Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:15][CH3:16])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoate (1.06 g, 3.36 mmol), THF (10 mL) and MeOH (10 mL). To the solution was added aq. LiOH (1.0 M, 5.04 mL). The mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuo, and the resulting aqueous solution was acidified with aq HCl (1.0 M) and then transferred to a separatory funnel. The solution was twice extracted with EtOAc and the combined organics were dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid as a colorless solid foam (1.00 g, 99% yield).
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][C:3]=1[CH2:17][CH3:18].FC(F)(F)C([O-])=[O:22].[K+].FC(F)(F)C(O)=O>>[CH2:17]([C:3]1[S:4][C:5]2[N:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[OH:22])[CH3:18]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)c1nc2sc(CC)c(N)c2c(=O)[nH]1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2sc(CC)c(O)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The diazonium fluoborate salt is prepared as in Procedure 63 from the amino compound produced in Procedure 51 yielding 0.03 mole of the required diazonium fluoborate. The latter is added in one portion to a solution of 0.03 mole of potassium trifluoroacetate in 13 ml. of trifluoroacetic acid at 0° C. The mixture is stirred at 25° C. for one hour and then refluxed overnight. The trifloroacetic acid is evaporated in vacuo to give a residue which is triturated with water and filtered to give the desired product.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](=[O:7])[CH3:6].[CH:11](OC)(OC)[O:12]C.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2]/[N:3]=[C:4](/[C:8]([O:12][CH3:11])([O:10][CH3:18])[CH3:9])\[C:5](=[O:7])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Reactant: CON=C(C(C)=O)C(C)=O
Solvent: CO
Product: CO/N=C(\C(C)=O)C(C)(OC)OC
Temperature: 50 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
4.3 g (0.03 mol) of pentane-2,3,4-trione 3-(O-methyloxime) and 6.2 g (0.06 mol) of trimethyl orthoformate were dissolved in 15 ml of methanol and admixed with a spatula tip of p-toluenesulfonic acid. The mixture was subsequently stirred at 50° C. for 5 h, after which the solvent was distilled off. This gave 5.5 g of an oil (98% yield) (phys. data see Tab. 1).
Reaction SMILES: [ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[NH:6])#[N:3].C([OH:18])(C)C>>[ClH:1].[ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[NH:6])(=[O:18])[NH2:3]
Reactant: CC(C)O
Reactant: N#CNC(=N)NCc1ccncc1
Agent: Cl
Product: N=C(NCc1ccncc1)NC(N)=O

Procedure:
Concentrated HCl (21 ml) is added to a mixture of 1-cyano-3-(4-pyridylmethyl)guanidine (10.0 g) in 500 ml of isopropanol. A pale yellow precipitate forms. The stirred suspension is heated on a steam bath and boiled for ten minutes. The solvent is evaporated under reduced pressure and the residual solid treated with 25 ml of concentrated HCl. The solution is heated on a steam bath for several minutes and diluted with isopropanol (50 ml) and allowed to cool. The resulting solid is collected and dred in air, extracted into 900 ml of methanol, which is filtered, and concentrated on a not plate. The hot solution is diluted with ethyl acetate and concentrated further. A white precipitate forms on cooling which is collected and dried in air giving the desired amidinourea dihydrochloride, MP 208°-209.5° C. w/dec.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CO>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: CO
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 75 °C
Yield: 74 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and methanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was slowly heated under nitrogen to reflux (75° C.) and kept at this temperature overnight. The reaction mixture was allowed to cool to below 50° C. and water (15 mL, 3 vol) was added. The precipitated light yellow solid was isolated by filtration, then was washed twice with water (5 mL) and dried to provide olanzapine in 74% yield (4.35 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[N:16]1[CH:21]=CC=[CH:18][CH:17]=1.C(OCC)(=[O:24])C>>[ClH:8].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([O:24][CH2:18][CH2:17][NH:16][CH3:21])=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Product: CNCCOC(=O)c1cc(OC)c(OC)c(OC)c1
Product: Cl
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 3,4,5-trimethoxybenzoyl chloride (2.54 g) and pyridine (0.97 mL). After stirring at 60° C. for 14 hrs., 3,4,5-trimethoxybenzoyl chloride (1.30 g), pyridine (0.97 mL) and ethyl acetate (10 mL) were added, and the mixture was stirred at 60° C. for 24 hrs. The reaction mixture was filtered and ethyl acetate (50 mL) and water (30 mL) were added to the filtrate. After partitioning, ethyl acetate layer was washed with 1N hydrochloric acid (30 mL), water (30 mL), an aqueous copper (II) sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:1). A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the purified product. After stirring at room temperature for 4 hrs, the mixture was concentrated under reduced pressure. Toluene (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the solid was filtrated. After washing with ethyl acetate (15 mL), the solid was dried under reduced pressure to give the title compound (1.79 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]3[C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:12]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:27])[NH2:30]
Reactant: N
Reactant: COC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-3-yl)benzo[d]oxazole-7-carboxylate (360 mg, 0.92 mmol) was added to a solution of ammonia in methanol (10 mL) and the mixture was stirred at room temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4), the organic phase was dried with anhydrous sodium sulfate and evaporated under reduced pressure. 200 mg benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. Yield: 26%. LC-MS (ESI) m/z: 380 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:26]4[CH2:27][CH2:28][CH2:29][S:25]4(=[O:31])=[O:30])=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3C)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 58.2 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodo-2-methylphenyl)methanone (487 mg) described in Preparation Example 154 and isothiazolidine 1,1-dioxide (136 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (279 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:10][OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CO[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a round bottom flask containing a stir bar and (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid (2.5 g, 10.7 mmol) in THF (80 mL) under nitrogen was cooled to −30° C. in a dry ice/acetone bath. To this cold solution was added isobutyl chloroformate (1.7 mL, 12.9 mmol) followed by the addition of N-methylmorpholine (1.4 mL, 12.9 mmol). Mixture was stirred for 15 min at −30° C. N-Methylmorpholine salt develops and was filtered from mixture. Mother liquor was cooled to −30° C. where upon sodium borohydride (0.61 g, 16.1 mmol) was added followed by the addition of water (10 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. Reaction mixture was stirred for 30 min at room temperature. Reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford tert-butyl((2R,3R)-1-hydroxy-3-methoxybutan-2-yl)carbamate (2.0 g, 9.1 mmol, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J=6.26 Hz, 3H) 1.45 (s, 9H) 3.33 (s, 3H) 3.55-3.84 (m, 4H). LCMS m/z 220.2 (M+H)+, Rt 0.57 min.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.ClC1C2N=CC(Cl)=CC=2[N:34]=[CH:35][N:36]=1>>[Cl:24][C:21]1[CH:20]=[N:19][C:18]2[C:17]([NH:16][C:11]3[CH:10]=[C:9]([C@:6]4([CH3:8])[CH2:5][C@@H:4]([C:26]([F:29])([F:28])[F:27])[O:3][C:2]([NH2:1])=[N:7]4)[C:14]([F:15])=[N:13][CH:12]=3)=[N:36][CH:35]=[N:34][C:23]=2[CH:22]=1
Reactant: Clc1cnc2c(Cl)ncnc2c1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(Nc3ncnc4cc(Cl)cnc34)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The title compound was synthesized using steps and procedures analogous to those described in Method B (step 2) above, but using (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a) and 4,7-dichloropyrido[3,2-d]pyrimidine (intermediate 9). MS m/z=456.0 [M+H]+. Calculated for C18H14ClF4N7O: 455.8
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O:27][CH:28]([CH2:33][CH2:34][CH3:35])[CH:29](Br)[CH2:30][CH3:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37](C)C=O.C(N)CN>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O:27][CH:28]([CH2:33][CH2:34][CH3:35])[CH:29]([C:36]#[N:37])[CH2:30][CH3:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCC(OC(=O)c1ccccc1)C(Br)CC
Reactant: CN(C)C=O
Agent: CCCCCCc1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: NCCN
Product: CCCC(OC(=O)c1ccccc1)C(C#N)CC
Yield: 66 %

Procedure:
2.65 g (5.10-3 moles) of p-hexyl biphenyl-3-bromo-4-heptyl benzoate and 0.6 g (6.7×10-3 moles) of cuprous cyanide are introduced into 10 ml of dimethyl formamide. After the solution has been heated under reflux for 7.5 hours, it is cooled and poured into a mixture of 60 ml of deionized water and 5.5 ml of ethylene diamine. After stirring, the solution is extracted with ether. 2.2 g of crude product are obtained, being purified by chromatography on a column of silica, followed by recrystallization from ethanol. 1.6 g of pure product are obtained, corresponding to a yield of 66%.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:6]2[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]2=[O:7])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC1CCC(=O)N1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CCC(=O)N1S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
A flame dried flask was charged with 444 mg sodium hydride (60% wt in oil, 11.1 mmol, 1.1 equiv) under N2. The solid was washed (2×hexanes) followed by the addition of 100 mL anhydrous THF. The solution was cooled to 0° C. followed by the addition of 1 g 5-methyl-2-pyrrolidinone (10.09 mmol, 1.0 equiv). The solution was allowed to stir for 20 min, followed by the addition of 1.96 g 4-fluorobenzenesulfonyl chloride (10.09 mmol, 1.0 equiv) in 10 mL THF. After stirring for an additional 50 min, the solution was diluted with sat. NaHCO3, and the THF was removed under reduced pressure. The solution was then extracted (3×EtOAc), dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 30% EtOAc/hexanes) gave the product 1-(4-fluorobenzenesulfonyl)-5-methyl-2-pyrrolidinone as a white solid (949 mg, 3.69 mmol, 37%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17]C(=O)C2C=CC=CC=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.O1CCCC1>[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][OH:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCO)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 9 h
Yield: 61 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-(2-benzoyloxyethoxyimino)acetate (syn isomer, 8.5 g.) in a mixture of 1 N aqueous sodium hydroxide (35 ml.), methanol (40 ml.) and tetrahydrofuran (40 ml.) was stirred at 40° C. for 9 hrs. and at room temperature for 12 hrs. The reaction mixture was treated in a conventional manner to give 2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetic acid (syn isomer, 3.3 g.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][NH2:24]>>[ClH:1].[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH:3]=1
Reactant: NCC(O)CN
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl
Product: Cl
Product: NCC(O)CNc1cc(-c2ccc(Cl)c(Cl)c2)nc2ccccc12

Procedure:
The title compound, m.p. 230-24° C., and MS: m/e=362.1 (M+H+), was prepared from 4-chloro-2-(3,4-dichloro-phenyl)-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C@:15]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:13]([O:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]S(O)(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C@:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:14])[C@@H:13]([OH:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@]2(Cc3ccccc3)O[C@H]2C1
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@](O)(Cc2ccccc2)[C@@H](O)C1
Reaction time: 16 h

Procedure:
To a solution of 37.6 g (116 mmol) of (1R,6S) and (1S,6R)-6-benzyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester in 170 ml THF were added 37 ml H2SO4 (10%). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and extracted with sat. NaHCO3. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with sat. NaHCO3, dried over MgSO4 and the solvent was removed under reduced pressure to give 40.8 g (100%, purity ˜95%) of crude (3R,4R) and (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: C[C@H]1[O:7][C@@H](O[C@H]2C3C(=C(O)C(C(O)=O)=C(C)C=3)C3C(O)=C4C(=O)C5C(=C(O)C=C(OC)C=5)C(=O)C4=CC=3[C@@H]2O)[C@H](O)[C@@H](O[C@@H]2OC[C@@H](O)[C@H](O)[C@H]2O)[C@H]1N(C(OCC1C=CC=CC=1)=O)C.C1C=CC2N(O)N=NC=2C=1.[CH2:76]1[CH2:81][CH2:80][CH:79]([N:82]=[C:83]=[N:84][CH:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)[CH2:78][CH2:77]1>C1COCC1>[CH:85]1([NH:84][C:83]([NH:82][CH:79]2[CH2:78][CH2:77][CH2:76][CH2:81][CH2:80]2)=[O:7])[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1
Reactant: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](N(C)C(=O)OCc4ccccc4)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13 (52 mg, 0.058 mmol), HOBT (10 mg, 0.065 mmol) and DCC (16mg, 0.079 mmol) in THF (2 ml) was stirred for 1 hour at room temperature and filtered to remove resulting dicyclohexyl urea. The filtrate was concentrated and the residue was dissolved in 1 ml of 50% aqueous dioxane. To the mixture was added a solution of D-3,4-dihydroxyphenylalanine (D-DOPA) (24 mg, 0.12 mmol) and triethylamine (20 μl, 0.14 mmol) in 1 ml of 50% aqueous dioxane. The mixture was stirred for 1 day at room temperature and then dioxane was removed under reduced pressure. To the residue was added 50 ml of H2O and the mixture was acidified with 1N HCl to pH 2. The precipitate formed was collected by filtration and chromatographed on a column of C-18 silica gel (Bondpak C18, 20 i.d.×200 mm). The column was eluted with 30-40% acetonitrile-1/1000N HCl and the desired fraction was concentrated and lyophilized to give 4'N-CBZ protected title compound (23 mg, yield 37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/C(O)=O)=[CH:4][CH:3]=1.CC[N:16]([CH2:19]C)CC.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=[O:22]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:19](=[O:22])[NH:16][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=N/Nc1ccc(Br)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1[nH]cnn1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of compound 84a (1.14 g, 4.69 mmol) in toluene (25 mL) was added Et3N (0.913 mL, 6.57 mmol) and (PhO)2PON3 (1.012 g, 4.69 mmol) and the mixture was heated slowly over 20 min to reflux. Gas evolution began at 75° C. and became more vigorous at 100° C. After 1 h at reflux, an additional portion of (PhO)2PON3 (0.304 mL, 1.41 mmol) was added and the reaction was refluxed for an additional 30 min. The mixture was cooled to rt and extracted with 1M NaOH (3×75 mL). The combined aqueous extracts were washed with Et2O (2×25 mL) and adjusted to pH 1 with 3M HCl. The resultant precipitate was collected by filtration, washed with water (3×20 mL), and dried under suction and then high vacuum to afford a beige solid which was recrystallized from EtOAc-heptanes to afford compound 84b as a granular light yellow solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C8H6BrN3O, 240.0/242.0 (M+H). found 240.1/242.1
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35]CS([O-])(=O)=O)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl.[C:42]1([C:48]2([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35][N:51]3[CH2:50][CH2:49][C:48]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:10])[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: Cc1cccnc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a solution of 3-methylpyridine-2-carboxylic acid (1.38 g, 10.1 mmol) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (1.75 mL, 20.2 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (50 mL). A solution of 5-(3-aminophenoxy)pyridin-2-amine (1.83 g, 9.09 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring at room temperature, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and washed with ethyl acetate-hexane to give the title compound (1.84 g, 57%) as a pale-brown solid.