Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.[Pd]>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)N(CC(=O)O)c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 150 °C
Yield: 5.1 %

Procedure:
A solution of [(4-bromophenyl)(methylsulfonyl)amino]acetic acid (intermediate 3, 20 mg, 65 μmol) in dimethoxyethane (1 mL) was added in one portion to a mixture of 4-cyanophenyl-boronic acid (9.5 mg, 65 μmol) and fibrecat FC1001 (2.71% Pd; 25 mg, 6.5 μmol) in a Smith microwave reaction vial. Aqueous sodium carbonate solution (1.0 M; 130 μL, 130 μmol) was added and the vial capped. The crude reaction mixture was heated at 150° C. for 15 min using a Smith Synthesiser microwave reactor. On cooling the vial was opened and the contents were filtered through a Whatman 5 μM filter tube, washing the filter cake with methanol (2×1 mL). The filtrate was evaporated and the resulting residue was purified using mass directed auto-preparative reverse phase HPLC to give the title compound (1.1 mg, 5%) as a white solid. LC/MS: 2.94 min; z/e 329, calcd (M−1) 329. 1H NMR (400 MHz: MeOD): 7.80 (4H), 7.75 (2H), 7.65 (2H), 4.45 (2H), 3.10 (3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:9]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])[CH3:8])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of N-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (965 mg, 2.86 mmol) in dichloromethane (10 mL) was cooled to 0° C. 4-(dimethylamino)pyridine (35 mg, 0.29 mmol), triethylamine (0.60 mL, 4.29 mmol), and acetic acid anhydride (0.32 mL, 3.43 mmol) were added. The reaction mixture was stirred for 5 hours, while it was warming slowly to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 10% sodium hydrogensulfate solution. The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined and washed with saturated sodium hydrogen carbonate solution. They were dried over magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica (90 g) with ethyl acetate/dichloromethane (1:3 to 1:1) to give 890 mg of 3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][S:11](=[O:14])(=[O:13])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.F[C:16]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:30])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][S:11](=[O:14])(=[O:13])[N:10]([C:16]3[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)CC(c2ccc(F)cc2)CN1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CC(c3ccc(F)cc3)CS2(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
18.00 g of 4-(4-fluorophenyl)isothiazolidine 1,1-dioxide, 20.59 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate (Journal of Medicinal Chemistry (1997), 40(13), 2017) and 81.75 g of Cs2CO3 were stirred in 500 ml of anhydrous DMF at RT for 5 hours. Then a further 2.00 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate were added, and the mixture was stirred at RT for 1 hour and left to stand at RT for 15 hours. The reaction mixture was poured into 1800 ml of water and stirred at RT for 1 hour, and the product was filtered off with suction. The product was then dissolved in 1 l of EA, and the solution was mixed with MgSO4 and activated carbon and stirred at RT for 15 minutes. It was then filtered and the solvent was removed in vacuo. 35.00 g of a colorless foam were obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.[NH3:22]>C(Cl)Cl>[F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:19])[C:16]([NH2:22])=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Reactant: N
Solvent: ClCCl
Product: C[C@@H](C(N)=O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a cooled mixture (0-5° C.) of (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (1 g, 3.16 mmol) in CH2Cl2 (20 mL), 1,1-carbonyldiimidazole (CDI) (0.512 g, 3.16 mmol) was added. After stirring for 1 h at 0-5° C. gaseous ammonia was bubbled into the mixture for 4 h and then left stirring at room temperature until the complete disappearance of the starting material. The reaction was quenched adding a H3PO4/H2PO4− buffer solution (pH=2.0, 5 ml), the two phases were separated and the organic one washed with the same buffer (3×10 mL) and water (3×10 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl) propanamide (788 mg, 2.5 mmol) as a white solid (79%) used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][C:48]([NH:50][C@H:51]([C:56](OC2C=CC([N+]([O-])=O)=CC=2)=[O:57])[CH2:52][C:53]([NH2:55])=[O:54])=[O:49])=[CH:42][CH:41]=1>CN(C)C=O>[NH:50]([C:48]([O:47][CH2:46][C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1)=[O:49])[C@H:51]([C:56]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:57])[CH2:52][C:53](=[O:54])[NH2:55]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
5.4 g of H-Lys(BOC)-Phe-His-OMe (compare Example 1) and 4.5 g of Z-Asn-ONP in 20 ml of dimethylformamide are stirred for 20 hours at room temperature. The peptide derivative is precipitated by adding ethyl acetate, filtered off and washed with ether. After recrystallisation from methanol the product melts at 182°-183°C. In a thin layer chromatogram RF100 = 0.57 (on silica gel). [α]D20 = -28° (c = 1 in dimethylformamide).
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N(CC)CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:22]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Reactant: CCCCCCCCO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O
Yield: 82.7 %

Procedure:
To a suspension of 2 (50.0 g, 0.245 mole), in ethanol-free chloroform (500 ml), was added triethylamine (75 ml, 0.538 mole) followed by octanol (80 ml. 0.508 mole). The resulting solution was refluxed for 45 hours, cooled and the chloroform removed by evaporation at 40° C. The residue was dissolved in ethyl acetate (400 ml) and this solution washed 3 times with cold saturated sodium bicarbonate solution (200 ml). The combined bicarbonate extract was washed twice with ethyl acetate (200 ml). The bicarbonate extract was then adjusted to pH 2 by the drop wise addition of concentrated HCl (≈78 ml). The cloudy solution was extracted with three portions of ethyl acetate (200 ml), the combined ethyl acetate extract dried (magnesium sulfate), filtered and evaporated, finally in high vacuum at 50° C. to give 3a (61.7 g, 90%) as an oil. The oil was dissolved in 200 ml of hot toluene on the steam bath and filtered from some insoluble material. The filtrate was kept at room temperature overnight, then, the crystals were collected, washed with toluene and dried to give 3a (43.09 g, 58%), mp 65.8°-66.7° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO.O>[C:1](=[N:14][OH:15])([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CC(=O)c1cc2ccccc2cn1
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc2ccccc2cn1
Yield: 89 %

Procedure:
A solution of 3-acetyl-isoquinoline (0.65 g), hydroxylamine (0.29 g) and sodium acetate (0.47 g) in a mixture of methanol (20 ml) and water (3 ml) was heated to reflux for 1.5 hours. The reaction was then poured into water and extracted with ethyl acetate. The combined extracts were dried, concentrated and triturated with hexane to give 3-acetyl-isoquinoline oxime (0.63, 89% yield) as a white crystalline solid m.p. 135°-142° C.; 1H NMR: 2.50(3H,s); 7.61(1H,t); 7.70(1H,t); 7.87(1H,d); 7.99(1H,d); 8.11(1H,s); 9.28(1H,s) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:38]([O:48][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCO
Product: CCCCCCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with decanol, mp 65°-67° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:30])[NH:10][C@@H:11]([CH2:24][C:25]2[NH:29][CH:28]=[N:27][CH:26]=2)[C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>CO.O>[NH:29]1[C:25]([CH2:24][C@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:30])[C:12]([NH:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:13])=[CH:26][N:27]=[CH:28]1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)Nc1c(C)cc(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H]2O[C@@H]2C(=O)O)c(C)c1
Yield: 67.8 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18b (51.6 mg, 0.1 mmol); LiOH (5 mg, 0.2 mmol); MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL): yielded 29 as a white solid (26.2 mg, 54.2%). 1H NMR (MeOD-d4, 400 MHz): δ 7.62 (s. 1H); 6.93 (s, 1H); 6.87 (s, 2H); 4.84-4.82 (m, 1H); 3.53-3.49 (d, 1H); 3.38-3.35 (d, 1H); 3.25-3.22 (m, 2H); 2.25 (s, 3H); 2.07 (s, 6H). 13C NMR (MeOD-d4, 100 MHz): 174.40, 172.62, 170.80, 168.89, 136.54, 135.74, 135.11, 133.43, 131.25, 128.18, 117.26, 54.20, 53.82, 53.69, 52.80, 29.34, 19.55, 16.86. ESI-HRMS (m/z): [M−H+] calcd. for C19H22N4O5: 385.1517, observed: 385.1516. HPLC Method 2: Rt=16.4 min, purity=95.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[OH:18].[C:19]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([O:18][C:4]2[CH:5]=[CH:6][C:7]([B:9]3[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]3)=[CH:8][C:3]=2[O:2][CH3:1])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 45 h
Yield: 71.5 %

Procedure:
To a solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.8 g, 3.2 mmol, 1 eq), 1-boc-4-hydroxypiperidine (0.97 g, 4.8 mmol, 1.5 eq) and triphenylphosphine (1.26 g, 4.8 mmol, 1.5 eq) in anhydrous THF (8 mL) was added DIAD (0.94 mL, 4.8 mmol, 1.5 eq) dropwise at 0° C. The solution was stirred at RT for 45 h. The solvent was removed, and the resulting light orange oily residue was treated with 20% AcOEt/c-hexane to give white crystals (PPh3O) which were filtered off and washed with the same mixture. The filtrate was evaporated to give an oily residue which was treated with c-hexane and a few drops of AcOEt to give a white precipitate that was removed by filtration and an oily residue that solidified upon standing. The crude product (1.93 g containing some c-hexane) was used as it was in the subsequent step. The remainder was purified by column chromatography (Isolute Flash Si II column, 25 g silica gel, 0-8% AcOEt in c-hexane) to give the pure desired product (0.991 g). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=5.10 min, [M+H]+ m/z 334.3.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].I[CH2:13][CH2:14][CH3:15].O>CN(C=O)C>[CH2:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:14][CH3:15]
Reactant: O=Cc1ccccc1O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccccc1C=O
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of salicylaldehyde (12.21 g, 0.1 mol) in DMF (65 ml) was cooled in an ice/water bath under argon and 60% sodium hydride in mineral oil (4.0 g, 0.1 mol) was added in several portions. The mixture was stirred for one hour and then iodopropane (16.99 g, 0.1 mol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, poured into water (800 ml) and stirred. The mixture was extracted with chloroform (3×), the chloroform layer was concentrated in vacuo and the dark oil thus obtained was distilled under vacuum (92-94° C. at 1.15 mm Hg) to afford 12.68 g (77%) of 2-propoxybenzaldehyde.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)=[O:3].ClC1C=C(C(OO)=[O:46])C=CC=1>ClCCl>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)(=[O:46])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methanesulfinyl-phenyl)-amide (85 mg, 0.15 mmol) (from Example 81 supra) in dichloromethane (4 mL) was added 3-chloro-benzenecarboperoxoic acid (52.6 mg, 0.3 mmol) (Aldrich). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with 2% of sodium sulfite solution, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl)-amide as a pale yellow solid. (Yield 81 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.ClCCl>[C:9]12([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[OH:8])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
17 g (0.1 mol) of 3-bromophenol, 15.22 g (0.1 mol) of 1-adamantanol and 50 ml of dichloromethane are introduced into a round-bottomed flask. 5 ml of concentrated sulphuric acid are added dropwise and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water, the mixture is neutralized with sodium bicarbonate and extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (50:50). After evaporation of the solvents, 15.2 g (50%) of the expected phenol, melting point 112°-114° C., are collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: C1CNCCNC1
Solvent: CC#N
Product: Brc1ccc(N2CCCNCC2)nc1
Yield: 50.3 %

Procedure:
A solution of 5-Bromo-2-fluoro-pyridine (2.0 g, 11.4 mmol), [1,4]Diazepane (2.2 g, 22.8 mmol) in CH3CN (5.0 mL) was stirred at 50° C. for 3 hrs. Filter of the solid and the mother solution was brine, and concentrated in vacuo to give the title product (1.47 g, 51%) as a brown solid. ESI MS m/z 256 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=7.0 Hz, 1H), 7.45 (dd, J=22.0, 6 Hz, 1H), 6.38 (d, J=22.0 Hz, 1H), 3.66 (m, 4H), 2.81 (t, J=15.0 Hz, 2H), 1.86 (m, 2H).
Reaction SMILES: [OH:1][CH: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.[NH2:15][C:16]1[C:21]2[CH2:22][CH2:23][O:24][C:20]=2[C:19]([C:25](Cl)=[O:26])=[CH:18][C:17]=1[Cl:28]>CN(C)C1C=CN=CC=1.ClCCl>[NH2:15][C:16]1[C:21]2[CH2:22][CH2:23][O:24][C:20]=2[C:19]([C:25]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:26])=[CH:18][C:17]=1[Cl:28]
Reactant: Nc1c(Cl)cc(C(=O)Cl)c2c1CCO2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2cc(Cl)c(N)c3c2OCC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (4.02 g) and N,N-dimethyl-4-pyridinamine (3.7 g) in dichloromethane (200 ml) was stirred at room temperature. A solution of intermediate (7) (4.8 g) in CH2Cl2 (200 ml) was poured into the solution. The reaction mixture was stirred for 3 hours at room temperature. The mixture was washed with water, a 5% NaOH solution and again water. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated. The residue (7.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 4.7 g of 1,1-dimethylethyl 4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]oxy]-1-piperidinecarboxylate (59%) (intermediate 8).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].Br[C:36]1[N:41]=[C:40]([CH3:42])[C:39]([NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[C:38]([CH3:51])[CH:37]=1.[N:52]1[C:57]2[CH2:58][CH2:59][NH:60][CH2:61][C:56]=2[CH:55]=[N:54][CH:53]=1>C1(C)C=CC=CC=1>[N:52]1[C:57]2[CH2:58][CH2:59][N:60]([C:36]3[N:41]=[C:40]([CH3:42])[C:39]([NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[C:38]([CH3:51])[CH:37]=3)[CH2:61][C:56]=2[CH:55]=[N:54][CH:53]=1
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Reactant: c1ncc2c(n1)CCNC2
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ncncc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (5 mg, 0.009 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (9 mg, 0.018 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (46 mg, 0.41 mmol), 1d (66 mg, 0.22 mmol) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (25 mg, 0.19 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford the tittle compound as a solid. 1H NMR (CDCl3, 400 MHz) δ 1.15 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.06 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.73 (s, 2H), 6.48 (s, 1H), 6.55 (s, 1H), 8.55 (s, 1H), 9.01 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.FC(F)(F)S(OCC(F)(F)F)(=O)=O.C(N(CC)CC)C>CC(C)=O>[F:16][C:17]([F:22])([F:21])[CH2:18][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2C12CCN(CC(F)(F)F)CC2

Procedure:
A mixture of spiro[indoline-3,4′-piperidin]-2-one, [PCT Int. Appl. WO 0145707 A1 (2001)] trifluoroacetic acid salt (3.66 g, 11.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.63 mL, 11.6 mmol), and triethylamine (8.06 mL, 57.9 mmol) in acetone (30 mL) was heated at reflux for 16 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3. The aqueous layer was extracted two more times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=285 (M+1).