Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C[N:51](C)C=O>>[CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:51])[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:12][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Solvent: Ic1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1

Procedure:
1-[4-(2-Carbamoylpyridin-4-yloxy)-2-fluorophenylcarbamoyl]-cyclopropanecarboxylic acid benzyl ester (2 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature, and water (0.481 ml) was added. Iodobenzene diacetate (2.87 g) was added at room temperature with stirring, and the reaction mixture was stirred for 2.5 hours. Water (40 ml) was added to the reaction mixture, and the reaction was quenched by the addition of a 2N aqueous solution of sodium hydroxide until pH became 11and ethyl acetate was added and the layers were separated. The organic layer was washed with water and a 5% aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resultant crude brown oil was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:1, then 1:2) to give the title compound (819 mg) as cream crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].FC1C=CC=CC=1CBr.C1(C(Cl)=O)CCC1>>[Cl:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: Clc1ccccc1CBr
Reactant: O=C(Cl)CCCCl
Agent: Fc1ccccc1CBr
Agent: O=C(Cl)C1CCC1
Product: O=C(CCCCl)Cc1ccccc1Cl
Yield: 79 %

Procedure:
Following a procedure similar to that described in Preparation 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-chlorobutyryl chloride were used in place of the 2-fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a yellow oil in a yield of 79%.
Reaction SMILES: C[O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.B(Cl)(Cl)Cl.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1
Reactant: COc1ccsc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a mixture of 3-[3-(3-methoxy-2-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.500 g, 1.14 mmol) and methylene chloride at −5° C. is added boron trichloride (1M in methylene chloride, 2.30 ml, 2.3 mmol) via syringe. The resultant mixture is stirred two hours at −5° C., warmed to room temperature, stirred overnight and poured into cold 10% hydrochloric acid. The mixture is extracted with methylene chloride. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to an oil. The oil is crystallized in ether to afford the title compound as pale yellow-green crystals (0.350 g, 72.2%) which is characterized by NMR spectral analysis.
Reaction SMILES: Cl.C[O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:13][C:14](=[O:33])[CH2:15][NH:16][C:17](=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]=1)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1>>[NH:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([NH:16][CH2:15][C:14]([NH:13][C@H:6]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][C:4]([OH:34])=[O:3])=[O:33])=[O:32]
Reactant: COC(=O)C[C@H](NC(=O)CNC(=O)CCCCNc1nc2ccccc2[nH]1)c1cccnc1
Agent: Cl
Product: O=C(O)C[C@H](NC(=O)CNC(=O)CCCCNc1nc2ccccc2[nH]1)c1cccnc1

Procedure:
A 6N HCl solution (5 ml) of 24-8 (33 mg, 0.073 mmol) was stirred under ambient conditions for 18 hr. The reaction was concentrated to give a viscous gum which was purified by prep HPLC (Delta-Pak C18, gradient elution over 40 min., 5-50% CH3CN/H2O-0.1% TFA) to give 24-9.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C:20]=3[F:34])[CH2:15][CH2:14]2)=[CH:9][N:8]=1)(=O)=O.C1COCC1.[CH3:42][O:43][CH2:44][CH2:45][NH2:46].O>CCOC(C)=O>[F:34][C:20]1[C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:9]=[N:8][C:7]([NH:46][CH2:45][CH2:44][O:43][CH3:42])=[N:12][CH:11]=3)[CH2:14][CH2:15]2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:25][OH:26]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCN(c3cnc(OS(=O)(=O)C(F)(F)F)nc3)CC2)c1F
Reactant: COCCN
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNc1ncc(N2CCN(c3cccc(CO)c3F)CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yl trifluoromethanesulfonate (200 mg) was mixed with THF (4 ml), and 2-methoxyethanamine (864 mg) was added thereto, followed by stirring at 60° C. overnight. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (5 ml), and a 1 M TBAF/THF solution (1.6 ml) was added thereto, followed by stirring at room temperature overnight. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain [2-fluoro-3-(4-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}piperazin-1-yl)phenyl]methanol (105 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][OH:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(F)cc1)n1cc(CO)cc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Yield: 79.7 %

Procedure:
Using {1-[(4-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanol (405 mg), tetra-n-propylammonium perruthenate (42 mg), N-methylmorpholine N-oxide (247 mg) and molecular sieves 4A powder (1.0 g), a procedure as in Reference Example 6 was performed to give the title compound as a brown oil (yield 321 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2].I[Si](C)(C)C>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Oc2ccc(OC)nc2)c1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(Oc2ccc(O)nc2)c1
Yield: 68.9 %

Procedure:
A solution of 3-(6-methoxy-pyridin-3-yloxy)-benzoic acid ethyl ester (0.5 g, 1.83 mmol) in acetonitrile (8 ml) and iodotrimethylsilane (0.439 g, 2.2 mmol) was refluxed for 1 h, the mixture was diluted with water (8 ml) and extracted with chloroform. The extract was washed with 10% of aqueous Na2S2O3, water, dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford 0.327 g (69%) of 3-(6-hydroxy-pyridin-3-yloxy)-benzoic acid ethyl ester as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: NCCCN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNCCCN1CCOCC1
Temperature: 70 °C
Yield: 45.9 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described in Example 278), and 4-(3-aminopropyl)morpholine (0.12 ml, 0.84 mmol) in DMF (5 ml) was heated to 70° C. for 3 hours. The solvents were removed in vacuo and the residue taken up in dichloromethane. This was washed with water, dried (MgSO3), filtered and evaporated. The residue was purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(3-morpholinopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (67 mg, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH:10]2[CH2:13][O:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].NN>>[N+:1]([C:4]1[CH:9]=[C:8]([CH:10]2[CH2:11][O:12][CH2:13]2)[CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(C2COC2)cc1[N+](=O)[O-]
Agent: NN
Product: Nc1ccc(C2COC2)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 69.1 %

Procedure:
A suspension of N-(2-nitro-4-oxetan-3-ylphenyl)acetamide (125 mg, 0.529 mmo) in aqueous hydrazine (8 ml, 160 mmol) was heated at 70° C. for 2 h, the reaction mixture was cooled to 45° C. and the hydrazine was removed in vacuo to yield a solid. The crude material was purified by flash chromatography (SiO2, eluting with 20% EtOAc/CH2Cl2 to yield the desired product (71 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][CH2:26][CH:27]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:27][CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)[C@H]1CC[C@@H](NCCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cis-4-amino-cyclohexanecarboxylic acid benzyl ester (8 g, 34 mmol) and benzyloxyacetaldehyde (4.8 mL, 34 mmol) in 1,2-dichloroethane (2 L), was stirred at room temperature overnight. Then NaBH(OAc)3 (11 g, 51 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Most of the solvent was then removed by vacuum. EtOAc (1 L) was added, and the resulting solution as washed with brine. The organic layer was dried over MgSO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography with flash silica gel (1:1 heptane/EtOAc) to yield cis-4-(2-benzyloxy-ethylamino)-cyclohexanecarboxylic acid benzyl ester as an oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:9][C:4]=2[C:3]([OH:2])=[O:24])[CH:29]=[N:30][CH:31]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cncc(Cl)c1
Yield: 8.7 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 5-chloropyridine-3-boronic acid (available from Combi-Blocks Inc.; 63 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(5-chloro-pyridin-3-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (8 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.47-8.55 (m, 3H), 8.34 (d, J=2.0 Hz, 1H), 8.29 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 8.02 (t, J=2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2].N[C:24]1C=C2C(=CC=1)NC(CCC)=C2>>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([CH2:1][CH2:2][CH3:24])=[CH:11]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1
Reactant: CCCc1cc2cc(N)ccc2[nH]1
Product: CCCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1

Procedure:
Refer to 45a) using 5-amino-2-propylindole.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)[NH2:3]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of hydrazine monohydrate (9.71 g) dissolved in ethanol (200 mL) and cooled at 0° C., added was a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15.0 g) dissolved in ethanol (200 mL), and stirred for 1 hour. The precipitated solid was collected through filtration, washed with distilled water and dried to give the entitled compound as a white solid (9.66 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:19])[C:8]([CH3:20])=[CH:7]1)[CH3:2]>C(O)C.ClCCl.[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9](=[O:19])[C:8]([CH3:20])=[CH:7][N:6]2[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21]
Reactant: CCOC(=O)Cn1cc(C)c(=O)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(C)c(=O)c2c(N)cccc21

Procedure:
A solution of (3-Methyl-5-nitro-4-oxo-4H-quinolin-1-yl)-acetic acid ethyl ester (Compound 301B, 250 mg, 0.86 mmol) in ethanol and dichloromethane (10 mL/20 mL) was cautiously treated with palladium on charcoal (10%) (30 mg) and hydrogenated at atmospheric pressure for 1 hr. The mixture was filtered and the filtrate was concentrated to a residue which upon trituration with t-butyl methyl ether gave the desired product as 150 mg of a light yellow solid (67%). 1H NMR of compound C (CDCl3, 300 MHz): δ 1.24 (t, 3H, J=7.5 Hz), 2.04 (s, 3H), 4.22 (q, 2H, J=7.5 Hz), 4.58 (s, 2H), 6.18 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.5 Hz, 1H), 7.24 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][O:13][C:19]2=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCCNCc1ccc(Br)nc1
Solvent: ClCCl
Product: O=C1OCCCN1Cc1ccc(Br)nc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a solution of 196 (0.9 g, 3.67 mmol) in DCM (30 mL) was added CDI (0.595 g, 3.67 mmol), and the reaction mixture was stirred at RT over weekend. The mixture was then concentrated and the residue was purified by flash column chromatography (eluent EtOAc) to afford the title compound 197 (373 mg, 38% yield) as colorless oil. MS: 271 (HM+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COC[CH2:12]1.[CH2:16]([C@H:18]1[O:23][CH2:22][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]1=[O:37])[CH3:17].ICC>COCCOC>[CH2:16]([C:18]1([CH2:11][CH3:12])[O:23][CH2:22][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]1=[O:37])[CH3:17]
Reactant: CC[C@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COCCOC
Solvent: CCI
Product: CCC1(CC)OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (1.64 mL, 1.64 mmol) at −78° C. was added dropwise a solution of tert-butyl (2R,5R)-2-ethyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (500 mg, 1.64 mmol) in DME (25 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodoethane (0.131 mL, 1.64 mmol) was added. After stirring at −78° C. for 30 min, then at −30° C. for 30 min, the reaction mixture was cooled to −78° C. and quenched with saturated aqueous NH4Cl (20 mL) then extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 70:30, to give the title compound. MS: m/z=278 (M−C4H7).
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Na].[OH-].[Na+]>O.C(O)(=O)C>[CH:19]1([N:9]2[CH2:8][CH2:7][C:6]3([CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]3)[CH2:11][CH2:10]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(C3CCCCC3)CC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (3.2 g) and a 10% acetic acid-anhydrous N,N-dimethylformamide (50 mL) solution of cyclohexanone (1.9 mL) were stirred at room temperature for 4 hours. To the resultant solution, sodium tiacetoxy borohydride (5.2 g) was added. The reaction solution was stirred at room temperature for 15 hours. To the reaction solution, water (100 mL) and an aqueous 1N-sodium hydroxide solution (100 mL) were added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=1:0→8:2) to obtain the title compound having the following physical properties (3.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[C@H:8](O)[CH2:7][CH2:6][NH:5]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH:8]([N:58]=[N+:59]=[N-:60])[CH2:7][CH2:6][NH:5]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1NCC[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)[C@H]1NCCC1N=[N+]=[N-]

Procedure:
Reaction of cis-3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
Reaction SMILES: NC1C=CC=CC=1C([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=O.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C>[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21])([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]

Procedure:
t-Butyl 2-aminobenzoate ##STR103## A mixture of 2-nitrobenzoyl chloride (15 mL, 110 mmol) and t-BuOH (100 mL) were heated at reflux for 3 h. The cooled mixture was poured onto ice-water, basified with Na2CO3 and extracted with CH2Cl2 (×2). The combined organic extracts were washed with brine, the solvents evaporated in vacuo and the residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5) as eluant to give t-butyl 2-nitrobenzoate (4.9 g, 22 mmol) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10]Cl.[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C.C(#N)C>[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[O:20][CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:28][CH2:27]2
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)CCOc1ccc2c(c1)CCC(c1ccccc1)O2

Procedure:
Cesium carbonate (230 mg) and an excess of 2-(dimethylamino)ethyl chloride in ethyl acetate were added into a solution of 2-phenylchroman-6-ol (150 mg) in acetonitrile (5 ml). The reaction mixture was refluxed for 30 minutes. After removing the solvents, the residue was taken up in water and extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated NaCl-solution and dried with Na2SO4. The dimethyl[2-(2-phenylchroman-6-yloxy)-ethyl]amine was crystallised from heptane. 1H NMR (400 MHz, d6-DMSO) δ: 7.43-7.30 (m, 5H), 6.75-6.67 (m, 3H), 5.03 (dd, 1H, J 10.0, 2.2 Hz), 3.95 (t, 2H, J 5.9 Hz), 2.94 (ddd, 1H, J −16.7, 10.9, 5.8 Hz), 2.69 (ddd, 1H, J −16.7, 5.2, 3.3 Hz), 2.58 (t, 2H, J 5.9 Hz), 2.13 (m, 1H), 1.96 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]=[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]=[N:7][OH:8].Br.[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29]Br)[CH2:23]1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][O:8][N:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH2:3][CH:2]([CH3:15])[CH3:1])[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: CC(C)CC=C(C=NO)c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=CC(=CCC(C)C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.6 %

Procedure:
A mixture of the above oxime (2.0 g, 10 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (3.4 g, 10 mmol), potassium carbonate (4.7 g, 34 mmol) and acetone (25 ml) was stirred at room temperature for 4 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (75 g, cyclohexane/ethyl acetate, gradient 3/1 to 2/1) to give 1.3 g of (R)-1-(2-(((5-methyl-2-phenyl-2-hexen-1-ylidene)-amino)oxy)ethyl)-3- piperidinecarboxylic acid ethyl ester.