Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH2:22])C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC(OC)=O>C1COCC1>[NH2:22][C@H:21]([C:20]([OH:31])=[O:19])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: COC(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The para-toluenesulfonic acid salt of tyrosine benzyl ester (5.05 g, 11.4 mmol) was dissolved in THF (50 mL) containing DIEA (2.18 mL, 12.5 mmol) and di-tert-butyidicarbonate (2.98 g, 13.7 mmol) was added in one portion. The reaction was stirred 1.5 h at room temperature. Volatiles were removed under reduced pressure and the residue was dissolved in Et2O (150 mL). The solution was washed successively with water (25 mL), 5% citric acid (25 mL) and 5% NaHCO3 (25 mL). After drying (MgSO4), the solvent was evaporated under reduced pressure and the residue dissolved in acetone (100 mL). Cesium carbonate (4.83 g, 14.8 mmol) and methyl bromoacetate (1.3 mL, 13.7 mmol) were added and the heterogeneous mixture was stirred overnight at room temperature. Solids were then removed by filtration (acetone for washings) and the filtrate evaporated. The residue was dissolved in Et2O (150 mL) and washed with water (25 mL) and brine (25 mL). After drying (MgSO4), the solution was concentrated and the residue purified by flash chromatography using 25-50% EtOAc/hexane as eluent. The fully protected tyrosine derivative was obtained as a colorless oil (3.61 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:22]([C:30]1[CH:31]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([C:30]1[CH:31]=[C:32]([CH2:36][C:37]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=3)=[O:9])[CH:3]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(=O)c4ccccc4)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 2-(3-benzoylphenyl)acetic acid to afford the title compound in 86% yield, 31 mg.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C[O:12][C:13]([N:15]=C=O)=O>C(Cl)Cl>[C:13](=[O:12])([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH2:15]
Reactant: O=C=NC(=O)OCC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Benzyl carbamate is prepared by dissolving 354 mg. (3.28 mmoles) benzyl alcohol in 3 ml. methylene chloride in a 2-neck 10 ml. flask fitted with a condenser topped with a drying tube and serum cap. The solution is cooled in an ice bath and 0.48 ml. (770 mg., 3.5 mmoles) of trichloroethoxycarbonyl isocyanate is introduced with a syringe through the serum cap. An exotherm is noted. After stirring at room temperature for 40 minutes, the solution is concentrated to an oil and recrystallized from cyclohexane to yield 980 mg. of benzyl 2,2,2-trichloroethyl imidodicarboxylate, m.p. 88.5°-89.5° C. An analytical sample has a m.p. 89.5°-90.5° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[K+].OO>O.S([O-])([O-])(=O)=O.[Mn+2]>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=O
Reactant: C=Cc1ccccc1
Agent: [Mn+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCCCCCCCCCCC
Product: c1ccc(C2CO2)cc1
Yield: 90 %

Procedure:
To a mechanically stirred solution of styrene (0.01 mol), dodecane (0.001 mol), urea (0.208 mol), potassium bicarbonate (0.003 mol) and manganese sulphate (0.1 mmol) in 10.0 ml of water at 30° C. is added 30% aqueous hydrogen peroxide (0.5 mol) in three equal portions over a period of 4 hours. After 5 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded styrene oxide in 90% yield with selectivity 90%.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][C@H:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:16]3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>O1CCCC1.C(OC)(C)(C)C.Cl>[C:24]1([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C@@H:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH:14]=2)[O:19]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H](c2ccccc2C)O3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H]1CCc2cc(O[C@H]3CC[C@H](C(=O)O)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.75 g (1.9 mmol) of trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester was dissolved in 10 ml of tetrahydrofuran. 94 mg (3.9 mmol) lithium hydroxide (dissolved in 2 ml of water) were added. The solution was stirred at room temperature overnight until no starting material could be detected by RP-HPLC. The solution was diluted with methyl tert-butyl ether, and 2N hydrochloric acid was added until a pH of 2. After phase separation, the organic layer was dried over magnesium sulfate and the solvent was evaporated. The resulting product crystallized on standing to yield 0.65 g of the title compound.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH3:47][C:48]1[CH:49]=[C:50]([CH:59]=[CH:60][CH:61]=1)[CH2:51][S:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55]>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:53]([S:52][CH2:51][C:50]1[CH:59]=[CH:60][CH:61]=[C:48]([CH3:47])[CH:49]=1)[C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSCc1cccc(C)c1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1cccc(C)c1
Yield: 83.4 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl (3-methylbenzylthio)acetate (7.9 g) in ethanol (100 cc). Diethyl 2-dimethylamino-5-(3-methylbenzylthio)-2,4-hexadienedioate (11 g) is obtained in the form of a brown oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:23])[CH3:22])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:26].[I:31]NC(=O)CCC(N)=O>FC(F)(F)S(O)(=O)=O.CO>[Cl:1][C:2]1[C:29]([F:30])=[CH:28][C:27]([I:31])=[C:4]([CH:3]=1)[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:23])[CH3:22])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:26]
Reactant: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: NC(=O)CCC(=O)NI
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Product: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1cc(Cl)c(F)cc1I)CC2
Reaction time: 0.17 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (43 mg, 0.10 mmol; Example 13) and N-iodosuccinamide (22 mg, 0.1 mmol) in trifluoromethanesulfonic acid at 0° C. was stirred for 10 minutes. The mixture was diluted with methanol and subjected to preparative HPLC purification on C-18 reverse stationary phase column eluting with a gradient of water—acetonitrile in the presence of 0.1% trifluoroacetic acid. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:23]3[CH2:24][CH2:25][CH:21]([OH:20])[CH2:22]3)=[O:19])=[CH:13][N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Reactant: OC1CCNC1
Product: CCc1cc(-c2ccc(C(=O)N3CCC(O)C3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and 3-hydroxy-pyrrolidine to afford the title compound. MS: m/e=328 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]1[O:4][CH2:3]1.C([NH:24][CH2:25][CH2:26][NH:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[N:31]([CH3:36])[C:30](=[O:37])[CH:29]=1)C1C=CC=CC=1>C(O)C>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:24][CH2:25][CH2:26][NH:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[N:31]([CH3:36])[C:30](=[O:37])[CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1ccccc1OCC1CO1
Reactant: Cn1c(NCCNCc2ccccc2)cc(=O)n(C)c1=O
Solvent: CCO
Product: CCCCOc1ccccc1OCC(O)CNCCNc1cc(=O)n(C)c(=O)n1C
Reaction time: 10 h
Yield: 74 %

Procedure:
4.5 g of 2-n-butoxyphenyl glycidyl ether ##STR27## are heated under reflux together with 5.8 g of N-benzyl-N'-[1,3-dimethyl-2,4-dioxopyrimid-6-yl]ethylenediamine ##STR28## (in 150 ml of ethanol) for 2 hours. The resulting solution is then cooled and concentrated in vacuo. A resinous residue remains. This residue is dissolved in 150 ml of dioxane (without further purification) and then hydrogenated with H2 in the presence of Pd/C at 20° C. for 10 hours. The catalyst is then filtered of; the filtrate is concentrated; and the residue is recrystallized once from toluene. N-[3-(o-Butoxyphenoxy)-2-hydroxypropyl]-N'-[1,3-dimethyl-2,4-dioxopyrimid-6-yl]ethylenediamine of the formula ##STR29## is thus obtained.
Reaction SMILES: CN(C)CC[N:5]1[C:13]2[CH:12]=[CH:11][C:10](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:9]3[C:25](=[O:32])[C:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:31]=4[C:7]([C:8]=23)=[N:6]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>N1C=CC=CC=1>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:10]1[CH:11]=[CH:12][C:13]2[NH:5][N:6]=[C:7]3[C:31]4[CH:30]=[N:29][CH:28]=[CH:27][C:26]=4[C:25](=[O:32])[C:9]=1[C:8]=23
Reactant: CN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCN(C)C)-c3cnccc3C(=O)c24)cc1
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1ccncc1-3
Reaction time: 1 h

Procedure:
A solution of 2-[2-(dimethylamino)ethyl]-5-(p-toluenesulfonyloxy) isoquino[8,7,6-cd]indazole-6(2H)-one of Example 2 (0.463 g) and 2-(dimethylamino)ethylamine (0.80 mL) in dry pyridine (4.63 mL) is heated at 80° C. for 1 h, 30' under a nitrogen blanket. The solution is then concentrated to dryness and the dark residue obtained is partitioned between brine (30 mL) and ethyl acetate (4×25 mL). The combined organic solutions are dried over Na2SO4 and concentrated to about 3 mL. After addition of n-hexane (12 mL) and stirring for one hour the precipitate is collected by suction and dried at 40° C. under vacuum to give 2-[2-(dimethylamino)ethyl)]5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.23 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=O)#[N:2].[OH-].[Na+].Cl.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[NH:19])OC)=[CH:14][CH:13]=1>CO.CCOC(C)=O>[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[N:19]=[C:4]([CH2:3][C:1]#[N:2])[NH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: N#CCC(=O)NN
Reactant: COC(=N)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCc1nc(-c2ccc(F)cc2)n[nH]1
Yield: 47 %

Procedure:
2-Cyanoacetohydrazide (172 mg, 1.74 mmol) and NaOH (66 mg, 1.66 mmol) were added to a solution of methyl 4-fluorobenzimidate hydrochloride (300 mg, 1.58 mmol) in dry MeOH (5 mL) and the mixture was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 20-25% EtOAc in petroleum ether) to yield 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile (150 mg, yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.04-7.99 (m, 2H), 7.39-7.33 (m, 2H), 4.11 (s, 2H). MS (ESI) m/z: Calculated for C10H7FN4: 202.07. found: 203.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.Cl.[CH3:37][O:38][C:39](=[O:87])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([C:72]4[CH:73]=[N:74][C:75]([N:78]5[CH2:83][C@H:82]([CH3:84])[NH:81][CH2:80][C@H:79]5[CH3:85])=[CH:76][CH:77]=4)=[O:71])=[C:65]([CH3:86])[N:64]=3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:37][O:38][C:39](=[O:87])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([C:72]4[CH:73]=[N:74][C:75]([N:78]5[CH2:83][C@H:82]([CH3:84])[N:81]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:8])[CH3:1])=[O:6])[CH2:80][C@H:79]5[CH3:85])=[CH:76][CH:77]=4)=[O:71])=[C:65]([CH3:86])[N:64]=3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)NC[C@H]5C)nc4)c(C)n3)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)c(C)n3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of (s)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.13 mg, 0.019 mmol), and HATU (8.52 mg, 0.022 mmol) was stirred in DMA (1 mL) for 10 min and then [(S)-1-((S)-2-{4-[4-(5-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-6-methyl-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 4 HCl (15 mg, 0.018 mmol; Preparation 59) and N,N-diisopropylethylamine (16.3 μL, 0.093 mmol) were added. The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the tri-TFA salt of the title compound (11 mg). m/z): [M+H]+ calcd for C44H55N9O5 790.43 found 790.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[F:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>C1COCC1>[F:16][C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:2][NH:20][CH2:19][C:18]([F:22])([F:21])[F:17]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(CBr)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
A mixture of tert-butyl 3-bromomethyl-4-fluorobenzoate (14 g, 48 mmol) and 2,2,2-trifluoroethylamine (25 g, 250 mmol) in THF (300 mL) was stirred under argon at RT for 4 d, concentrated, and the residue partitioned between Et2O and 10% K2CO3. The organic phase was washed with 10% K2CO3 and brine, dried, and concentrated. The residue was purified by chromatography (silica gel, step gradient, 0-8% ethyl acetate/hexane) to give the title compound as a pale yellow oil (10.7, 72%): MS (ES) m/e 308.3[M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1)(=O)=O>CN(C)C=O>[N:1]([CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=1)=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCN=[N+]=[N-])cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium azide (0.29 g) was added to a solution of ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-(2-phenoxyethyl)propionate, which is the product of Reference example 3(g), in dimethylformamide (8 ml). The mixture was stirred at 70° C. for 2 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated to afford the desired compound (546 mg) as a syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(Cl)(Cl)Cl.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(OCC)(=O)C.O.C(N(CC)CC)C>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:22](=[O:24])[C@H:12]([CH2:13][S:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](CSCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)[C@H](CSCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
N-Benzyloxycarbonyl-S-benzyl-L-cysteine (1.73 g) and glycine ethyl ester hydrochloride (0.70 g) are suspended into chloroform (20 ml) and therein is dissolved triethylamine (1.4 ml). To the solution is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.07 g) with stirring under ice-cooling. The mixture is stirred for 2 hours and then allowed to stand overnight. To the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated and washed with water, 1 N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the resulting residue is crystallized from petroleum ether to give N-(N-benzyloxycarbonyl-S-benzyl-L-cysteinyl)glycine ethyl ester (1.25 g), melting pont: 89°-93° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>O1CCCC1>[OH:20][C:17]1([CH2:1][C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(O)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1ccc(CC2(O)CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred suspension of 6-methylpyridin-3-ol (5.01 g, 45.9 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium solution (1.6 M in n-hexane, 63 mL, 101 mmol) dropwise at −20° C. After addition, the mixture was allowed to warm to room temperature and stirred at the same temperature for 1 h. Then the mixture was cooled to −78° C., and tetrahydro-4H-pyran-4-one (5.06 g, 50.5 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with acetic acid (11.6 mL) and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with acetone/n-hexane (1:1 to 2:1) to give 7.87 g (82%) of the title compound as a yellow oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1.91 g, 9.53 mmol), 3-fluoroaniline (1.06 g, 9.53 mmol) and acetic acid (0.55 ml, 9.53 mmol) in 1,2-DCE (50 ml) was stirred at room temperature overnight. Sodium tri(acetoxy)borohydride (2.82 g, 13.3 mmol) was then added and the reaction mixture was stirred for 8 h, then allowed to stand at room temperature. The reaction mixture was diluted with DCM and washed with NaHCO3 solution, dried over MgSO4 and then concentrated to give the product which was purified by column chromatography. Elution with 0-40% EtOAc/pentane gave the title compound as a white solid (2.3 g). δH (CDCl3, 250 MHz) 7.08 (1H, q), 6.35 (3H, m), 4.04 (1H, br s), 3.65 (1H, br s), 3.38 (1H, m), 2.92 (2H, m), 2.02 (2H, m), 1.47 (9H, s), 1.34 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[C:12](=[O:22])[O:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12](=[O:22])[C:11]=1[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: CCC(c1cccc(N)c1)c1c(O)c2ccccc2oc1=O
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(c1cccc(NS(=O)(=O)CC)c1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
14.75 mg of 3-[1-(3-aminophenyl)propyl]-4 hydroxy-coumarin is dissolved in 1 ml of methylene chloride with 8.1 microliters of pyridine added. To this solution, at room temperature with protection from moisture, is added 5.14 microliters of ethylsulfuryl chloride. The reaction is allowed to stir, at room temperature, for 18 hours. 5 ml of methylene chloride is added to the reaction mixture, the resulting mixture is washed twice with 1 ml of water, and the methylene chloride solution is separated, dried over anhydrous sodium sulfate and evaporated to dryness to yield 28 mg of crude title product. Chromatography over 15 g of silica gel using 5% methanol in chloroform as solvent gives 6.8 mg of pure title product.