Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O>C(Cl)Cl.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[O:9][N:8]=2)=[O:12])=[CH:15][C:16]=1[CH3:23]
Reactant: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a stirred solution of crude 1-(5-tert-butylisoxazol-3-yl)-3-(3-methyl-4-nitrophenyl)urea (2.0 g, 6.1 mmol) from Step 1 of this example in DCM (10 mL) was added AcOH (1.8 mL, 31.2 mmol), followed by zinc (1.99 g, 31.2 mmol) in small portions. The resulting mixture was stirred at rt for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was carefully quenched with sat. NaHCO3 (50 mL) at rt, and the resulting biphasic mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 0-65% EtOAc in hexanes, to give 1-(4-amino-3-methylphenyl)-3-(5-tert-butylisoxazol-3-yl)urea (560 mg, 61% over two steps). LC-MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21]Br>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH2:21][CH2:20][Br:19])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: BrCCBr
Reactant: CC(=O)c1cc(Cl)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)cc(Br)c1OCCBr
Temperature: 50 °C
Reaction time: 8 h
Yield: 123.4 %

Procedure:
A suspension of 3′-bromo-5′-chloro-2′-hydroxyacetophenone (2.4 g, 10 mmol), potassium carbonate (2.8 g, 20 mmol) and 1,2-dibromoethane (3.5 mL, 41 mmol) in anhydrous N,N-dimethylformamide (30 mL) was stirred at 50° C. overnight. After cooling, the reaction mixture was diluted with water (100 mL), and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL, twice) and brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title reference compound (4.4 g) as orange oil (Quantitative).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(I)cc(C=O)cc1OC
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 5-iodovanilline (502 mg, 1.8 mmol) in acetone (25 mL) was added cesium carbonate (766 mg, 2.35 mmol), followed by ethyl bromoacetate (0.30 mL, 2.7 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 320 mg of a yellow solid (49% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.28 (t, J=7.2 Hz, 3H), 3.97 (s, 3H), 4.23 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.55 (s, 1H), 7.95 (s, 1H), 9.89 (s, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.2, 57.4, 62.1, 70.5, 92.4, 113.9, 135.1, 135.5, 153.1 (2C), 169.4, 169.5, 191.0.
Reaction SMILES: [OH:1][C:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH2:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.[C:27]([O:30][CH2:31]C)(=O)C.O>COC(OC)O>[OH:1][C:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH2:8][O:9][CH2:27][O:30][CH3:31])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)(CO)Cc1ccc(OC)cc1
Reactant: CCOC(C)=O
Agent: COC(O)OC
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOC(=O)C(O)(COCOC)Cc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
A solution of 1.06 g of ethyl 2,3-dihydroxy-2-(4-methoxybenzyl)propanoate in 20 ml of dimethoxymethanol was cooled to 0° C. under an atmosphere of nitrogen gas. 0.94 g of 2,6-lutidine and 1.59 ml of 1,1,1-trimethylsilyl tri-fluoromethanesulfonate were sequentially added, and the mixture was stirred for 1 hour. 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 1.00 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH2:7][C:8]([O:10]CC)=O)=[CH:4][C:3]=1[F:15].[O-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]2[CH2:7][C:8](=[O:10])[NH:18][C:17]2=[O:16])=[CH:4][C:3]=1[F:15]
Reactant: CCOC(=O)CNc1ccc(Br)c(F)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN(c2ccc(Br)c(F)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-(4-bromo-3-fluoro-anilino)acetate (86 g, 0.31 mol) in acetic acid (1.5 L) and water (100 mL) was added a solution of potassium cyanate (50 g, 0.6 mol) in water (200 mL). The reaction mixture was stirred at room temperature for 12 h and then evaporated to dryness. Then 1.5 L of 25% HCl was added to the residue and the mixture was heated to reflux for 3 h. After cooling to room temperature, the solid was filtered and dried to give the title compound. LC-MS: calculated for C9H6BrFN2O2 271.96 observed m/e: 273.35 (M+H)+ (Rt 3.44/6.5 min).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].C([O-])(O)=O.[Na+].[S:18](N)([NH2:21])(=[O:20])=[O:19].Cl>O>[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:9][S:18]([NH2:21])(=[O:20])=[O:19])([O-:4])=[O:3]
Reactant: NS(N)(=O)=O
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3-nitrobenzylamine hydrochloride, (1.89 g, 10.0 mmol) in water (10 mL) is treated with NaHCO3 (840 mg, 10.0 mmol) and sulfamide, (960 mg, 10.0 mmol). The mixture is heated at reflux for 5 h. The cooled mixture is acidified to pH 2 with 1N aqueous HCl and the precipitate is filtered, washed with water and dried under vacuum at 50° C. to afford 3-nitrobenzyl sulfamide as a tan solid: [M−1]−=230.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:60]=1
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:8]([O:15][C:16]([N:18]1[CH:19]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:25](=[O:27])[O:26][CH2:1]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccccc1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCC1C(=O)OCN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To 1 liter of toluene were added 300 g of DL-N-benzyloxycarbonylglutamic acid, 48 g of paraformaldehyde and 12 g of p-toluenesulfonic acid monohydrate, and azeotropic dehydration was then carried out for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was dissolved in 500 ml of ethyl acetate, after which the resulting solution was washed with water and then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain oily DL-3-benzyloxycarbonyl-4-(2-carboxyethyl)oxazolidin-5-one.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]([OH:5])[CH3:4].[C:7](O)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][CH:3]([O:5][C:7](=[O:11])[CH:8]=[CH:9][CH3:10])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)C(C)O
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)C(C)C
Yield: 52.4 %

Procedure:
3-Methyl-butan-2-ol (180 g), crotonic acid (165 g), toluene (200 mL), and PTSA (8 g) were charged into to a 2-L reaction flask fitted with a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged at reflux for about 13-15 hours till GC analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with brine, sodium carbonate, and brine, and further purified by fractional distillation to provide but-2-enoic acid 1,2-dimethyl-propyl ester (157 g) with a boiling point of 53° C. at 0.77 mmHg.
Reaction SMILES: [CH2:1]([O:4]C1CCCCO1)[C:2]#[CH:3].C([Mg]Br)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17]>CCOCC.O1CCCC1>[OH:4][CH2:1][C:2]#[C:3][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17]
Reactant: C#CCOC1CCCCO1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(C#CCO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
A solution of 3.3 ml (23.2 mmols) of tetrahydro-2-(2-propinyloxy)-2H-pyran [R. A. Earl et al., Organic Syntheses 60, 81 (1981)] in 23 ml of anhydrous tetrahdrofuran was added dropwise to 7.8 ml (23.2 mmols) of a 3 molar solution of ethyl-magnesium bromide in ether at room temperature in the course of 30 minutes. The mixture was then subsequently stirred at room temperature for 1.5 hours. This solution was added dropwise to a well-stirred solution, cooled to -20° C., of 5.0 g (23.2 mmol) of 4-nitrobenzyl chloroformate in 25 ml of tetrahydrofuran in the course of 1.5 hours. The mixture was then subsequently stirred at -15° C. for 30 minutes and at 0° C. for 1.5 hours, and was then left to stand at 0° C. for 12 hours, whereupon the magnesium salts crystallized out. The salts were filtered off, with exclusion of moisture, and washed two times with a little toluene. The filtrate solution was washed 5 times with saturated NaCl solution and dried over MgSO4. The solvent was evaporated off in vacuo, the residue was dissolved in 25 ml of anhydrous methanol and the solution was stirred with 1 ml of the ion exchanger Dowex-50-X4 (H+ form, prewashed with anhydrous methanol) at room temperature for 1 hour. The ion exchanger was separated off, the filtrate solution was concentrated in vacuo and, finally, the residue was dried under a high vacuum. The treatment with the ion exchanger was repeated as described above. The crude product was chromatographed on 300 g of silica gel (toluene:ethyl acetate 4:1) and 2.07 g (38%) of 4-nitrobenzyl 4-hydroxy-2-butinoate were obtained as colorless crystals, melting point: 93°-94° C., RF : 0.27 (toluene:ethyl acetate 4:1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:21](=[O:22])[C:20]3[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Product: COC(=O)C1CCc2cc(C(=O)c3ccc(Cl)cc3)c(O)cc21

Procedure:
Analogously to the process described in Example 5, 19 g of 6-methoxy-indane-1-carboxylic acid methyl ester and 48 g of p-chlorobenzoyl chloride give 5-(p-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester of melting point 96°-98° C. (from ether-petroleum ether).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20].C(=O)(O)[O-].[Na+]>CC#N>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[C:19](=[O:20])[CH2:18][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: O=C(CBr)N1CCc2ccccc2C1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CN1CCC(c2n[nH]c3cc(F)ccc23)CC1)N1CCc2ccccc2C1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.8 g, 18.9 mmol) in CH3CN (200 ml) was added 2-bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4.8 g, 18.9 mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. The reaction mixture was warmed to reflux (4 hours), cooled to room temperature and filtered through a pad of celite. The solids were washed with DCM and the combined filtrates were concentrated. The remaining residue was purified via preparative HPLC (silica gel, 5-10% MeOH/DCM) to give 4.1 g of 1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethanone which was used without further purification. To a suspension of the latter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithium aluminum hydride (11.3 ml of 1.0M solution in THF, 11.3 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux (5 hours), cooled to room temperature and carefully quenched with water (10 ml). The precipitated salts were removed via filtration and washed with 1:1 EtOAc/DCM. The combined filtrates were concentrated and the remaining oil was purified via flash column chromatography (silica gel, 10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt was prepared in methanol (30 ml) with maleic acid (3.0 eq.), m.p. 185°-187° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39][O:40]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:40][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared, according to the procedure of Example 16, Step C, using 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yloxazol-4-yl)-ethyl ester to produce a white solid (19%). MS [EI+] 520 (M+H)+, [EI−] 518 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8]1.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([C:30]1[C:29]([CH3:36])=[N:1][C:2]2[C:3]([C:26]=1[NH2:27])=[C:4]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH:23]=[CH:24][CH:25]=2)=[O:32])[CH3:35]
Reactant: N#Cc1c(N)cccc1OCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCNC3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 110c) and ethyl 3-oxobutanoate as a yellow oil (21%). MS 344 (MH+).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: Oc1ccccc1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Product: CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method 15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH2+:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=2[N:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]3[C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])=[N:23][C:22]=2[CH:24]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1c1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-((benzyloxy)carbonyl]piperidinium chloride (see EP 530167 A1 9303031 and 2,5-dichloro-1,3-benzoxazole [see J.O.C. (1996), 61(10), 3289-3297]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-(5-chloro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [OH-].[K+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[OH:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1>O1CCCC1>[Cl:15][C:16]1[N:17]=[C:18]([Cl:23])[C:19]([O:14][C:8]2[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:13])=[CH:20][N:21]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1ncc(Oc2c(Cl)cccc2Cl)c(Cl)n1
Yield: 55.1 %

Procedure:
Potassium hydroxide/ethanol (10%; 0.035 mol) was added to a solution of 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). The mixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added. The mixture was stirred overnight at 60° C. The reaction was quenched with NaOH 1N solution. The aqueous layers were extracted with EtOAc several times and then the organic layers were combined and washed with NaOH 3N and saturated NaCl, dried and concentrated. The residue was recrystallized from CH2Cl2/hexane. The precipitate was filtered off and dried, yielding 5.98 g 2,4-dichloro-(2,6-dichlorophenoxy)pyrimidine (55%) (interm. 12).
Reaction SMILES: [N:1]1([C:7](=[O:23])[CH2:8][CH:9]([CH2:13][CH:14]2[CH2:16][CH:15]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](O)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:24][CH:25]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:26]([C:28]1[O:29][CH:30]=[CH:31][N:32]=1)[OH:27]>>[N:1]1([C:7](=[O:23])[CH2:8][CH:9]([CH2:13][CH:14]2[CH2:16][CH:15]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([NH:24][CH:25]([C:26]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[O:27])[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(CCc1ccccc1)[C@H](O)c1ncco1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1
Product: O=C(NC(CCc1ccccc1)C(=O)c1ncco1)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1

Procedure:
It is similarly prepared according to general procedure given for example X above but using 4-Morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyric acid and (S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[CH3:32][C:33]([CH3:62])([O:35][C:36](=[O:61])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:55]([C:54]3[CH:53]=[C:52]([CH2:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][C:36]([O:35][C:33]([CH3:62])([CH3:34])[CH3:32])=[O:61])[CH:60]=[CH:59][CH:58]=3)=[O:56])=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][C@@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21][CH2:20]4)[CH:29]=[CH:30][N:31]=3)[CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of (S)-2-(2-amino-5-cyclobutoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 132b (0.048 mmol, 20 mg), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (0.053 mmol, 24 mg) and DIEA (0.29 mmol, 38 mg) in DMF (0.16 mL) was added HATU (0.053 mmol, 20 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. TLC to give a yellow syrup (13.8 mg, 34%). MS (ES, m/z): 836.07 [M+H]+.