Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of N-(2-Aminoethyl)carbamic acid tert-butyl ester (1.86 g, 11.5 mmol) and triethyl amine (3 mL) in CH2Cl2 (100 mL) at 0° C., was added (4-bromophenyl)chlorosulfone (2.93 g, 11.5 mmol). The mixture was stirred for 3 hours, before the solvent was removed. The residue was dissolved in EtOAc (150 mL), washed with sat. NaHCO3 (50 mL), sat. NaCl (50 mL), 1N HCl (50 mL), sat. NaCl (2×50 mL), dried over MgSO4, and evaporated to give 3.8 g of the title compound as a white solid in 100% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([C:13](=[O:14])[NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5].CC(C)(C)CC(N1CCC2(C(=O)N(C3C=CC(C(O)C(F)(F)F)=CC=3)CC2)CC1)=O.Br[C:50]1[CH:55]=[CH:54][C:53]([CH:56]([OH:61])[C:57]([F:60])([F:59])[CH3:58])=[CH:52][CH:51]=1>>[F:59][C:57]([F:60])([CH3:58])[CH:56]([C:53]1[CH:52]=[CH:51][C:50]([N:12]2[CH2:11][CH2:10][C:9]3([CH2:15][CH2:16][N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:18])([CH3:17])[CH3:1])[CH2:7][CH2:8]3)[C:13]2=[O:14])=[CH:55][CH:54]=1)[OH:61]
Reactant: CC(F)(F)C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)CC(=O)N1CCC2(CCNC2=O)CC1
Agent: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(F)(F)F)cc1)C2=O
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(C)(F)F)cc1)C2=O

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(3,3-dimethyl-butyryl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 165 A) and 1-(4-bromo-phenyl)-2,2-difluoro-propan-1-ol (synthesis: R. Mogi, et al, Journal of Fluorine Chemistry; 10; 2007; p 1098). White solid. MS (ESI): 423.24 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[O:30]([CH2:34][CH2:35][NH2:36])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][O:30][CH2:34][CH2:35][NH:36][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: NCCOCCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCOCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2,2′-oxybis(ethylamine) (31.3 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide (20.3 mg, 19.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H34Cl2N4O2S+H [(M+H)+]: 517.2132. found: 517.2133.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(OC)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccc(OC)cc2)nc2cccnc21
Yield: 29.5 %

Procedure:
Solid N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester, 12.8 g (0.039 mole) was heated in glass in a Wood's metal bath at 210°-220° C. for 6 minutes. The residue was dissolved in methylene chloride, treated with charcoal, and filtered through a Celite pad. The filtrate (dark orange) was treated with Florisil® to give a pale orange filtrate. The filtrate was evaporated to a solid, which was recrystallized from tetrahydrofuran-petroleum ether. The solid was collected, washed with tetrahydrofuranpetroleum ether and dried under high vacuum at 50° C. overnight to give 3.58 g (29.5%) of title compound, mp 107°-8° C.
Reaction SMILES: [Cl-].[C:2]([C@@H:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH3+:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([OH:4])=[O:3].C(N(CC)C(C)C)(C)C.[C:36]([O:40][C:41]([NH:43][C:44](=[N:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])SC)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(O)(C)C>[C:51]([O:50][C:48]([NH:47][C:44]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:22]=[CH:23][C:7]([CH2:6][C@H:5]([O:24][CH2:25][CH3:26])[C:2]([OH:4])=[O:3])=[CH:8][CH:9]=2)=[CH:20][CH:19]=1)=[N:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCO[C@@H](Cc1ccc(OCCCc2ccc([NH3+])cc2)cc1)C(=O)O
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@@H](Cc1ccc(OCCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.08 h
Yield: 26.9 %

Procedure:
4-(3-{4-[(2S)-2-Carboxy-2-ethoxyethyl]phenoxy}propyl)benzenaminium chloride (152 mg, 0.4 mmol) was in isopropyl alcohol (3 ml). N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) was added. The mixture was stirred for 5 minutes, then 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (290 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 7 days and thereafter evaporated in vacuum to dryness. Water and ethyl acetate were added into the residue. The mixture was acidified with 1% hydrochloric acid, pH˜5 and there was some precipitation. The two phase mixture was filtered and then separated. The pH of the water phase was further adjusted to ˜3 and the water phase was extracted with ethyl acetate (×2). All organic phases were combined and washed with brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. Chromatography of the residue on an ISOLUTE column (SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and MeOH/DCM (0.5: 99.5) as eluant gave the desired product (63 mg), yield 27%.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:21]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1F
Yield: 62.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.59 g, 31%). EI-MS m/z 292 (M+H)+
Reaction SMILES: [CH:1]1([C:7]2([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:18]([O:22][C:23](=[O:24])[NH:25][C@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:27]([N:10]1[CH2:9][CH2:8][C:7]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH2:11]1)=[O:28])([CH3:20])([CH3:21])[CH3:19]
Reactant: CCCC(=O)C1(C2CCCCC2)CCNCC1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
2.1 g (8.9 mmol) of 1-(4-cyclohexylpiperidin-4-yl)butan-1-one, 2.6 g (8.9 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid, 1.88 g (9.8 mmol) of EDC and 1.2 g (9.8 mmol) of HOBT are dissolved in 30 mL of DMF. The mixture is stirred at room temperature for 2 hours. The solution is washed with aqueous 2.5% citric acid solution and extracted with ethyl acetate. The organic phase is washed with aqueous 10N NaOH solution and then dried over sodium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel (eluent: 70/30 heptane/ethyl acetate). 1.4 g of tert-butyl[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate in the form of a colourless oil are obtained in a yield of 31%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.Cl.[NH2:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].CCN(C(C)C)C(C)C.CN1CCCC1=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(F)cc1Br
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1cnc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a microwave vial were added 3-bromo-5-fluoropyridine-2-carbonitrile (150 mg, 0.746 mmol), tert-butyl [(2S)-1-aminopropan-2-yl]carbamate hydrochloride (157 mg, 0.755 mmol), DIPEA (0.260 mL, 1.49 mmol), and N-methyl-2-pyrrolidone (1.5 mL). The mixture was then heated by microwave irradiation to a temperature of 150° C. for 30 minutes. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and washed with water. The organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl {(2S)-1-[(5-bromo-6-cyanopyridin-3-yl)amino]propan-2-yl}carbamate. MS ESI calc'd. for C14H20BrN4O2 [M+H]+ 355 and 357. found 355 and 357.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][CH3:10])[O:8][C:6](=[O:7])[CH2:5][CH2:4]1)[CH3:2].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>O>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:8])([CH2:9][CH3:10])[CH2:1][CH3:2]
Reactant: NCCCCCCCCCCCCN
Reactant: CCC1(CC)CCC(=O)O1
Solvent: O
Product: CCC(O)(CC)CCC(=O)NCCCCCCCCCCCCN
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A procedure reported previously by us was followed. γ,γ-Diethyl-γ-butyrolactone (2.7 g, 19.1 mmol, 1.0 eq), 1,12-diaminododecane (9.6 g, 47.7 mmol, 2.5 eq), and water (8.0 mL) were combined. The solution was refluxed under a nitrogen atmosphere overnight. A yellow solution was formed. After cooling to room temperature, water was removed under reduced pressure. The yellow oily residue was purified by flash column chromatography (SiO2, Et2O/CH3OH/CH3CN/Et3N=5:2:2:1) to give 6 as a light yellow solid (2.0 g, 30%): Rf=0.5 (SiO2, Et2O/CH3OH/CH3CN/Et3N=5:2:2:1); 1H NMR (400 MHz, CDCl3) δ 5.67 (br s, 1H), 3.20 (q, 4H, J=7.2 Hz), 2.67 (t, 2H, J=7.2 Hz), 2.25 (t, 2H, J=7.2 Hz), 2.02 (br s, 3H), 1.74 (t, 2H, J=7.2 Hz), 1.50-1.40 (m, 8H), 1.33-1.20 (m, 16H), 0.84 (t, 6H, J=7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 174.2, 73.9, 42.2, 39.9, 33.7, 31.0, 30.9, 29.73, 29.69, 29.4, 27.1, 27.0, 8.1; HRMS (ESI) m/z calcd for C20H43N2O2 [M+H]+ 343.3325. found 343.3321.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>CO>[CH2:1]([CH:8]1[C:9]2([C:28]3[NH:29][C:30]4[C:35]([C:27]=3[CH2:26][CH2:25][NH:24]2)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([N:20]([CH3:22])[CH3:21])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2ccccc2)C1
Reactant: NCCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1(c2ccccc2)CCC2(NCCc3c2[nH]c2ccccc32)C(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(±)-2-benzyl-4-dimethylamino-4-phenylcyclohexanone (307 mg, 1 mmol) together with tryptamine (160 mg, 1 mmol) was dissolved in methanol and stirred at RT for 24 h. The solvent was then removed in a vacuum and the residue dissolved in 1,2-dichloroethane (20 ml). The mixture was mixed with trifluoroacetic acid (1.7 ml, 22.8 mmol) and stirred for 24 h at RT. For work up the reaction mixture was mixed with 2N NaOH (20 ml) and stirred for 20 min. The organic phase was separated and the aqueous phase extracted with dichloromethane (4×20 ml). The combined organic phases were dried with MgSO4. The solvent was then concentrated by evaporation in a vacuum. One of the possible diastereoisomers was isolated from the residue obtained (260 mg) by means of chromatographic purification [silica gel 60 G (10 g); ethyl acetate/ethanol 1:1 (80 ml), methanol (60 ml)].
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]([C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:24])=[O:22])([CH3:19])([CH3:18])[CH3:17].BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C>>[C:16]([O:20][C:21]([N:23]([C@H:25]1[CH2:29][CH2:28][N:27]([S:12]([C:10]2[C:11]3[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:26]1)[CH3:24])=[O:22])([CH3:19])([CH3:17])[CH3:18].[ClH:15]
Reactant: O=S(=O)(Cl)c1cccc2cncc(F)c12
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3cncc(F)c23)C1
Product: Cl

Procedure:
That is, (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]-1-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 22a) was prepared by using 4-fluoro-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 31, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 31, Step B in a similar manner to obtain the compound of Example 18-3 as hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.C(Cl)CCl.[NH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1 g, 3.62 mmol) in dry dichloromethane (30 mL) was added dimethylaminopyridine (884 mgL, 7.24 mmol), EDC (1.388 g, 7.24 mmol), and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (742 mg, 3.98 mmol) sequentially at room temperature under nitrogen. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@@H:32](CN)[C:33]([OH:35])=[O:34])=O)(C)(C)C.F[C:39]1C=CC=CC=1[N+]([O-])=O.C([O-])(O)=O.[Na+]>O.CN(C=O)C>[CH3:39][O:35][C:33](=[O:34])[CH2:32][N:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]1=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 80 °C
Yield: 83 %

Procedure:
(2S)-2-tert-Butoxycarbonylamino-3-(2-nitrophenyl-amino)-propionic acid. (2S)-2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and NaHCO3 (8.25 g, 98 mmol) was taken into 130 ml of DMF and heated at 80° C. for 18 h. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of H2O and extracted with Et2O (3×150 ml). The aq. solution was acidified to pH 5 with 10% NaHSO4 and extracted with EtOAc (3×250 ml). The combined extracts were dried over anhydrous Na2SO4, filtered, and evaporated to give 12.64 g (83%) of the title compound as an orange amorphous solid: 1H NMR (CD3OD) δ 8.15-8.10 (1H, d), 7.54-7.48 (1H, t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O-:5].[CH3:6][CH2:7][CH2:8][CH2:9][O-:10].[CH3:11][CH2:12][CH2:13][CH2:14][O-:15].[OH2:16].[V:17].O=[V].[ClH:20].Cl.Cl.[NH3:23]>C(O)CCC>[CH3:1][CH2:2][CH2:3][CH2:4][O-:5].[CH3:6][CH2:7][CH2:8][CH2:9][O-:10].[CH3:11][CH2:12][CH2:13][CH2:14][O-:15].[OH2:16].[V:17].[Cl-:20].[NH4+:23]
Reactant: N
Reactant: Cl
Agent: O=[V]
Agent: [V]
Agent: CCCC[O-]
Solvent: CCCCO
Solvent: O
Product: [Cl-]
Product: [NH4+]

Procedure:
Vanadates, such as butyl vanadate, have been prepared by reacting vanadium oxytrichloride with an excess of butyl alcohol in the presence of ammonia to form butyl vanadate and ammonium chloride. The butyl vanadate solution was separated from the ammonium chloride crystals by filtration. However, since the crystalline ammonium chloride has a tendency to plug the filter, it is difficult to filter off the butyl vanadate. Moreover, the filtration step must be conducted in a closed system to prevent hydrolysis of the butyl vanadate, thus resulting in an expensive process.
Reaction SMILES: Cl[CH:2]1[CH:8]2[CH:6]([CH2:7]2)[CH2:5][NH:4][C:3]1=[O:9].C([OH:14])(C)(C)C>>[CH:8]12[CH2:7][CH:6]1[CH2:5][NH:4][CH:2]2[C:3]([OH:9])=[O:14]
Reactant: CC(C)(C)O
Reactant: O=C1NCC2CC2C1Cl
Product: O=C(O)C1NCC2CC21

Procedure:
0.9 g of IV prepared in experiment (c) was refluxed for 16 hours in t-butanol containing 0.5 g potassium. The reaction mixture was allowed to cool, the solvent was evaporated under reduced pressure and the residue was poured into 20 ml of water. Dilute (4 N) hydrochloric acid was added until the solution was acidic and then extracted thrice with methylene chloride. The water layer was then passed over a column filled with Dowex 50W-X8 ion-exchange resin. Eluting the resin with ammonium hydroxide then gave the cis isomer of 3-azabicyclo(3.1.0)hexane-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.[CH2:25]([N:27]([CH2:30]C)[CH2:28]C)C.C(Cl)(Cl)=[O:33].C1C=CC=CC=1.CNC>ClCCl>[CH3:25][N:27]([CH3:30])[C:28]([N:8]1[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:5]([CH3:24])[N:4]=[C:3]1[O:2][CH3:1])=[O:33]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cl
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: CNC
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC1=NC(C)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (3.34 g, 10.0 mmol) and distilled triethylamine (6.3 ml, 45 mmol) in dichloromethane (10 ml) in an ice bath under argon was treated dropwise via syringe with 1.3M phosgene in benzene solution (9.2 ml, 12 mmol) over 3 to 5 minutes. After stirring at 0° C. for 1.5 hours, the reaction mixture was treated with 40% aqueous dimethylamine (3.3 ml, 15 mmol), capped with a septum, and stirred at room temperature for about 21/2 days. The reaction was then evaporated and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried (potassium carbonate), and evaporated to give the title compound (crude) as a brown oil (4.75 g).
Reaction SMILES: [CH:1]([S:4][CH:5]([C:17]([OH:19])=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C:36]1[CH:49]=[CH:48][CH:47]=[CH:46][C:37]=1[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>C(Cl)Cl>[CH:1]([S:4][CH:5]([C:17]([NH:35][C:36]1[CH:49]=[CH:48][CH:47]=[CH:46][C:37]=1[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39])=[O:19])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
α-(isopropylthio)-N-(benyloxycarbonyl)glycine 22B was dissolved in methylene chloride (200 mL) under nitrogen atmosphere at 0° C. in a three necked flask carrying an additional funnel. To the stirred solution was added N-methylmorpholine (2.11 mL, 19.3 mmol) followed by isobutylchloroformate (2.48 mL, 19.2 mmol). This was stirred for 15 minutes at 0° C. and then heated to reflux. To the refluxing reaction mixture was added a solution of 2-aminobenzophenone 23 (3.59 g, 18.19 mmol) in dry methylene chloride (26 mL) over 20 minutes. The reaction mixture was stirred for 20 more minutes after the addition and then left stirring overnight at room temperature. The reaction mixture was washed with 10% citric acid, saturated sodium bicarbonate solution and brine, then dried over magnesium sulphate. Solvent evaporated at reduced pressure to give 9.30 g of the crude product 24. This was used without further purification.