Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccncc1
Product: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,5-bis-trifluoromethyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 60) was reacted with pyridine-4-yl-boronic acid to give the title compound as yellow amorphous solid. MS: 552.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[CH:31][CH:30]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)=[CH:33][CH:34]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncco2)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)[C@@H]1CCCCC[C@H]1CO
Yield: 87.6 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (80 mg, 0.25 mmol), cesium carbonate (164 mg, 0.50 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (72 mg, 0.30 mmol) according to the procedure described for 4-Chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (Example 40) to give 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (104 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.31 Hz), 7.73-7.75 (1H, m), 7.71-7.73 (1H, m), 7.69 (1H, s), 7.51 (1H, s), 7.48 (2H, s), 7.44-7.47 (1H, m), 7.21 (1H, s), 4.69 (1H, d, J=15.86 Hz), 3.99 (1H, d, J=15.61 Hz), 3.74-3.85 (1H, m), 3.67 (1H, dd, J=11.58, 4.28 Hz), 3.28 (1H, dd, J=11.58, 2.27 Hz), 2.27 (1H, br. s.), 1.42-1.65 (6H, m), 1.12-1.39 (5H, m). LC/MS R.T.=2.25 min; [M+H]+=475.22. HRMS [M+H]+ calc'd 475.1458, found 475.1459.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([OH:25])[C@@H:5]([NH:14]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1>C(O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([OH:25])[C@@H:5]([NH2:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.[CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccc(F)c(F)c1
Solvent: CCO
Product: COC(=O)/C=C/c1ccc(F)c(F)c1
Product: COC(=O)[C@H](O)[C@@H](N)c1ccc(F)c(F)c1
Reaction time: 16 h

Procedure:
(2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (>12.2 g, 33.3 mmol maximum) was dissolved in 750 mL ethanol. The flask was purged with argon and palladium on carbon (2 g, 10% wt) was added. The suspension was then purged, filled with hydrogen, and stirred 16 h. The suspension was piirged with argon, filtered through celite and concentrated in vacuo to give (2R,3S)-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester from trans-3,4-difluorocinnamic acid methyl ester).
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH:7]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([Si:5]([CH3:25])([CH3:26])[O:6][C:7]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)/C=C/c1ccc(CC(CN(C)C)O[Si](C)(C)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC(=Cc1ccc(/C=C/C(=O)O)cc1)O[Si](C)(C)C(C)(C)C
Yield: 54.5 %

Procedure:
This product was prepared by refluxing for four hours (E)-3-[4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylaminopropanyl)phenyl]acrylic acid, methyl ester (0.8 g, 2.03 mmol) and NaOH (1N) (4 mL, 2 equiv.) in 10 mL of MeOH. Evaporation of the solvent in vacuo and treatment with 5 mL of HCl (1N) gave the title compound (0.4 g, 60%) as a beige solid solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:35][NH2:36].[CH2:37](O)[CH3:38]>>[CH3:27][O:26][CH2:25][CH2:24][NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:35][N:36]=[CH:22][C:17]4[CH:15]=[CH:16][CH:4]=[C:37]([CH3:38])[CH:18]=4)[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)=[CH:18][CH:19]=1
Reactant: NN
Reactant: COCCNc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCNc1ccc(-c2cc3nc(NN=Cc4cccc(C)c4)cc(N4CCOCC4)n3n2)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-2-{4-(2-methoxy-ethyl-amino)-phenyl}-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (32.6 mg, 0.0841 mM) and then potassium carbonate (12.8 mg, 0.0925 mM) and hydrazine monohydrate (40.8 μL, 0.841 mM) were added to the suspension. This suspension was stirred at 150° C. for 30 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and then the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (9.9 μL, 0.0841 mM) were added to the suspension and then the mixture was stirred at room temperature for 30 minutes. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) and further the resulting solid was washed with methanol to thus give the title compound (10.6 mg, overall yield of these two steps: 26%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:28]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:59][C@@H:60]([CH2:90]O)[CH2:61][N:62]1[CH:66]=[CH:65][C:64]([NH:67]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:63]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:67][C:64]2[CH:65]=[CH:66][N:62]([CH2:61][C:60]([OH:59])([CH3:90])[CH3:28])[N:63]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 14.7 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.53 mmol) in dichloromethane (12 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (305 mg, 1.6 mmol) and N,N-diisopropylethylamine (387 mg, 3.0 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (245 mg, 1.7 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 82 mg, 0.53 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (40 mg, 15%) as an light yellow solid.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=C(Br)C=CC=1Cl.C(OCC)C.[CH3:27][N:28]1[CH2:33][CH:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(OCC)C.[Cu]I.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:32]2[CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CCOC(=O)C1=CCN(C)CC1
Agent: [Cu]I
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of magnesium (10.76 g) in diethyl ether (110 mL) was added a trace amount of iodine. About one-tenth of a solution of 3,4-dichlorobromobenzene (100 g) in diethyl ether (110 mL) was added slowly at 35-40° C., and the mixture was vigorously stirred until the reaction started. When the reaction started, the rest of the 3,4-dichlorobromobenzene/diethyl ether solution was added slowly while cooling the reaction mixture to 35-40° C. When all was added, the mixture was stirred at 40° C. for 1 hr, and then cooled to 0° C. To the reaction mixture was added copper(I) iodide (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction mixture was washed with aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=O.C(=O)=O.[OH-].[Na+]>O>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:10]1[C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:14]
Reactant: Nc1ccccc1O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1-c1nc2ccccc2o1

Procedure:
An intimate mixture of 2-aminophenol (109.13 g) and isatoic anhydride (203.9 g) was heated at 140° C. for 2 to 4 h until the formation of carbon dioxide ceased. Then the mixture was placed under vacuum (at a constant pressure of 50 mmHg) and the heating was continued at 180° C. for 3 to 4 h until the formation of water ceased. The melt was poured into a porcellanic mortar and, after cooling, the cold material was pestled, then boiled in a solution of caustic soda (12 g) in water (3.5 L) for 2 to 3 h. After cooling, the precipitate was isolated by filtration, and washed with cold water until the pale blue fluorescence disappeared in the washings. The precipitate was dried at 80° C. to afford 2-(benzo[d]oxazol-2-yl)phenylamine (180 to 185 g). The product was used without further purification in the next stage of preparation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](S(CC)(=O)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([NH:28][CH2:27][CH2:26][CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(S(=O)(=O)CC)nc1C
Reactant: CN1CCC(CCCN)CC1
Solvent: CCO
Product: CCOC(=O)c1cnc(NCCCC2CCN(C)CC2)nc1C
Temperature: 100 °C

Procedure:
A mixture of 2-ethanesulfonyl-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (0.30 g, 1.18 mmol) and 3-(1-methyl-piperidin-4-yl)-propylamine (0.18 mg, 1.10 mmol) in EtOH (3 mL) was heated in a sealed tube at 100° C. for 6 h. The mixture was concentrated and purified by FCC to give 200 mg (53%). 1H NMR (CDCl3): 8.88-8.72 (m, 1H), 5.60-5.44 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.52-3.39 (m, 2H), 2.91-2.77 (m, 2H), 2.64 (s, 3H), 2.26 (s, 3H), 1.94-1.85 (m, 2H), 1.72-1.57 (m, 4H), 1.41-1.20 (m, 8H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OCC)=[O:7].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][OH:7]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCBr)c1ccccc1
Yield: 98.2 %

Procedure:
According to the procedure given for the synthesis of 206e, 205b (23.70 g, 79.21 mmol) was reduced with LiBH4 (3.45 g, 158.4 mmol) and methanol (5.24 g, 163.5 mmol) in anhydrous CH2Cl2 (150 mL) to give 206b (20.0 g, 98%) as an oil. NMR (CDCl3): δ 7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, 2H, J=6.0), 1.96-1.44 (m, 5H), 1.32 (s, 3H). 13C NMR (CDCl3): δ 144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS (LSIMS, nba): Calcd for C12H16Br (MH+−H2O): 239.0435, found: 239.0444.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40].Cl.CN(C)CCCN=C=NCC.O1CCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:42][S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:40])=[O:41])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Cc1cccc2ccc(NC(=O)CC3CCCC3)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cccc2ccc(NC(=O)CC3CCCC3)cc12
Reaction time: 24 h
Yield: 51.3 %

Procedure:
To a mixture of 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoic acid (375 mg), 2-methylbenzenesulfonamide (231 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (259 mg) in methylene chloride (9 ml) was added 4-dimethylamino pyridine (165 mg); and the mixture was stirred for 24 h. The mixture was added to 60 ml of 1:9 tetrahydrofuran:ethyl acetate: and the organic solution was washed (1N HCl, water, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatorgraphy, eluting methylene chloride:acetone:methanol (90:8:0, 90:8:1, 90:8:2 successively). The crude product was recrystallized from 2:8 methanol:methylene chloride and petroleum ether to give the title compound as a colorless solid (263 mg, 51%); mp 248.0°-249.0° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 8.1 %

Procedure:
The title compound (9.3 mg) was prepared from 164.0 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 63.8 mg of 4-chlorophenylboronic acid as in Example 196. MS (ESI): exact mass calculated for C19H18ClN3, 323.12. found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.33-7.25 (m, 4H), 7.23-7.16 (m, 3H), 7.09-7.06 (m, 2H), 3.10-3.07 (m, 2H), 3.03-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.66-2.63 (m, 2H).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[C:13]([O:17][C:18]([NH:20][C@@:21]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:25](=[O:27])[C@@H:24]2[C@H:22]1[C@H:23]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CCCCCC>[C:13]([O:17][C:18]([NH:20][C@@:21]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26](=[CH:6][N:7]([CH3:9])[CH3:8])[C:25](=[O:27])[C@@H:24]2[C@H:22]1[C@H:23]2[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CN(C)C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Tert-butoxybis(dimethylamino)methane (481.1 ml, 2.33 mol) is added to a suspension of di-tert-butyl(1S,2S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (600 g, 1.46 mol) in dry toluene (3.6 L) at room temperature under nitrogen. The mixture is heated at 80° C. for 3 hour and 45 minutes, then cooled to room temperature and stirred overnight. The reaction volume is reduced in vacuo, diluted with methyl tert-butyl ether (1.8 L) and hexane (1.8 L), and stirred for 3 hours at 15° C. After 3 hours, the resulting solid is collected by filtration, washed with cold hexane (2×1.8 L), and dried under vacuum to obtain the title compound (620.4 g, yield 91%). HPLC-MS: 98%.
Reaction SMILES: C(OC([NH:11][C@H:12]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[CH:13]=O)=O)C1C=CC=CC=1.[CH2:23]([NH2:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[O:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[CH2:23]([N:37]([CH:13]1[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]([OH:16])[C@H:12]1[NH2:11])[C:39](=[O:38])[CH2:40][CH2:41][CH2:42][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCN
Reactant: O=C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3.1 g of 2-(benzyloxycarbonylamino)-2-deoxy-D-glucose were dissolved in 40 ml of dimethylformamide, 3.2 g of tetradecylamine were added and the mixture was warmed at 80° C. for 4 hours, under a water pump vacuum. The mixture was cooled to room temperature, diluted with 50 ml of tetrahydrofuran and stirred in the presence of 5 ml of ion exchanger SC 108 (H+ form). The exchanger resin was filtered off and 1 g of sodium carbonate and 3.3 g of stearoyl chloride were added to the filtrate. After the mixture had been stirred for five hours, the solid constituents were filtered off and the filtrate was evaporated in vacuo. The resulting syrup was purified by column chromatography on silica gel (eluting agent methylene chloride/methanol=20:1).
Reaction SMILES: Cl[C:2]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[Cl:11])=[O:3].[CH3:12][C:13]([C:25]([N-:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH2:14].C(N(CC)CC)C>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C:13]([NH:14][C:2](=[O:3])[O:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[Cl:11])([CH3:12])[C:25](=[O:26])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17]1
Reactant: CC(N)(Cc1c[nH]c2ccccc12)C(=O)[N-]CCc1ccccc1
Reactant: O=C(Cl)O[C@@H]1CCCC[C@H]1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)O[C@@H]1CCCC[C@H]1Cl)C(=O)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of trans(±)-2-chlorocyclohexyl chloroformate (0.16 g, 0.75 mmol) in anhydrous THF (5 mL) at room temperature was added dropwise a solution of α-methyl-DL- tryptophylphenethylamide (0.23 g, 0.7 mmol) in THF (5 mL), followed by a solution of triethylamine (0.07 g, 0.7 mmol) in THF (5 mL). The reaction was complete after 30 minutes by thin layer chromatographic analysis. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 mL) and washed successively with 1M aqueous citric acid (2×20 mL), saturated NaHCO3 solution (2×20 mL), 1M NaOH solution (20 mL) and water (4×20 mL). The organic phase was dried over MgSO4 and filtered. Removal of the solvent by vacuum distillation gave the title compound (0.273 g, 81%), a white solid crystallized from ether-hexane, mp 69°-78° C. (ether-hexane); IR (film) 1709 and 1656 cm-1 ; NMR (CDCl3) δ1.2-1.4 (3H, m), 1.54 (3H, s), 1.6-1.8 (3H, m), 2.03-2.23 (2H, m), 2.63-2.69 (2H, m), 3.2-3.5 (4H, m), 3.72-3.79 (1H, m), 4.67-4.73 (1H, m), 5.23 (1H, br.s), 6.1-6.2 (1H, m), 7.0-7.6 (10H, m), 8.08 (1H, br.s); Anal. (C27H32N3O3Cl), C, H, Cl, N.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(OCC)(=O)C>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CCCc1cc(-c2ccccc2)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1cc(-c2ccccc2)ccc1OC(=O)OCC
Reaction time: 8 h
Yield: 93.1 %

Procedure:
At 5 to 10° C., 18.4 g (0.17 mol) of ethyl chloroformate are added dropwise with cooling to a solution of 36.3 g (0.17 mol) of 4-hydroxy-3-propyl-biphenyl in 160 ml of ethyl acetate and 17.2 g (0.17 mol) of triethylamine. The solution is left standing overnight at 20° C. and washed with water and dilute hydrochloric acid, and the organic phase is dried and concentrated 45 g (yield 93.2% of theory) of (4-phenyl-2-propyl-phenyl) ethyl carbonate are obtained as a pale oil of log p=4.76 (pH=2.3).