Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:27]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])=[CH:12][CH:13]=1)([CH3:27])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Methyl α-methylthio(p-phthalimidophenyl)acetate (978 mg) was dissolved in 10 ml of anhydrous dimethylformamide, and under ice cooling, 120 mg of sodium hydride (65% content) was added. The mixture was stirred for 10 minutes. Then, 0.25 ml of methyl iodide was gradually added. The temperature was adjusted to room temperature, and the mixture was stirred for 5 minutes. An aqueous solution of ammonium chloride (500 mg/30 ml) was added, and the mixture was extracted four times with 20 ml of methylene chloride. The organic layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with 20 ml of hexane to afford 788 mg of methyl α-methylthio-α-(p-phthalimidophenyl)propionate as colorless crystals in a yield of 77%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[I-].[K+].[CH3:29][CH:30]=[CH:31][CH2:32][NH2:33]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:33][CH2:32][CH2:31][CH:30]=[CH2:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 39, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-nitro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 42 8-Bromo-1-[(allylethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C>C(Cl)Cl.O>[C:17]1([C:12]([CH2:13][CH2:14][C:15]#[CH:16])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCC(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
To a solution of oxalyl chloride (7.0 mL, 76.6 mmol) in methylene chloride (200 mL) under argon atmosphere at -78° C. was added dropwise dimethylsulfoxide (11.9 mL, 152 mmol). After stirring for 15 minutes 1-hydroxy-1-phenylpent-4-yne (11.14 g, 69.6 mmol) in methylene chloride (20 mL) was added dropwise. After stirring at -78° C. for 1 hour triethylamine (48 mL, 340 mmol) was added and the orange reaction mixture was allowed to warm to room temperature. Water (100 mL) was added, the layers separated, and the organic extract was washed with 1% hydrochloric acid solution (4×100 mL), saturated sodium bicarbonate solution, brine, and dried (MgSO4). Evaporation of solvent under reduced pressure gave a solid which was recrystallized from petroleum ether to afford 5.25 g product. The mother liquors were distilled by Kugelrohr (80° C., 0.1 mm Hg) to give an additional 8.3 g (75 %) of product. 1H NMR (CDCl3) δ: 1.99 (t, J=2.69 Hz, 1H), 2.63 (t, J=7.21 Hz, 1H), 2.64 (t, J=6.17 Hz, 1H), 3.25 (t, J=6.23 Hz, 1H), 3.26 (t, J=7.20 Hz, 1H), 7.44-7.58 (m, 3H), 7.96-7.99 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd].CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)C(C)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)c1ccc(N)c(F)c1
Reaction time: 6 h

Procedure:
10% Palladium on carbon is added to a solution methyl 2-(3-fluoro-4-nitrophenyl)propanoate in methanol and the mixture is charged with H2 (g). After stirring the reaction mixture for 6 h, the mixture is filtered using celite packed filter and purified by column chromatography to obtain methyl 2-(4-amino-3-fluorophenyl)propanoate.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:26]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)([CH2:31][CH3:32])[C:27]([O:29][CH3:30])=[O:28])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:26]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)([CH2:31][CH3:32])[C:27]([O:29][CH3:30])=[O:28]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cc(F)cc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added rapidly dropwise to a stirred solution of methyl 2-(4-(tert-butoxycarbonylamino)-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.92 g, 2 mmol) in DCM (10 mL) at 0° C. After 1 h, the reaction was quenched by careful addition of saturated aqueous sodium bicarbonate, followed by extraction with ether. The organic layers were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound. LC/MS m/z=361.1 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[S:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH:11]=[C:10]1[C:18](=[O:20])[CH3:19]>CN(C=O)C.CCOC(C)=O.O>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:19]/[C:18]([C:10]1[S:9][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH:11]=1)=[O:20]
Reactant: CC(=O)c1cc2cnccc2s1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)/C=C/C(=O)c1cc2cnccc2s1
Temperature: 70 °C

Procedure:
N,N-dimethylformamide-dimethylacetal (DMF-DMA) (9.5 ml) was added to a solution of 1-(thieno[3,2-c]pyridin-2-yl)ethanone (3.17 g) in 20 mL DMF. The reaction was heated to 70° C. overnight. The reaction was then cooled to room temperature. The DMF was removed on a rotary evaporator to obtain a dark brown orange solid. The residue was diluted with EtOAc and water. A large amount of yellow solid was evident. This was collected by filtration (3.54 g). This solid was dried in a 50° C. vacuum oven.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:14]=[C:13]([O:28][CH:29]([CH3:31])[CH3:30])[CH:12]=2)=[N:7][CH:8]=1.P(Br)(Br)Br.[CH2:37]([O:39][P:40]([O:44]CC)[O:41][CH2:42][CH3:43])[CH3:38]>ClC(Cl)C.C(Cl)Cl>[CH:29]([O:28][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[CH:14]=1)[C:10]([NH:9][C:6]1[CH:5]=[N:4][C:3]([CH2:2][P:40](=[O:44])([O:41][CH2:42][CH3:43])[O:39][CH2:37][CH3:38])=[CH:8][N:7]=1)=[O:32])([CH3:30])[CH3:31]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2cnc(CO)cn2)c1
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOP(=O)(Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)cn1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.4 %

Procedure:
To a solution of N-(5-hydroxymethyl-pyrazin-2-yl)-3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzamide (130 mg, 0.28 mmol) in 2.8 mL of dichloroethane was added 0.56 mL of a 1 M solution of PBr3 in CH2Cl2 and the solution stirred for 4 h at rt. Then triethylphosphite (0.5 mL, 2.8 mmol) was added and the resulting solution microwave heated at 120° C. for 5 min. Then the mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3, brine, dried (MgSO4) and evaporated. The residue was adsorbed to SiO2 and subjected to MPLC on a 12 g SiO2 column eluting with % EtOAc in hexanes (time): 65-95 (30 min ramp) to provide 33 mg (20%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 6H, J=6 Hz), 1.30 (d, 6H, J=6 Hz), 3.22 (s, 3H), 3.50 (d, 2H, J=21 Hz), 4.02 (m, 4H), 4.78 (septet, 1H, J=6 Hz), 6.97 (t, 1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz), 7.35 (t, 1H, J=2 Hz), 7.51 (t, 1H, J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.41 (dd, 1H, J=1, 2 Hz), 9.29 (d, 11-1, =1 Hz). 11.17 (s, 1H); LCMS (m/z): 578.6 [C26H32N3O3PS+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[N-]=[C:12]=[S:13]>>[Cl:1][C:2]1[C:3]([N:9]=[C:12]=[S:13])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: [N-]=C=S
Agent: Cl
Product: S=C=Nc1ncc(Cl)cc1Cl

Procedure:
3,5-Dichloro-2-amino pyridine (8.15, 0.05 mol) was treated with thiophosgenes (10% soln. in toluene, 55 ml). The mixture was refluxed until clear solution was obtained and no further hydrochloric acid gas was being evolved. The mixture was cooled, and the solid which crystallised was removed by filtration. The mother liquors, after evaporation and crystallisation of the residual oil, yielded 5.5 g. (55%) of the required isothiocyanate as pale yellow needles m. pt. 45°-6°.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=O)[C:4]1=O.[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].N1CCCCC1.C(O)(=O)C>O>[OH:16][C:15]1[N:17]=[C:4]2[C:3]([CH3:11])([CH3:2])[CH2:7][CH2:6][C:5]2=[CH:8][C:14]=1[C:12]#[N:13]
Reactant: CC1(C)CCC(C=O)C1=O
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC1(C)CCc2cc(C#N)c(O)nc21
Temperature: 100 °C
Reaction time: 26 h
Yield: 13.8 %

Procedure:
To a solution of 3,3-dimethyl-2-oxocyclopentanecarbaldehyde sodium salt (5 g, 30.9 mmol) in water (10 mL) was added cyanoacetamide (2.5 g, 30.9 mmol), piperidine (2.6 g, 30.9 mmol in 10 mL water) and acetic acid (1 mL) in that order. The reaction mixture was stirred at 100° C. for about 26 h and then cooled to a temperature of about 20-35° C. The reaction mass was adjusted to pH value of about 6 and was then filtered off to obtain a crude product. The crude product was purified by column chromatography (60-120 mesh silica gel) with 10% ethyl acetate in petroleum ether as the eluent to obtain the desired product as a brown liquid (0.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][O:7][C:8]2=[O:9])([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.O>C1(C(F)(F)F)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:8](=[O:9])[O:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2c1cccc2[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Yield: 93.6 %

Procedure:
5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide, and 196 mg of benzoyl peroxide are refluxed in 80 ml of benzotrifluoride and exposed to light until the reaction is completed. It is added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent is removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtained as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[C:42]=2[CH3:48])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[C:42]=2[CH3:48])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c1C

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (330 mg, 70%).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[C:19]([CH3:27])([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH3:20])=[CH:14][CH:13]=1>CC(N(C)C)=O>[SH:3][CH2:2][CH2:1][S:4][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:28])[C:19]([CH3:20])([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH3:27])=[CH:16][CH:17]=1
Reactant: SCCS
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCS)cc1)N1CCOCC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
22.5 g (0.24 mol) of 1,2-ethanedithiol are dissolved in 70 ml of dry dimethylacetamide, 10.0 g of potassium carbonate are added and the solution is heated to about 40° C. 10.1 g o(0.04 mol) of 1-(4-fluorophenyl)-2-methyl-2-morpholine-4-yl-propane-1-one (prepared as described in example 1b) in 30 ml of dry dimethylacetamide are added dropwise. The suspension is stirred for 5 h, then the solid is filtered off and washed with toluene. From the filtrate the excess 1,2-ethanedithiol and toluene are distilled off. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (20:80) as eluent. The resulting product has a melting point of 92-93° C. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.31 (s,6H), 1.75 (t, 1H), 2.57 (t,4H), 2.80 (q,2H), 3.21 (t,2H), 3.70 (t,4H), 7.29 (d,2H), 8.51 (d,2H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[NH2:22][C:23]1[CH:48]=[CH:47][C:26]([CH2:27][N:28]2[C:33](=[O:34])[C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:30]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[N:29]2)=[CH:25][CH:24]=1>O1CCCC1>[CH3:38][O:37][C:35]([C:32]1[C:33](=[O:34])[N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:48][CH:47]=2)[N:29]=[C:30]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH:31]=1)=[O:36]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc(N)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc(NC(=O)c3cccnc3)cc2)c1=O
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a suspension of nicotinic acid (38 mg, 0.31 mmol) in tetrahydrofuran (2 ml), N-[3-(dimethylamino)-propyl]-N′-ethylcarbodiimide.hydrochloride (WSC.HCl) (60 mg,0.31 mmol) was added at room temperature, followed by stirring for 5 minutes. A solution of 2-(4-aminobenzyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (76 mg, 0.21 mmol) in tetrahydrofuran (2 ml) was then added, followed by stirring at the same temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform (30 ml). The solution was washed successively with water (30 ml) and a saturated aqueous solution of sodium chloride (brine) (30 ml), and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel preparative chromatography [developer: chloroform/methanol (10/1)], followed by crystallization from chloroform-hexane. The title compound (78 mg, 79.7%) was obtained as yellow prisms.
Reaction SMILES: Br[C:2]1[C:7]([N+]([O-])=O)=[CH:6][CH:5]=[C:4]([Br:11])[C:3]=1[OH:12].C[Si]([C:17]#[C:18][C:19]1([OH:27])[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)(C)C>N1C=CC=CC=1>[Br:11][C:4]1[C:3]2[O:12][C:18]([C:19]3([OH:27])[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[CH:17][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#CC1(O)CN2CCC1CC2
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1Br
Solvent: c1ccncc1
Product: OC1(c2cc3cccc(Br)c3o2)CN2CCC1CC2
Yield: 29.2 %

Procedure:
2,6-Dibromonitrophenol (3.0 g, 0.0119 mol), 3-[(trimethylsilyl)ethynyl]quinuclidin-3-ol (2.66 g, 0.0119 mol; obtained in Step 1), Cu2O (1.70 g, 0.0119 mol) and pyridine (200 mL) were added to a round bottom flask. The resulting mixture was heated at reflux overnight, filtered through Celite, and the solvent was evaporated. The residue was purified by chromatography on silica gel using ethyl acetate (250 mL) and methanol (500 mL) as eluents. The methanol fraction was evaporated to yield 1.12 g (29%) of the title compound. HPLC purity=90%, m/z=322 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26](=[O:29])[N:27]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]=3)[N:28]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Product: CC1(C)C=C(n2nc(-c3ccc(Cl)cc3)ccc2=O)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 6-(4-Chloro-phenyl)-2H-pyridazin-3-one as starting materials, the title compound were prepared as white solids.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[N:5]=[CH:6][N:7]([C:17]=2[N:18]=[CH:19][N:20]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10].ClC1C=CC=C(C(OO)=[O:29])C=1.O>C(O)(=O)C>[CH3:1][NH:2][C:3]1[N+:20]([O-:29])=[CH:19][N:18]=[C:17]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10]
Reactant: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: CNc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Yield: 45 %

Procedure:
A solution of N6 -methyladenosine (2 g, 6.7 mmol) and m-chloroperbenzoic acid (2.3 g, 13.4 mmol) in acetic acid (20 ml) was stirred at room temperature for two days. Water (20 ml) was added to the reaction mixture, and a resulting thick precipitate was removed by filtration and discarded. The filtrate was co-evaporated repeatedly with water under high vacuum, and the foamy residue was chromatographed on a silica gel column (CHCl3 : MeOH 2:1). The product was obtained as a white solid (mp 145° C., crystallization from EtOH) in 45% yield (0.9 g). 1H NMR (DMSO)d: 8.62 (s, H-2), 8.55 (s, H-8), 5.88 (d, J=5.4 Hz, 1H, H-1), 4.51 (`t`, J=5.1 Hz, 1H, H-2'), 4.15 (`t`, J=4.5 Hz, 1H, H-3'), 3.94 (ABq, 1H, H-4'), 3.61 (ABdq, J=12, 4 Hz, 2H, H-5'), 3.46 (s, 3H, Me) ppm. MS (CI) m/e: 298 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCCCC(Oc1ccc(CCN)cc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC(Oc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 32 %

Procedure:
By the reaction of 2-[4-(2-aminoethyl)-phenoxy]-n-hexanoic acid with 4-chlorobenzenesulphonyl chloride in the presence of aqueous potassium carbonate solution, in a manner analogous to that described in Example 1, there is obtained a yield of 32% of theory of 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy}-n-hexanoic acid; m.p. 138°-139° C. (recrystallized from ethyl acetate and cyclohexane).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[C:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[C:3]1=[O:24].[H][H]>C(O)(=O)C>[NH:14]1[CH2:15][CH2:16][CH:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:24])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CN1C(=O)C(=C2CCN(Cc3ccccc3)CC2)c2ccccc21
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C1C1CCNCC1
Yield: 87.4 %

Procedure:
A mixture of 16 g of the product of Step A, 150 ml of acetic acid and 2 g of 10% palladized carbon was saturated with hydrogen at 50° C. for 2 hours and after the reaction was finished, the mixture was filtered. The filtrate was evaporated to dryness and the residue was taken up in water. The mixture was made alkaline with concentrated sodium hydroxide solution and was extracted 4 times with 100 ml of methylene chloride. The combined organic phases were washed with a little water, dried and evaporated to dryness to obtain 9.5 g of 1,3-dihydro-3-(piperidin-4-yl)-2H-indol-2-one melting at ≃80° C.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[S:61][C:51]=2[C:52]([N:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(N4CCOCC4)cc3)nc12

Procedure:
From 4-morpholin-4-yl-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1.CCN(CC)CC>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([O:38][CH3:37])[CH:44]=2)=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: COc1cc(N)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(C#N)cc2F)ccn1
Yield: 66.3 %

Procedure:
A solution of 4-cyano-2-fluoro-benzoic acid (6.7 g, 40.58 mmol), HATU (15.4 g, 40.58 mmol), 2-methoxypyridin-4-amine (5.0 g, 40.58 mmol) and Et3N (22.62 mL, 162.3 mmol) in dichloromethane (60.3 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-50%) to yield 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 66%) as a white solid. ESI-MS m/z calc. 271.07. found 272.1 (M+1)+; Retention time: 1.17 minutes (3 minutes run).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>C(#N)C>[O:27]1[CH2:26][CH:25]1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC1CO1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(Nc1ccccc1OCC1CO1)c1ccccc1

Procedure:
To a stirred solution of N-(2-Hydroxy-phenyl)-benzamide (0.81 g, 3.80 mmol), and cesium carbonate (1.61 g, 4.94 mmol) in acetonitrile was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between dichloromethane and water. After evaporation of the organic solvent the residue was crystallised from petroleum ether and diethyl ether yielding (0.741 g, 73%).