Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2].C1N(CCS(O)(=O)=O)CCOC1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl-].[Mg+2].[Cl-].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+].[Cl-].[Na+]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)N1CCOCC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)CCN1CCOCC1
Product: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)N1CCOCC1

Procedure:
A mixture of 7.77 g of (1R,2R)-2-(morpholine-4-carbonyl)-4-oxo-cyclopentanecarboxylic acid ethyl ester in 148 ml of aqueous buffer (10 mM 2-(N-morpholino)ethanesulfonic acid; 0.5 M D-glucose [2.7 equ.]; 2 mM magnesium chloride) was adjusted to pH 6.5. Under stirring the reduction was started by the addition of the cofactor NADP (779 mg [0.03 equ.]), the cofactor regeneration enzyme-glucose dehydrogenase (77 mg GDH 102 [Codexis]) and the reductase (387 mg KRED-NADP-131 [Codexis]). During the 21 h reaction time the pH was maintained at pH 6.5 by the addition of 31.9 ml 1M NaOH. At this time point the reaction mixture was blended with the use-test previously carried out, in which 1.5 g (1R,2R)-2-(morpholine-4-carbonyl)-4-oxo-cyclopentanecarboxylic acid ethyl ester were reduced under exactly the described conditions. Under stirring the mixture was adjusted to pH 2.8, saturated with 43.6 g sodium chloride and stirred for at least 10 min. after the addition of 17 g filter aid—Dicalite—and 300 ml ethyl acetate. Subsequently the filter aid was removed and the filtrate was adjusted to pH 7.0 prior to extraction. The aqueous phase was extracted twice with 300 ml ethyl acetate. Treatment of the combined organic phases with sodium sulfate, evaporation and drying over night under a high vacuum yielded in 8.73 g of (1R,2R,4R)-4-hydroxy-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester as a pale yellow oil. MS: 272.1 (M+H)+; chiral GC: ee 95.2% [BGB-176, 30 m; H2; 2° C./min, 150° C. to 220° C.].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:17])[CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>CC(C)=O>[F:17][C:4]1[CH:3]=[C:2]([NH:1][C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:7]=[CH:6][C:5]=1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C(=O)OC)c1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of dimethyl 2-(4-amino-2-fluorophenyl)malonate (3.0 g, 12.448 mmol, 1.0 eq) in acetone (30 mL) was added pyridine (3.0 mL, 37.344 mmol, 3.0 eq) and phenyl chloroformate (1.89 mL, 14.937 mmol, 1.2 eq) at 0° C. and the mixture was stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (1:4) as eluent to get dimethyl 2-(2-fluoro-4-(phenoxycarbonylamino)phenyl)malonate (3.5 g, 78%, white solid; TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH3:37])[C:15]([N:17]([CH2:27][C:28]1[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[S:31][CH:32]=1)[C@@H:18]([CH3:26])[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:16]>>[S:31]1[CH:32]=[C:28]([CH2:27][N:17]([C@@H:18]([CH3:26])[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:37])[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 72 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[C:20]1([CH2:26][CH2:27][CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CCCc2ccccc2)c1=O
Yield: 94 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 3-phenylpropyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 94.0%.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:20]([O:19][CH2:17][CH3:18])=[O:21])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Yield: 73.3 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane 1.49 g (6.6 mmol) (as prepared in Example 1) was reacted with ethylchloroformate 1.3 mL (13.2 mmol) and pyridine (3.3 mL) as described in example 2 to give 1.51 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH3:23])[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@@H:14]([OH:24])[CH:13]=[CH:12][C@@H:11]35)(=O)C.FC(F)(F)S(O)(=O)=O.IN1C(=O)CCC1=O>ClCCl>[CH:7]1[C:8]2[CH2:9][C@H:10]3[N:22]([CH2:21][CH2:20][C@@:16]45[C@H:11]3[CH:12]=[CH:13][C@H:14]([OH:24])[C@@H:15]4[O:19][C:18]([C:17]=25)=[C:5]([OH:4])[CH:6]=1)[CH3:23]
Reactant: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.2 g (6.9 mmol) of Thioglycoside [14], 1.5 g (4.6 mmol) of freshly prepared, vacuum-dried 3-O-Acetylmorphine and 6.0 g 3 Å Molecular Sieves in 60 mL Dichloromethane was stirred at room temperature for 30 min and cooled to −15° C. by an ice-salt-acetone bath. Trifluoromethanesulfonic acid (TfOH) (1.0 g, 6.7 mmol) was added dropwise while keeping the temperature at below −10° C. and then N-Iodosuccinimide (NIS) (1.55 g, 6.9 mmol) was added in three portions. The resulted mixture was stirred for 4 hours at −5° C. and for an additional 30 min. at room temperature. Then the reaction mixture was diluted with Dichloromethane, filtered through Celite, stirred for 30 min with saturated aq. Sodium Hydrogen Carbonate solution (60 mL) and the aqueous layer was separated. The organic layer was washed twice with 60 mL portions of Sodium Thiosulphate saturated aqueous solution and water. The combined aqueous solution was washed with 60 mL of Dichloromethane. Combined organic solution was dried over Sodium Sulfate anhydrous, filtered and evaporated under reduced pressure. After separation on Silica Gel collumn compound [13] 1.93 g (51%) and 0.4 g of Morphine were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=O.ClCCl.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(F)cnc1Cl
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To an oven-dried, 250 mL, round-bottomed flask were added the crude 2-chloro-5-fluoronicotinamide (1.05 g, 6.00 mmol) from above, anhydrous dichloromethane (25 mL), and triethylamine (2.12 g, 2.92 mL, 21.0 mmol). The flask was sealed with a septum and cooled to 0° C. in an ice bath. Neat trifluoroacetic anhydride (1.89 g, 1.25 mL, 9.00 mmol) was added slowly via syringe and the resulting solution was stirred at 0° C. for 30 minutes then allowed to warm to room temperature over 1 hour. Water (20 mL) was added, and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a golden oil. The product was purified by flash chromatography (silica gel: 10% ethyl acetate, 90% hexanes—product Rf˜0.3) to give 862 mg (92%) of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 8.66 (dd, J=7.8, 3.0 Hz, 1H), 8.82 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][C:3]=1[C:9]#[N:10].[C:11](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O.C(COC)OC>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH3:11])[C:3]=1[C:9]#[N:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1[nH]c(Br)c(Br)c1Br
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: Cn1c(Br)c(Br)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Tribromo-pyrrole-2-carbonitrile (1.0 g, 0.003 mol) is dissolved in a mixture of acetone and dimethoxyethane. Potassium carbonate (0.45 g, 0.0033 mol) is added followed by methyl iodide (0.478 g, 0.0033 mol). After stirring overnight at room temperature, the reaction mixture is poured into water and filtered. The filter cake is air dried to give the title compound as a white solid, 0.8 g (80%), mp 115°-119° C.
Reaction SMILES: [NH2:1][C:2]([N:9]([CH2:11][CH3:12])[CH3:10])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO.C>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]([CH2:11][CH3:12])[CH3:10])[C:3]=1[C:7]#[N:8]
Reactant: CCN(C)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CCN(C)c1nsc(N)c1C#N
Yield: 85.9 %

Procedure:
A mixture containing 60 g of 3-amino-2-cyano-3-(ethylmethylamino)propenethioamide and 250 ml of ethanol was heated to reflux, while 40 ml of 30% hydrogen peroxide (11.1 g of active H2O2) were added dropwise at such a rate as to maintain an even reflux. After the peroxide addition was completed, the reaction mixture was heated for 30 minutes. Charcoal was added to the hot solution. The charcoal was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was recrystallized from toluene to yield 51 g of 5-amino-4-cyano-3-(ethylmethylamino)isothiazole, mp 94°-95°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:18]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:11][O:12][C:34](=[O:36])[N:13]1[C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[N:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H](COCc1ccccc1)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC[C@H](COCc2ccccc2)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
(R)-3-Benzyloxy-2-[4-(4-bromo-phenyl)-thiazol-2-ylamino]-propan-1-ol (110 mg, 0.26 mmol), prepared in the previous step, was dissolved in methylene chloride (10 mL), cooled to 0° C. and triethylamine (0.36 mL, 2.6 mmol) was added followed by triphosgene (0.19 g, 0.65 mmol). The mixture was stirred for 3 h, diluted with methylene chloride and washed with saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone in hexane) afforded the title compound (35 mg, 30%). HRMS: calcd for C20H17BrN2O3S+H+, 445.02160; found (ESI, [M+H]+), 445.0201; Analytical HPLC: purity 100% at 210-370 nm, 11.1 min; 93.8% at 238 nm, 11.1 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4](C2C=CC(NC(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)=CC=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:39](C1C=CC=CC=1)[C:40]([O:42]C)=[O:41]>CN(C=O)C>[N:1]1([CH2:39][C:40]([OH:42])=[O:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CN1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of intermediate (10) (0.019 mol) and Na2CO3 (0.019 mol) in DMF (125 ml) was stirred at room temperature. Methyl 2-bromo-2-phenylacetate (0.01907 mol) was added dropwise. The mixture was stirred for 3 hours. The solvent was evaporated. The residue was taken up in water and DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0; 99.5/0.5) and separated by high performance liquid chromatography over Chiralpak AD (eluent: hexane/ethanol 70/30) in its enantiomers. The desired fractions were collected and the solvent was evaporated, yielding 1-piperidineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1A)-(intermediate 29, mp. 158° C., [α]D20=−28.86° (c=124.95 mg/5 ml in CH3OH)) after crystallisation from 2-propanol and 1-piperidineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1B)-(intermediate 30, mp. 160° C., [α]D20=+27.69° (c=24.38 mg/5 ml in CH3OH)) after crystallisation from 2-propanol.
Reaction SMILES: Br[CH:2](C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[NH4+:15]>>[NH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: [NH4+]
Reactant: CC(Br)CCCCCCCC(=O)O
Agent: [OH-]
Product: NCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9-bromodecanoic acid (2.0052 gr, 8.46 mmol) was added to a round bottom flask containing 80 mL of aqueous ammonium hydroxide (25% NH3). The resulting mixture was stirred for 24 hours at room temperature, after which the aqueous solution was evaporated under reduced pressure, resulting in product 8a as a white solid at quantitative yield. 1H-NMR (200 MHz, CD3OD): 1.25-1.4 (m; 8H), 1.5-1.7 (m; 4H), 2.23 (t; J=7.31 Hz; 2H), 2.87 (t; J=7.45 Hz; 2H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>O>[S:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 78 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
In a 1 L reaction flask equipped with a condenser, 34.25 g (0.25 mol) of anthranilic acid, 411 g of water and 63.59 g (0.6 mol) of sodium carbonate were heated. The resulting reaction solution was maintained at an inner temperature of 78° C. for 30 minutes and then cooled to 67° C., and 57.2 g (0.3 mol) of tosyl chloride was added in two portions. The reaction solution gradually generated heat upon addition of tosyl chloride and turned homogeneous at 78° C. The reaction solution was aged at 80° C. for 1 hour. Crystals started to separate out in the first ten or so minutes of the aging. The completion of the reaction was confirmed by liquid chromatography, and the reaction solution was carefully neutralized with concentrated hydrochloric acid and allowed to cool. The crystals were collected by filtration at room temperature and washed with 100 ml of dilute hydrochloric acid at pH 3 and with 125 ml of water. Recrystallization from 247 g of n-propanol afforded 56.97 g of tosylanthranilic acid in a 78.3% yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)CCl.C1C=[N:21]C2N(O)N=NC=2C=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: On1nnc2cccnc21
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 89.3 %

Procedure:
2-amino-3-bromo-5-methylbenzoic acid (2.06 g, 8.95 mmol) was dissolved in DMF (19 ml) and EDC (2.10 g, 11.0 mmol), HOAt (1.56 g, 11.5 mmol), ammonium chloride (2.03 g, 38.0 mmol), and iPr2NEt (6.5 ml, 37.3 mmol) were added. The reaction was stirred at room temperature under nitrogen for 21.5 hours, and then poured into water (50 ml), resulting in the formation of a precipitate. The suspension was filtered and the solid was washed with water and dried in vacuo to give title compound (1.83 g, 89%). MS (ESI pos. ion) m/z: 229 (M+H). Calc'd Exact Mass for C8H9BrN2O: 228.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH:19]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7])[CH3:18]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC1(C)CC(=O)C(C)(C)O1
Product: CN(C)C=C1C(=O)C(C)(C)OC1(C)C
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 2,2,5,5-tetramethyl-dihydro-furan-3-one (2.84 g, 20.0 mmol, 1.0 equiv; commercially available) and tert-butoxy-bis(dimethylamino)methane (3.65 g, 20.9 mmol, 1.05 equiv; commercially available) was heated to 60° C. for 24 h (in analogy to a procedure described in H. H. Wasserman and J. L. Ives J. Am. Chem. Soc. 1976, 98, 7868-7869). The residue was purified by flash column chromatography on silica eluting with diethyl ether to yield 3.3 g (84% yield) of the title compound. MS (EI): 197 [M]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17](C)[C:18](=O)OC(C)(C)C)[CH2:13]2)[C:9]2[CH2:8][CH2:7][C:6]3[O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]4[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:18][NH:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[CH2:8][CH2:7][C:6]4[O:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]5[C:5]=4[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2nc(N)nc3c2CCC2=C3C3CCCCC3O2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2nc(N)nc3c2CCC2=C3C3CCCCC3O2)C1
Reaction time: 16 h

Procedure:
A solution of the product from Example 2C (51 mg, 0.115 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.18 mL) at ambient temperature and stirred for 16 hours. The mixture was diluted with dichloromethane (20 mL) and basified with sodium hydroxide (1 N). The organic layer was separated, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with ammonium hydroxide/methanol/dichloromethane (0.8/8/92) to provide the title product: 1H NMR (CD3OD) δ 1.10-1.22 (m, 1H), 1.25-1.36 (m, 1H), 1.42-1.55 (m, 1H), 1.56-1.68 (m, 2H), 1.78-1.90 (m, 1H), 1.95-2.07 (m, 2H), 2.11-2.31 (m, 2H), 2.48 (t, 2H), 2.55-2.60 (m, 3H), 2.98-3.09 (m, 3H), 3.49-3.56 (m, 1H), 3.65-3.77 (m, 2H), 3.80-3.91 (m, 2H), 4.68-4.75 (m, 1H); MS (DCl/NH3) m/z 342 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:17][C:9](=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Yield: 62.3 %

Procedure:
278 g of benzyl bromide were added to a stirred solution of 215 g of D-leucic acid and 246 g of triethylamine in 2.5 l of ethy acetate. The mixture was then heated under reflux for 5 hours, cooled and filtered to remove triethylamine hydrobromide. The filtrate was washed twice with 2M hydrochloric acid, water, saturated sodium bicarbonate solution and then saturated sodium chloride solution. The organic extract was dried over magnesium sulfate and evaporated to give 225 g of D-leucic acid benzyl ester as a yellow liquid.