Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Yield: 94.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl pyrrolidin-3-ylcarbamate (931 mg, 5 mmol) followed by reduction to afford the desired product (813 mg, 94%) as a purple solid: ESI MS m/z 279 [C14H22N4O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.C1(C)C=CC=CC=1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([O:13][CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A solution of tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy)piperidine-1-carboxylate (0.019 g, 0.052 mmol) in methanol (2.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.008 g, 0.057 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with toluene, the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→1:4)) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy}piperidine-1-carboxylate (0.020 g, 79%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=[O:3].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(C(C)=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(C(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of 3-methoxyacetophenone (3 g; 20 mmol) in methanol (60 mL) is added sodium borohydride (1.13 g; 30 mmol) in four portions over one hour. The reaction is stirred at room temperature overnight, neutralized with saturated ammonium chloride, and extracted with ethyl acetate. The organics are separated, washed with water, and dried over magnesium sulfate. The solvent is removed to give 2.62 grams of 1-(3-methoxyphenyl)-ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C1COCC1>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:22][CH:23]=1
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.6 %

Procedure:
To a stirred solution of 3-Amino-4-hydroxy benzoic acid (0.136, 0.00089 mols) and pyridine (0.211 g, 0.00267 mols) in 13 ml dry THF is added 4-trifluoromethoxybenzoyl chloride (0.2 g, 0.00089 mols) and the solution is stirred under nitrogen atmosphere at RT for 10 hrs and then refluxed for 3 hrs. The reaction mixture is rotary evaporated and the residue is slurried in water and filtered to get the amide (0.175 g) which is taken for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C@H:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)[C:3]=1[OH:58].C([O-])([O-])=O.[K+].[K+].Br[CH2:66][CH2:67][CH2:68][OH:69]>CC(C)=O>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C@H:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)[C:3]=1[O:58][CH2:66][CH2:67][CH2:68][OH:69]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCO)c(Br)c2Cl)cc1
Temperature: 55 °C
Reaction time: 15 h
Yield: 103.5 %

Procedure:
To a suspension of crude compound 28 (1.33 g, 1.54 mmol) and K2CO3 (0.322 g, 2.31 mmol) in acetone (20 mL) was added 3-bromopropanol (0.30 mL, 2.31 mmol) at r.t. The mixture was stirred at 55° C. for 15 hours. The reaction mixture was cooled to r.t and filtered off to remove inorganic salts. The filtrate was concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 29 (1.47 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16].CN(C)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: CC(C)OCC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)C
Solvent: c1ccccc1
Product: CC(C)OCC1CN(C(=O)C(Cl)(Cl)Cl)C(C)(C)O1

Procedure:
To 20.8 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene was added 5.5 grams of trichloroacetyl chloride. To this solution was added dropwise with cooling, 3.1 grams of trimethylamine. After washing with water, drying and removal of the benzene in vacuo, there was obtained 8.1 grams of the title compound, nD30 1.4603. Analytical data supports the structure.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([CH:34]2[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.C[Si](N[Si](C)(C)C)(C)C.[Li].CO>C1COCC1.C(Cl)Cl>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([C:7]2[C:2]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([CH:34]4[CH2:35][CH2:36]4)=[O:33])=[CH:29][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: Nc1ccc(NC(=O)C2CC2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (100 mg, 0.319 mmol) and N-(4-aminophenyl)cyclopropanecarboxamide (56.2 mg, 0.319 mmol, Enamine Ltd, Ukraine) in THF (5 mL), argon was bubbled through for 2 min, and the tube was sealed. The reaction mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amine (1 N in THF, 1 mL, 1 mmol) was added dropwise. The red solution was stirred at 0° C. for 1 h and then warmed to room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (25 g) eluting with a gradient of 2% to 5% 2 M NH3.MeOH in DCM to give N-(4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (90 mg, 0.192 mmol, 60% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.69 (s, 1H); 10.12 (s, 1H); 9.73 (dd, J=7.92, 1.86 Hz, 1H); 8.87 (s, 1H); 8.35 (dd, J=4.70, 1.76 Hz, 1H); 7.76 (d, J=9.00 Hz, 2H); 7.57 (d, J=8.80 Hz, 2H); 6.99 (dd, J=7.82, 4.69 Hz, 1H); 5.84 (dd, J=10.95, 1.76 Hz, 1H); 4.04 (d, J=12.63 Hz, 1H); 3.71-3.81 (m, 1H); 2.91 (s, 3H); 2.27-2.38 (m, 1H); 1.97-2.07 (m, 2H); 1.73-1.85 (m, 2H); 1.56-1.67 (m, 2H); 0.72-0.82 (m, 4H). m/z (ESI, +ve ion) 470 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCOCC3)co2)C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (400 mg, 1.21 mmol) (obtained as described in Reference Example 72(3)) in dimethylformamide (20 ml) was added potassium thioacetate (827 mg, 7.24 mmol) at room temperature and was stirred in an oil bath (80° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-acetylthio-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (266 mg, yield 71%) as a pale brown solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])(=O)=O.[CH3:22][NH2:23]>CO>[CH3:13][O:12][C:9]([CH3:11])([CH3:10])[CH2:8][C@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][NH:23][CH3:22]
Reactant: CN
Reactant: COC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Solvent: CO
Product: CNC[C@H](CC(C)(C)OC)NC(=O)OC(C)(C)C
Temperature: 120 °C

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-4-methoxy-4-methylpentyl methane-sulfonate (1.08 g, 2.99 mmol) in MeOH was added methylamine in methanol (33 wt %, 4.0 mL). The resulting solution was heated in CEM microwave reactor at 120° C. for 5 min. Reaction completion was confirmed by LC-MS. Solvent was removed under vacuum to give a crude (S)-tert-butyl 4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate, which was used for the next step without purification. MS m/z 261 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CO>[N:22]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:5][CH:4]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Reactant: C1CNCCN1
Solvent: CO
Product: COC(=O)c1cccc2nc(-c3ccc(CN4CCNCC4)cc3)oc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the mixture of methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (250 mg, 0.72 mmol) in methanol (2 mL), was added piperazine (186 mg, 2.16 mmol), and the resulting mixture was stirred at room temperature for 17 hr, then the solvents were evaporated to give methyl 2-(4-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate LC-MS (ESI) m/z 352 [M+1]+.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].[O:17]1[CH:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>CO.O>[ClH:1].[OH:17][CH:19]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(CNCC(O)COc2ccccc2)cc1

Procedure:
To a solution of 18.0 g (0.76 mmol) of N-[4-(aminomethyl)phenyl]methanesulfonamide hydrochloride in 200 mL of methanol, add a solution of 3.04 g of sodium hydroxide in 10 mL of water. Stir for fifteen minutes. Add 11.14 g (0.076 mmol) of 1,2-epoxy-3-phenoxy propane and reflux for 4.5 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). Remove the solvent in vacuo. Chromatograph the oil on 800 g of silica gel using a mixture of methylene chloride:methanol:triethylamine (97:2:1) initially and changing to methylene chloride, methanol, triethylamine (95:4:1). Combine the fractions containing product and remove the solvent in vacuo. Dissolve the product in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystallize the salt from acetonitrile:methanol to obtain the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].Br[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1>CN(C)C=O.[Ag].[N+]([O-])([O-])=O.[Ag+]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C=Cc1ccc(CBr)cc1
Agent: [Ag+]
Agent: [Ag]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(Cc2ncc[nH]2)cc1
Temperature: 100 °C

Procedure:
A suspension of 1.75 g of silver salt of imidazole, which was prepared from imidazole and silver nitrate in a sodium hydroxide solution, and 2.7 g of ethyl p-bromomethylcinnamate in 50 ml of N,N-dimethylformamide was heated at 100° C. for 7 hours.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C.Cl>ClCCl>[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: Cc1c(O)ccc([N+](=O)[O-])c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Trifluoromethanesulfonic anhydride (1.57 mL, 8.77 mmol) was added to 2,3-dimethyl-4-nitrophenol (1.12 g, 6.70 mmol) and triethylamine (2.5 mL, 17.9 mmol) in dichloromethane (40 mL) at 0° C. under Ar atmosphere and the resulting mixture was allowed to stir overnight at r.t. 2M HCl (50 mL) was then added and the solution was extracted with dichloromethane (3×100 mL). The organic extracts were combined, washed with saturated aqueous NaHCO3 (100 mL), diluted with n-heptane (200 mL), and passed through a pad of silica gel to give 1.96 g (98%) of 195JP07 as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:15])[CH3:3].C(N(CC)CC)C.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH3:1]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)CCn1c(N)nc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc3ccccc3n2CCN(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(N,N-Dimethylaminoethyl)-2-aminobenzimidazole (0.40 g, 1.96 mmol) was dissolved in CH2Cl2 (50 mL) and cooled to 0° C., triethylamine (2 mL) was added followed by 4-methybenzoyl chloride (0.26 g, 1.96 mmol). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for an additional 1 h. The volatiles were evaporated and then the residue was purified by column chromatography using CH2Cl2-MeOH (9.8-0.2). The oily material collected (0.2 g) was dissolved in anhydrous ethyl ether and transformed to the hydrochloride salt. MS 322 (M+1). 1H NMR (DMSO): δ 2.48 (s, 3H), 2.81 and 2.86 (2s, 6H), 3.54 (m, 2H), 4.73 (m, 2H), 35 7.34 (m, 4H), 7.52 (2m, 2H), 8.14 (d, 2H), 10.79 (broad s, NH).
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([CH2:45][C:46]([OH:48])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[NH2:4][C:46](=[O:48])[CH2:45][CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CC(N)=O)C1
Yield: 57.5 %

Procedure:
PyBOP (1.946 g, 3.74 mmol) was added to a solution of [1-(tert-Butoxycarbonyl)azetidin-3-yl]acetic acid (0.805 g, 3.74 mmol) in DMF (10 mL). The mixture was stirred in an ice-bath, ammonia gas was bubbled in for 3 mins and then the mixture was stirred at rt overnight. The reaction mixture was concentrated, water (15 mL) and saturated, aqueous NaHCO3 (5 mL) were added, and the mixture was extracted with EtOAc (20 mL×3). The extracts were combined, washed with water (20 mL) and brine (10mL), dried (Na2SO4) and evaporated. Column chromatography of the residue (ISOLUTE SI, 50 g/150 ml), eluting with EtOAc and heptane (50:50), then EtOAc and then MeOH and EtOAc (1:99, 2:98 and 5:95), gave the title compound (0.461 g, 57.5%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.42 (s, 9H), 2.53 (d, 2H), 2.85-2.96 (m, 1H), 3.60 (dd, 2H), 4.09 (t, 2H), 5.78 (s, br, 2H); 13C NMR (100 MHz, CDCl3): 25.4, 28.3, 39.7, 54.3 (br), 79.4, 156.3, 173.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[C:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:15]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:48]([C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1)([O-:50])=[O:49]>O1CCCC1>[N+:48]([C:51]1[CH:52]=[CH:53][C:54]([C:55]([O:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[C:15]2=[O:28])=[O:56])=[CH:58][CH:59]=1)([O-:50])=[O:49]
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCN(CC#CCN2CCCC2)C1=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A solution of 0.9 g of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was added dropwise to a solution of 0.9 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone, 1.1 g of triphenylphosphine and 0.9 g of 4-nitrobenzoic acid in 30 ml of dry tetrahydrofuran. The mixture was stirred overnight and the solvent was removed in vacuo. The residue was purified by chromatography (silica gel), giving 1.2 g of the desired product as off white crystals, [α]D26° =+41°-(dichloromethane); mp 89°-90° C.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:21]([O-])=O)[C:16]([Cl:20])=[CH:17][C:18]=2[CH3:19])=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:16]([Cl:20])=[CH:17][C:18]=2[CH3:19])[NH2:21])=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc([N+](=O)[O-])c(Cl)cc2C)ccc(C(C)=O)c1O
Agent: [Ni]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cc(N)c(Cl)cc2C)ccc(C(C)=O)c1O

Procedure:
4.0 g of Raney nickel are added to a solution of 19 g (45 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chloronitrobenzene in 200 ml of tetrahydrofuran and the whole is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is concentrated to dryness by evaporation under reduced pressure and the residue is recrystallised from ether/hexane. 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chloroaniline having a melting point of 81° C. is obtained.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:29][C:28]([F:30])([F:31])[CH:27]([CH3:32])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:20][CH:19]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1NCc2ccccc21
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
At 0° C., 222.6 mg (1.67 mmol) of 2,3-dihydro-1H-isoindol-1-one were added to 66.9 mg (1.67 mmol, 60% pure) of sodium hydride in 2 ml of DMF. The mixture was stirred for 30 min, and 600 mg (1.39 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate were then added at 0° C. The reaction mixture was stirred for a further 2 h, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 108 mg (19% of theory) of the target compound.
Reaction SMILES: [CH:1](/[CH2:9][C:10]([OH:12])=[O:11])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13]S(O)(=O)=O.C[O-].[Na+]>CO.C(OC)(OC)OC>[C:3]1(/[CH:2]=[CH:1]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C/C=C/c1ccccc1
Reactant: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)C/C=C/c1ccccc1

Procedure:
A solution of 3.24 mg (20 mmol) of (E)-styrylacetic acid in 20 ml of methanol,2 ml of trimethyl orthoformate and 192 mg (2 mmol) of methanesulphonic acid was stirred at 50° C. under argon for one hour. For the working-up, the mixture was neutralized with 2 mmol of sodium methylate and subsequently the solvent mixture was distilled off under reduced pressure. There was obtained methyl (E)-4-phenyl-but-3-enoate as a colourless liquid in quantitative yield; MS: 176 (M)+.