1 (methylene chloride:methanol:concentrated ammonia solution=90:10:1).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].Cl>O1CCCC1.O>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:19])=[O:18]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (1.11 g) in tetrahydrofuran (40 mL) was added ethyl diethylphosphonoacetate (6.29 mL) dropwise under ice cooling. After stirring the mixture under ice cooling for 30 minutes, a solution of 2-nitrobenzaldehyde (3.0 g) in tetrahydrofuran (30 mL) was added thereto under ice cooling. The solution was stirred at room temperature for 8 hours. Water and 3N hydrochloric acid were then added to the solution and it was extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=3:2) to give the title compound (3.74 g).
Reaction SMILES: C(OCCO)C.[S-2].[Na+].[Na+].[Na].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[CH:15](S)[NH:16][C:17]2=[NH:24].C1(S([O-])(=O)=O)C=CC=CC=1.[NH:36]=[C:37]1[NH2+:41][C:40](=[NH:42])[CH2:39][S:38]1>>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[C:15](=[C:39]1[S:38][C:37](=[NH:36])[NH:41][C:40]1=[NH:42])[NH:16][C:17]2=[NH:24]
Reactant: COc1ccc(OC)c2c1C(=N)NC2S
Reactant: N=C1CSC(=N)[NH2+]1
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CCOCCO
Product: COc1ccc(OC)c2c1C(=N)NC2=C1SC(=N)NC1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 140 parts of 2-ethoxyethanol stirred at 100° C under an atmosphere of nitrogen there was added 8.6 parts of 60 percent active solid sodium sulfide and the resultant solution was filtered to remove undissolved material. The filtrate was mixed with 94 parts of dimethylformamide and 11.3 parts of 3,6-dimethoxy-phthalonitrile and the mixture stirred at 25° C for a period of 1 hour. The reaction mixture was then heated to 95° C over a period of 1 hour, cooled to 25° C and filtered to remove undissolved material which was found to be (4.5 parts) unreacted 3,6-dimethoxyphthalonitrile. The filtrate, which contained approximately 0.04 mole of the sodium salt of 4,7-dimethoxy-1-imino-3-mercaptoisoindoline was stirred and there was added 10.7 parts of 2,4-diiminothiazolidinium benzenesulfonate. Stirring was continued overnight at 25° C. The product which separated was collected by filtration, washed successively with four portions of 12.0 parts each of methyl alcohol and finally dried in vacuo to obtain 4.5 parts of 4,7-dimethoxy-1-imino-3-(2,4-diimino-5-thiazolidinylidene)isoindoline as a red solid which melted at 227°-246° C (dec).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A solution of (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this mixture was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed by triethylamine (1.39 mL, 10 mmol). After removing the ice bath, the reaction was stirred for 4 h. The mixture was poured into ice water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using EtOAc in hexanes (0-40%) gave benzyl ((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H), 2.10-1.79 (m, 2H), 1.45 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[NH4+].[OH-]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:4]([CH2:5][CH2:6][CH3:7])[NH:8][C:7]=12
Reactant: Cc1ccnc(N)c1N
Agent: [NH4+]
Agent: [OH-]
Product: CCCc1nc2nccc(C)c2[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 174.5 %

Procedure:
A mixture of burytic acid (6.57 mL, 71.9 mmol), 2,3-diamino-4-picoline (8.05 g, 65.4 mmol) (Lappin, G. R., Slezak, F. B. J. Am. Chem. Soc. (1950) 72, 7806-7) and polyphosphoric acid (50 g) was heated to 100° C. with stirring for 3 hours. The reaction was monitored by tlc of NH4OH neutralized aliquots. Basification (NH4OH), extraction (CH2Cl2, 4×50 mL), drying (K2CO3), purification (by filtering through 100 g SiO2, EtOAc elution), and concentration gave 10.0 g (95%) of the title compound as an amorphous tan solid which was judged pure by 1H NMR and tlc: mp 110°-112 ° C. (without recrystallization); 1H NMR (300 MHz, CDCl3) δ 8.13 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz), 3.01 (t, 2H, J=7.8 Hz), 2.67 (s, 3H), 2.07-1.93 (m, 2H), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:8]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:7][C@@H:6]1[O:36][C@H:37]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C@@H:38]1[S:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)C.[Na]>C1(C)C=CC=CC=1.CO>[CH2:12]([O:11][C@H:10]1[C@H:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:8]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:7][C@H:6]([O:36][C@H:37]2[C@@H:49]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@H:48]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[O:46][C@@H:38]2[S:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:5]1[OH:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)O[C@@H]1[C@@H](O[C@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2Sc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: O[C@@H]1[C@@H](O[C@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2Sc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Compound 14 (6 g, 5.9 mmol) was dissolved in 40 ml of a toluene/methanol (1/1) mixture). We then added sodium (cat.). After 15 min, the solution was neutralized with Amberlite resin IR 120 (H+), filtered and concentrated. Silica gel chromatography (elution: cyclohexane/ethyl acetate=3/1) of the crude product yielded 16 (5.45 g, 95%) in the form of a colorless syrup.
Reaction SMILES: [Cl-].[CH:2]1([S:5]([NH:8][C:9]([C@@:11]2([NH3+:16])[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]1([C@@H:47]2[NH:71][CH2:70][CH2:69][CH2:68][CH2:67][CH:66]=[CH:65][C:64]3[CH:72]=[C:60]([CH:61]=[CH:62][CH:63]=3)[C:59]3=[CH:73][C:55](=[CH:56][CH:57]=[CH:58]3)[CH2:54][O:53][C@H:52]3[CH2:74][N:49]([C@H:50]([C:75](O)=[O:76])[CH2:51]3)[C:48]2=[O:78])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:41]1([C@@H:47]2[NH:71][CH2:70][CH2:69][CH2:68][CH2:67][CH:66]=[CH:65][C:64]3[CH:72]=[C:60]([CH:61]=[CH:62][CH:63]=3)[C:59]3=[CH:73][C:55](=[CH:56][CH:57]=[CH:58]3)[CH2:54][O:53][C@H:52]3[CH2:74][N:49]([C@H:50]([C:75]([NH:16][C@:11]4([C:9]([NH:8][S:5]([CH:2]5[CH2:4][CH2:3]5)(=[O:7])=[O:6])=[O:10])[CH2:13][C@H:12]4[CH:14]=[CH2:15])=[O:76])[CH2:51]3)[C:48]2=[O:78])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCCC=Cc1cccc(c1)-c1cccc(c1)CO2
Reactant: C=C[C@@H]1C[C@]1([NH3+])C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCC/C=C/c1cccc(c1)-c1cccc(c1)CO2)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCCC=Cc1cccc(c1)-c1cccc(c1)CO2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
48 (1.2 eq.) and HATU (1.2 eq.) were added to a 0.12M solution of (9R,11S,14S,20E)-14-cyclohexyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,20,22,24-heptaene-11-carboxylic acid 111 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight then it was concentrated to dryness and the residue was dissolved in DMSO and purified by RP-HPLC (stationary phase: column WATERSXBRIDGE 19×150 mm, 5 μm; mobile phase: MeCN/H2O buffered with 0.1% TFA from 50% to 90% of MeCN in 14 min., run time 18 min.). Fractions containing the pure compound were combined and freeze dried to afford compound 146 (TFA salt) as an off white solid (4.0% over 3 steps). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 10.73 (s, 1H), 8.83 (s, 1H), 8.80-8.68 (m, 1H), 8.58-8.42 (m, 1H), 7.92 (s, 2H), 7.68 (d, J 7.6, 1H), 7.62 (d, J 7.6, 1H), 7.51-7.40 (m, 2H), 7.29 (t, J 8.1, 2H), 6.58 (d, J 15.7, 1H), 6.49-6.37 (m, 1H), 5.68-5.54 (m, 1H), 5.27 (d, J 16.9, 1H), 5.16 (d, J 11.6, 1H), 4.74 (d, J 11.9, 1H), 4.60 (d, J 11.9, 1H), 4.50-4.33 (m, 3H), 4.19 (d, J 11.1, 1H), 3.86 (dd, J 11.1, 3.8, 1H), 3.18-2.91 (m, 3H), 2.60-2.46 (m, partially obscured by residual DMSO-d6, 1H), 2.43-2.24 (m, 2H), 2.19 (q, J 8.8, 1H), 2.09-1.97 (m, 1H), 1.92-1.65 (m, 9H), 1.64-1.52 (m, 1H), 1.38-1.02 (m, 11H). MS (ES) m/z 729 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].O>CN(C)C(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH2:28][CH3:29])=[O:26])[N:7]2[CH:8]=1
Reactant: FC(F)(F)c1cn2c(Br)cccc2n1
Reactant: C=CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C/c1cccc2nc(C(F)(F)F)cn12
Temperature: 110 °C
Reaction time: 24 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (10.0 g, 37.7 mmol) in N,N-dimethylacetamide (60 mL) were added sodium acetate trihydrate (6.19 g, 75.0 mmol), ethyl acrylate (4.94 mL, 45.3 mmol) and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (2.76 g, 3.77 mmol) at room temperature, and the mixture was stirred under nitrogen stream at 110° C. for 24 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (6.74 g, yield 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:16][C@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H]3CO3)c2n1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)CN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
In a mixed solvent (16 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2R)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (Reference Example 77; 400 mg, 1.62 mmol) and 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 402 mg, 1.62 mmol), and the suspension was stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 288 mg (36%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CP(=O)([O-])[O-].C[C@H](NC(CC1C=C(F)C=C(F)C=1)=O)C([NH:19][C@H](C(OC(C)(C)C)=O)C1C=CC=CC=1)=O.C(N(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=O.[OH-].[NH4+]>Cl>[N:1]1[C:9]([NH2:19])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H](C(=O)OC(C)(C)C)c1ccccc1
Reactant: c1ncc2[nH]cnc2n1
Agent: CP(=O)([O-])[O-]
Agent: Cl
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Product: Nc1ncnc2nc[nH]c12

Procedure:
Purine-containing oligonucleoside methylphosphonates may be depurinated by treatment by hydrochloric acid at 65° C. The methylphosphonate linkage is resistant to hydrolysis by these conditions as shown by the stability of d-TpT and d-TpTpT. On the other hand, dimers or trimers containing purine bases such as d-ApA, dApT, dTpA or d-ApApA have half-lives between 92 and 144 min in 0.01 M hydrochloric acid. Following neutralization with ammonium hydroxide, the products of these reactions were characterized by reversed phase HPLC. d-ApA gave adenine, while both d-ApT and d-TpA gave adenine and thymidine as the sole products of the reaction. Adenine and d-ApA were the only products observed when d-ApApA was partially hydrolyzed. When d-CpCpApT was completely hydrolyzed in acid three products, d-CpC, adenine and thymidine, were observed in a molar ratio of 1:1:1.
Reaction SMILES: [C:1]([C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]([C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1)#[CH:12].C(N(CC)CC)C.[Cl-]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:11]#[C:12][C:5]2[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: CC(=O)c1cccnc1Br
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C#Cc2ncccc2C(C)=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
100 mg 3-Acetyl-2-bromopyridine, 140 mg 5-ethynyl-1,2,3-trimethoxybenzene 2.1, 101 μL triethylamine, 17 mg triphenylphosphinpalladium(II) chlorid, 1 mg Cu(I)I were suspended in 4 mL THF under argon atmosphere and stirred for 1 h at 25° C. The mixture was diluted with DCM and extracted with diluted aq. NH3 and saturated NH4Cl solution. The organic phase was concentrated and the mixture separated via FCC (10 g SiO2, Cyclohexane→cyclohexane/ethylacetate 70:30) to yield 90 mg 1-(2-(3,4,5-trimethoxyphenylethynyl)pyridin-3-yl)ethanone as solid. Analysis: HPLC-MS: Rt=1.21 min (method E) M+H=312.