Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.[N:19]1([CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:9][CH2:10]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([N:22]2[CH2:23][CH2:24][N:19]([CH:25]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28]3)[CH2:20][CH2:21]2)=[O:16])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(Cl)c(C2(C)CC2)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C2(C)CC2)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetic acid (110 mg, 0.41 mmol) and tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (118 mg, 0.49 mmol) in DMF (15 mL) at RT, BOP (217 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (192 mg, 95% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[F:9][CH2:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[N:12]=1>O>[F:9][CH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([OH:18])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(CF)n1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)nc(CF)nc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of fluoroacetonitrile (11 g) in ethanol (10.9 mL)-diethyl ether (186 mL) was bubbled with hydrogen chloride under ice-cooling until the solution was saturated with hydrogen chloride with stirring, and the mixture was stirred at the same temperature for 4 hours. The precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give ethyl 2-fluoroacetimidate hydrochloride (24.9 g). This material was suspended in ethanol (50 mL). To the suspension was added ethanol (130 mL) containing ammonia (about 5 g), and the mixture was stirred at room temperature overnight. The crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give 2-fluoroacetamidine hydrochloride (16.3 g). To a mixture of sodium methoxide (28% methanol solution, 83.6 mL) and methanol (145 mL) was added 2-fluoroacetamidine hydrochloride (16.3 g), followed by adding diethyl malonate (22.0 mL), and the mixture was heated at reflux for 11 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water (145 mL). The mixture was acidified by adding concentrated hydrochloric acid (18 mL), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g). To a mixture of fuming nitric acid (36 mL) and acetic acid (18 mL) was added 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g) slowly under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled in ice. To the mixture was added cold water, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give the title compound (16.8 g).
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])=[O:3].C([Li])CCC.[P:14](Cl)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][P:14]([CH2:1][S:2]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])=[O:3])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)OS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OC(C)C)OCC
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a rapidly stirred solution of 8.28 g (60 mmol) of isopropyl methanesulfonate in 150 mL of THF at -73° C. (internal temp.) was added 25 mL (60 mmol) of 2.4M n-butyllithium dropwise over 20 min. The internal temperature was not allowed to rise above -69° C. throughout the course of the addition. After an additional 15 min., 5.17 g (30 mmol) of freshly distilled diethyl chlorophosphate was added at a rate to keep the solution temperature below -69° C. The reaction mixture was stirred for 0.3 h at -73° C. and for 0.5 h at -40° C. when it was quenched with 125 mL of saturated NH4Cl solution. The reaction mass was warmed to room temperature and the THF removed under reduced pressure. The remainder was partitioned between methylene chloride and water (3×75 mL). The extracts were dried (Na2SO4), concentrated, and purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether to provide 5.20 g (67%) of title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+]>O.CO>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-(3-Amino-phenyl)-3,4-dihydro-1H-benzo[h]quinolin-2-one (0.29 g, 1 mmol) was dissolved in a mixture of con. sulfuric acid (2.5 ml), water (2.5 ml) and methanol (2.5 ml). The solution was stirred at 0° C. and a solution of sodium nitrite (0.83 g, 1.2 mmol) in water (1 ml) was slowly added. The solution was stirred at 0° C. for 0.5 hr and a solution of sodium azide (0.13 g, 2 mmol) in water (1 ml) was added. The mixture was stirred at 0° C. for 0.5 hr followed by overnight stirring at ambient temperature. Water was added and the precipitate separated by filtration. The product was purified by reverse phase HPLC (0.05 g, 0.15 mmol) (water-acetonitrile gradient, 0.05% formic acid, 90:10 to 10:90, 20 min, linear gradient; flow, 15 ml/min; column, Phenomenex Luna 5μ C18, 100×21.2 mm; UV 254 and 218 nm).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Methyl chloro(oxo)acetate (0.842 mL) was added to a stirred solution of methyl [trans-4-(4-aminophenyl)cyclohexyl]acetate (1740 mg) and pyridine (0.689 mL) in DCM (50 mL) at 0° C. After the addition was complete the mixture was allowed to warm to ambient temperature and stirred for 64 hours. The solution was diluted with DCM (100 mL), washed with water (50 mL) and brine (50 mL), then dried and concentrated in vacuo to give the title compound (2267 mg) as a solid; 1H NMR δ 7.60 (2H, d), 7.18 (2H, d), 3.83 (3H, s), 3.58 (3H, s), 2.58-35 (1H+DMSO, m), 2.21 (2H, d), 1.75 (5H, m), 1.43 (2H, m), 1.12 (2H, m); MS m/e MH− 332.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-methylaniline (25 g) and diketene (11.8 cm3) in toluene (100 cm3) was heated with stirring under reflux for 5 hours. On cooling to room temperature the precipitated solid was filtered off and recrystallised from hexane/ethyl acetate to afford N-[4-bromo-2-methylphenyl]-acetoacetamide, m.p. 109° (14.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)n3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 95 mg (0.34 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 16 mg (0.41 mmol) of 60% sodium hydride, 77 mg (0.41 mmol) of 2-bromomethyl-6-methyl-pyridine and 1 mL of N,N-dimethylformamide. Yield: 14 mg of a white solid: LC-MSD, m/z for C24H21N3O2 [M+H]+=384.1; HPLC retention time: 1.9 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:5])[CH3:2].[CH3:16]C(O)C>>[CH3:2][CH:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:5])[CH3:16]
Reactant: CCOC(=O)c1ccc2c(c1)COC2=O
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccc2c(c1)COC2=O
Temperature: 0 °C

Procedure:
Method B): 5-Ethoxycarbonylphthalid (52 g, 0.25 mole) is suspended in 2-propanol (1000 mL). Ti(iPro)4 (38 g, 0.14 mole) is added and the mixture is refluxed for 3 hours. The reaction mixture is cooled to 0° C. and the crystals are filtered off and washed with cold 2-propanol (70 mL). Yield: 47 g, 85%. DSC onset 144° C.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[Cl:8][CH:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1>CO.ClCCl>[Cl:8][CH:9]1[CH2:12][CH:11]([C:13]([O:15][CH3:2])=[O:14])[CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1CC(Cl)C1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(Cl)C1

Procedure:
TMS-diazomethane (2.0 M in diethyl ether, 2.2 ml, 4.4 mmol) was added dropwise to a solution of 3-chlorocyclobutanecarboxylic acid (540 mg, 4.0 mmol) in methanol (5.0 mL) and dichloromethane (5.0 mL) at 0° C. The reaction mixture was concentrated under reduced pressure to afford methyl 3-chlorocyclobutanecarboxylate. The material was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:12]([S:14]([C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH:22]=1)(=[O:16])=[O:15])[CH3:13]>C1COCC1>[F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([O:8][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:22][C:21]=2[C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH2:4][CH2:3]1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3cncn23)c1
Reactant: OC1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC2CCC(F)(F)CC2)c(-c2cn(C)c(=O)c3cncn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25° C. for 18 hours. The reaction contents were poured into ice-water (v/v=1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1=8.8 Hz, J 2=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz, 2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS: 452.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[NH:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=O)[CH2:6][CH2:5]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[N:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=13
Reactant: Cc1ccc(N2CCc3cc(Br)ccc32)c(NC(=O)N2CCN(C)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(Br)cc3c1N2CC3
Yield: 53.8 %

Procedure:
A solution of N-[2-(5-bromo-1-indolinyl)-5-methylphenyl]-4-methyl-1-piperazinecarboxamide (3.3 g, 7.68 mmoles) and phosphorus oxychloride (30 ml) was heated at reflux for 25 minutes under nitrogen. The solution was cooled and excess phosphorus oxychloride was removed at 55°-60° C. under vacuum. Ice-chilled 2N-sodium hydroxide solution (100 ml) and dichloromethane (250 ml) were added to the residue. The organic phase was separated and washed with brine (2 times, 100 ml), dried over anhydrous magnesium sulfate, and concentrated. Purification was accomplished by flash chromatography over aluminum oxide (Grade III, 100 g), eluted with dichloromethane (2 l). The fractions containing pure material were pooled and concentrated. Recrystallization from isopropanol (30 ml) yielded 1.7 g (53.9%) of product, mp 187°-189° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[C:18]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:17]=[CH:16][C:15]=3[CH3:26])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.I[CH3:28]>>[CH:1]1([CH2:4][N:5]([CH3:28])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[C:18]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:17]=[CH:16][C:15]=3[CH3:26])=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)CC4CC4)cc3)c2)o1

Procedure:
N-(Cyclopropylmethyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method H.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I>O>[Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:15])=[CH:4][CH:3]=1
Reactant: II
Reactant: Oc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 6-chloropyridin-2-ol (3.00 g, 23.2 mmol) and sodium carbonate (4.88 g, 46.4 mmol) in water (60 mL) was added iodine (5.84 g, 23.0 mmol), and the mixture was stirred at room temperature overnight. The resulting solid was collected by filtration, 1N hydrochloric acid was added to the obtained solid, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and to the obtained residue were added diisopropyl ether and hexane, and the resulting solid was collected by filtration to give the title compound (1.04 g, yield 18%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH:8]([OH:25])[CH2:9][N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH:8]([OH:25])[CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: NCC(O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NCC(O)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2-chloroacetyl chloride (1.25 g, 10.96 mmol) in CHCl3 was added to the solution of 1-amino-3-(dibenzylamino)propan-2-ol (2.5 g, 9.26 mmol) in CHCl3 (50 mL) in ice-bath. The mixture was stirred for 1 hour, then stirred at room temperature for 2 hours. The organic layer concentrated, the residue was purified by column to give white solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].C([O-])(O)=O.[Na+].[CH2:11]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>CCO>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:24]1[CH2:25][CH2:26][N:21]([CH2:11][C:12]2[CH:20]=[CH:19][C:18]3[O:17][CH2:16][O:15][C:14]=3[CH:13]=2)[CH2:22][CH2:23]1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(Cc2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To a mixture of epichlorohydrin (3.9 mL, 50 mmol) in EtOH (25 mL) and anhydrous NaHCO3 (4.2 g, 50 mmol), 1-piperonylpiperazine (11.0 g, 50 mmol) in EtOH (125 mL) was added dropwise over 45 min at 0° C., under nitrogen. After 16 h and removal of the EtOH in vacuo, the crude material was passed through silica gel (vacuum, 5% MeOH:CH2Cl2) to give pure product (3.85 g, 26.4%) as an amber oil. DCI/MS (M+1) 313. 400 MHz 1H NMR (CDCl3)δ: 7.25 (s, 1H), 6.7-6.8 (m, 2H), 5.9 (s, 2H), 4.6 (m, 1H),3.9 (m, 1H), 3.5 (m,2H), 3.4 (s, 2H), 2.4-2.7 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:32]/[C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Cl:28])[CH:30]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Reactant: O=Cc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2cccc(Cl)c2)COC1(C)C

Procedure:
In analogy to example 83c. from (R)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 3-chloro-benzaldehyde. Off-white solid. MS (ISP): 340.2 ([{37Cl}M+H]+), 338.2 ([{35Cl}M+H]+).
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:41])[CH2:9][CH2:10][C@@H:11]([C:27](N2[C@H](C3C=CC=CC=3)COC2=O)=[O:28])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Na+]>C1COCC1>[CH:1]1([O:7][C:8](=[O:41])[CH2:9][CH2:10][C@@H:11]([CH2:27][OH:28])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[N:14]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCC(=O)OC2CCCCC2)C(=O)N2C(=O)OC[C@H]2c2ccccc2)COC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H](CO)CCC(=O)OC2CCCCC2)COC1(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
The (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-5-oxo-2-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (8.12 g, 13.9 mmol, 1.0 equiv) was dissolved in a 4:1 mixture of THF:MeOH (150 mL) and the solution cooled to 0° C. Solid NaBH4 (1.05 g, 27.8 mmol, 2.0 equiv) was added in ca 200 mg portions over a 20 min period. The solution was stirred at 0° C. for 4 h. During this time two additional 500 mg portions of NaBH4 were added. After this time LC/MS analysis showed consumption of the starting material. The excess hydride reagent was quenched by the addition of 10,% citric acid. The mixture was diluted with ca 100 mL of EtOAc and the organic layer separated. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The alcohol was purified by flash chromatography on silica, (120 g), eluting with 0-41% EtOAc in hexanes. This afforded 5.2 g (90% yield) of (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a clear syrup. MS ESI +ve m/z 436 (M+Na).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:19]1[N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:22]=[C:21]([CH:28]=O)[CH:20]=1)[CH2:17][CH3:18]>>[C:24]([N:23]1[C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][C:21]([CH2:28][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:22]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: CCCc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1C(C)(C)C
Yield: 64.2 %

Procedure:
Compound 3 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.C(OCC)(=O)C>[C:21]([CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[CH:14][C:15]=1[O:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])#[N:22]
Reactant: N#CCc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccccc1CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (6.2 ml, 39.4 mmol) was added dropwise to an ice-cooled solution of 3-hydroxyphenyl acetonitrile (preparation 126) (4.2 g, 31.5 mmol), triphenylphosphine (10.34 g, 39.4 mmol) and tert-butyl 2-hydroxyethylcarbamate (5.4 ml, 34.9 mmol) in tetrahydrofuran (70 ml), and once addition was complete, the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 ml), washed with 1N NaOH solution, water, brine, then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (30:70) as eluant to give the desired product as a yellow/green oil, that crystallised on standing, (5.88 g, 68%).
Reaction SMILES: [CH:1]1([CH2:13][C:14]#N)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[NH4+:17]>CO.[Ni]>[CH:1]1([CH:13]([NH2:17])[CH3:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: N#CCC1Cc2cccc3cccc1c23
Reactant: [NH4+]
Agent: [Ni]
Agent: [OH-]
Solvent: CO
Product: CC(N)C1Cc2cccc3cccc1c23
Reaction time: 23 h

Procedure:
The nitrile obtained in Step B (900 mg, 4.66.10−3 mol), diluted with methanol (30 ml), is hydrogenated with vigorous stirring at ambient temperature in the presence of ammonium hydroxide (2 ml) and Raney nickel. After 23 hours, the starting material has disappeared. After filtering over Celite, then rinsing and evaporating off the solvent under reduced pressure, the title amine is obtained in the form of an oil, which is used without being purified.