Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:22]=[CH:23][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccc3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(C3CCNCC3)cnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.6 %

Procedure:
A mixture of 0.47 gm (1.5 mMol) 1-tert-butoxycarbonyl-4-(quinoxalin-2-yl)piperidine and 5 mL trifluoroacetic acid in 5 mL dichloromethane was stirred at room temperature for 18 hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 10% to 40% methanol and a trace of ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.133 gm (42%) of the title compound as a tan foam.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[OH-].[K+].CN(C)C(Cl)=[S:28].CCCCCC>O.O1CCCC1>[SH:28][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCc1cccc2ccc(O)cc12)c1ccccc1
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCCc1cccc2ccc(S)cc12)c1ccccc1

Procedure:
The product obtained in Step A (9 mmol) is added, with stirring, to a solution of potassium hydroxide (10 mmol) dissolved in 15 ml of water and 16 ml of tetrahydrofuran. The solution is cooled using a bath of ice and salt, and dimethylthiocarbamoyl chloride (9 mmol) dissolved in tetrahydrofuran (15 ml) is added dropwise with stirring. After stirring for half an hour while maintaining the cold temperature, the reaction mixture is extracted with chloroform. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The residue is taken up in diphenyl ether (10 ml) and refluxed for one hour under a nitrogen atmosphere. The diphenyl ether is removed by evaporation under reduced pressure until a solution of about 2 ml has been obtained. The 2 ml of distillate, which are still hot, are poured carefully into 50 ml of hexane to yield, after cooling, a solid which is isolated by filtration. The solid collected in that manner is added to a solution of potassium hydroxide (380 mg) dissolved in a water/methanol mixture (1 ml/10 ml). The solution is refluxed for 12 hours and then cooled and concentrated under reduced pressure. The residue is taken up in 20 ml of chloroform and extracted 3 times with water. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is chromatographed over silica gel to yield the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:19]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CC2CC2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of tert-butyl 3-(3-bromophenyl)propylcarbamate (57) (1.0 g, 3.1 mmol) and cyclopropyl acetylene (2.9 mL, 3.4 mmol, 70% soln in toluene) in diisopropylamine (4 mL) was added PdCl2(PPh3)2 (0.120 g, 0.17 mmol), tri-o-tolylphosphine (0.048 g, 0.16 mmol) and CuI (0.026 g, 0.16 mmol). The resulting mixture was degassed and stirred under nitrogen at 90° C. for overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (10-40% ethyl acetate-hexane gradient) gave tert-butyl 3-(3-(cyclopropylethynyl)phenyl)propylcarbamate. Yield (0.756 g, 79%). This alkyne was used for deprotection without futher purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([C:8]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[C:17]3[C:9]=2[C:10]2[CH2:11][CH2:12][CH:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:14][C:15]=2[NH:16]3)[CH:5]=[CH:6][CH:7]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](Cl)=[O:44]>C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:43](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)[C:3]=2[CH3:35])=[C:9]2[C:17]=1[NH:16][C:15]1[CH2:14][CH:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:12][CH2:11][C:10]2=1)(=[O:23])[NH2:22]
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3
Agent: Cl
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccccn2)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3

Procedure:
A solution of benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, TFA salt (Example 51-1, 55 mg, 0.094 mmol), TEA (0.066 mL, 0.472 mmol), and picolinoyl chloride hydrochloric acid salt (50.4 mg, 0.283 mmol) in DCM (8 mL) was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC to provide benzyl 8-carbamoyl-5-(2-methyl-3-(picolinamido)phenyl)-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, isolated as the TFA salt, as a white solid (26 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 8.59 (1H, t, J=4.8 Hz), 8.14 (1H, d, J=8.3 Hz), 7.89-7.99 (1H, m), 7.85 (1H, dd, J=9.9, 8.1 Hz), 7.50 (2H, dd, J=7.7, 2.0 Hz), 7.11-7.32 (6H, m), 7.01 (1H, d, J=7.9 Hz), 6.74 (1H, d, J=7.5 Hz), 4.96 (2H, s), 3.68-3.87 (1H, m), 2.96-3.10 (1H, m), 2.49-2.66 (1H, m), 1.82-2.11 (5H, m), 1.73 (1H, br. s.), 1.34-1.62 (1H, m). Mass spectrum m/z 575.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@H](C([O-])=O)CC([O-])=O.[NH4+].[NH4+].CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1>O>[NH2:13][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: [NH4+]
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A batch type process wherein the catalyst compositions are stirred in from 0.01 to 0.5 molar (preferably 0.05 to 0.3 molar) solution of phenylpyruvate in the presence of 0.015 to 0.75 molar ammonium L-aspartate (preferably 0.075 to 0.5 molar) and 0.4 to 0.000001 mmolar pyridoxal 5-phosphate (preferably 0.04 to 0.0004 mmolar in water at 5.0 to 10.0 pH (preferably 7.5 to 9.5 pH) for periods of 1.0 to 100 hours (preferably 8 to 48 hours) at temperatures below 50° C. (preferably 20° to 40° C.). Broadly from 0.05 to 50 g of immobilized cells, preferably from 1.0 to 15 g, are used per 0.1 mole of starting phenylpyruvate. After the conversion, the catalyst compositions may be removed by filtration or the equivalent for reuse in converting fresh batches of phenylpyruvate solutions. The product solutions are obtained in a form suitable for conventional processing to isolate the L-phenylalanine (ion exchange chromotography, precipitation, filtration, washing, recrystallization, drying).
Reaction SMILES: CO[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: COCCC1CCOC1=O
Product: CC(=O)OCCC1CCOC1=O
Temperature: 120 °C
Reaction time: 69 h
Yield: 65 %

Procedure:
In a stirred vessel there is heated to 120° C. a mixture of 20 g of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone, 100 g of glacial acetic acid, and 10 g of Nafion. Following a period of 69 h, the reaction is terminated (conversion: 89%) and the catalyst is separated by filtration. Following purification by distillation, there is obtained 65% of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone (based on the 3-(2'-methoxyethyl)-dihydro-2(3H)furanone used).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH2:34][OH:35])[CH2:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH:34]=[O:35])[CH2:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCC(CC(=O)N1CCc2ccccc2C1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
A solution of oxalyl chloride (0.460 mL) in CH2Cl2 (20 mL) was cooled to -78° C. whereupon DMSO (0.749 mL) was added dropwise over 15 mins. This mixture was stirred for 15 minutes. Whereupon a CH2Cl2 (10 mL) solution of 2-[3-(3,4-dichlorophenyl)-5-hydroxy-1-oxopentyl]-1,2,3,4-tetrahydroisoquinoline (1.0 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with Et3N (3 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2Cl2 (100 mL). The organic fraction was separated, washed sequentially with 1N HCl (1×50 mL), sat. NaHCO3 (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 5-15% EtOAc/Hex gave the title compound (800 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].C=O.[CH2:35]([OH:37])[CH3:36]>>[CH2:1]([O:8][C:9]1[C:14]2[C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][O:37][CH2:35][CH3:36])[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: c1ccc(COc2cccc3onc(OCCC4CCNCC4)c23)cc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Product: CCOCN1CCC(CCOc2noc3cccc(OCc4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of 4-(benzyloxy)-3-(2-piperidin-4-ylethoxy)-1,2-benzisoxazole (3.1 g, 8.4 mmol, EXAMPLE 7, Step 3) and potassium carbonate (1.2 g, 8.4 mmol) in ethanol (16.0 mL) was added paraformaldehyde (0.28 g, 9.2 mmol) at ambient temperature. After being stirred at room temperature for 14 h, the mixture was filtered. The filtrate was concentrated in vacuo to give 3.4 g (quant.) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:26]([Cu])#[N:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:26]#[N:27])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1

Procedure:
Prepared in analogy to that of Example 105(a) from 1-benzyl-2,3,7-tribromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 478 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(C(C)C)C(C)C.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28].[CH2:30]1[CH2:35][C@H:34]([C:36]([OH:38])=O)[N:33]([C:39]([O:41]CC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:80](O)(=O)[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91]C>C1COCC1.CN(C=O)C>[NH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:29][C:36]([C@H:34]1[CH2:35][CH2:30][CH2:31][CH2:32][N:33]1[C:39](=[O:41])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH3:80])=[O:38]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCC(=O)N1CCCC[C@@H]1C(=O)NCCCCCCN

Procedure:
To a 500 mg-batch of ArgoGel MB-OH (from Argonaut; loading 0.4 mmol/g, 0.2 mmol) was added a solution of 163 mg (1 mmol, 5 eq.) carbonyldiimidazole and 171 μl (1 mmol, 5 eq.) DIEA in 5 ml of dry THF, and the resulting mixture was allowed to react for 7 h at room temperature under gentle shaking. After this time, the resin was washed with THF (2×), DCM (2×), DMF (1×) and then directly used for the following step. The resin was allowed to react for 15 h at room temperature with a solution of 230 μl (2 mmol, 10 eq.) 1,6-hexanediamine (see compound VIIa in Scheme 2) and 342 μl (2 mmol, 10 eq.) DIEA in 5 ml DMF. After this time, the resin batches were washed with DMF (3×), DCM (1×), THF (2×), DCM (3×), and Et2O (2×) and dried in vacuo. To the resulting resin batch was added a solution of 211 mg (0.6 mmol, 3 eq.) Fmoc-D-pipecolic acid (see compound IIa in Scheme 2), 228 mg (0.6 mmol, 3 eq.) HATU, and 206 μl (1.2 mmol, 6 eq.) DIEA in 3 ml anhydr. DMF. After a reaction time of 8 h at ambient temperature, the resin was washed with DMF (5×), DCM (5×), DMF (5×), DCM (3×), Et2O (2×), and dried in vacuo. The resin was now treated with 4ml of a solution of 20% (v/v) piperidine in DMF for 20 min at room temperature, then washed with DMF (5×), DCM (5×), DMF (5×). To the resulting resin was added a solution of 129 mg (0.6 mmol, 3 eq.) tridecanoic acid (see compound V in Scheme 2), 228 mg (0.6 mmol, 3 eq.) HATU, and 206 μl (1.2 mmol, 6 eq.) DIEA in 3 ml anhydr. DMF. After a reaction time of 8h at room temperature, the reaction was worked up by washing with DMF (5×), DCM (5×), DMF (5×), DCM (3×), Et2O (2×), and the resin batches were dried in vacuo at r.t. O/N. The resin was treated with a solution of 20% (v/v) TFA in DCM for 10 min at room temperature, to release the title compound from the resin in 60% overall yield.
Reaction SMILES: [CH2:1]1[O:21][C:20]2[CH:19]=[CH:18][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][N:11]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:4][C:3]=2[O:2]1.[Li]CCCC.[F:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:39]=[C:38]([Cl:40])[O:37][N:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1>C(OCC)C.CCCCCC.C(OCC)(=O)C>[ClH:40].[CH2:1]1[O:21][C:20]2[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:38]3[O:37][N:36]=[C:35]([C:30]4[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=4)[CH:39]=3)[CH2:8][CH2:9][CH2:10][N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:4][C:3]=2[O:2]1
Reactant: Fc1cc(F)cc(-c2cc(Cl)on2)c1
Reactant: C1=CC=CN(CCCNCc2ccc3c(c2)OCO3)C=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cl
Product: Fc1cc(F)cc(-c2cc(N(CCCN3C=CC=CC=C3)Cc3ccc4c(c3)OCO4)on2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-methylenedioxybenzyl-(3-azepin-1-yl-propyl)amine in diethyl ether (26.7 ml of a 0.12 M solution in diethyl ether, 3.22 mmol) cooled to 0° C. is slowly added n-BuLi (1.51 ml of a 1.6M solution in hexane, 2.41 mmol). The resulting mixture is stirred at 0° C. for 10 min and 3-(3,5-difluorophenyl)-5-chloroisoxazole (347 mg, 1.61 mmol) is added at once. After stirring at 0° C. for 30 min, the reaction mixture is dilute with ethyl acetate, washed with water andbrine, dried over sodium sulfate, and concentrated in vacuo. The crude material is purified by flash chromatography (silica gel, 3% methanol containing 10% NH4OH in dichloromethane) to give the free base of the title compound as an oil. The free base is dissolved in dichloromethane (10 ml) and treated with 1 N HCl in diethyl ether (4 ml, 4 mmol) to provide after concentration in vacuo, 3,4-methylenedioxybenzyl-[3-(3,5-difluorophenyl)-isoxazol-5-yl]-(3-azepin-1-yl-propyl)-amine hydrochloride (513 mg, 63%) as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1sccc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 101.4 %

Procedure:
Reductive amination of 3-amino-thiophene-2-carboxylic acid methyl ester (3.0 g, 19.1 mmol) and 4-oxo-piperidine-1-carboxylic acid benzyl ester (4.46 g, 19.1 mmol) in THF (4.6 mL) employing Bu2SnCl2 (0.598 g, 1.92 mmol) and PhSiH3 (2.58 mL, 21.6 mmol) was carried out as described for example 19, step 1 gave 4-(2-methoxycarbonyl-thiophen-3-ylamino)-piperidine-1-carboxylic acid benzyl ester (7.25 g, quantitative). NMR 1H (CDCl3, 400 MHz): 7.4-7.3 (m, 6H), 6.9-6.78 (m, 1H), 6.7-6.6 (m, 1H), 5.14 (s, 2H), 4.15-4.0 (m, 2H), 3.81 (s, 3H), 3.6-3.45 (m), 3.1 (brt, 2H), 2.1-1.9 (m, 2H), 1.6-1.45 (m, 2H).
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:11][CH:12]=2)[CH2:4][O:3]1.C([O-])(=O)C.[NH4+:42].Cl>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:17]([C:16]2[NH:42][C:13]([C:10]3[N:11]=[CH:12][C:7]([CH:5]([OH:6])[CH2:4][OH:3])=[CH:8][CH:9]=3)=[CH:14][CH:15]=2)[CH2:18][CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)nc2)O1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
To a solution of 1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (232 mg) in acetic acid (5 mL) was added ammonium acetate (540 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (218 mg). To a solution of the obtained crude product in tetrahydrofuran (5 mL) was added 1M hydrochloric acid (5 mL), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (155 mg, yield 78%) as a colorless amorphous solid. MS: 471 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[K+].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15]>CC(C)=O.C(Cl)Cl>[C:1]([NH:12][C:11]([NH:19][CH2:18][CH2:17][N:16]([CH2:20][CH3:21])[CH2:14][CH3:15])=[S:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCN(CC)CCNC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 70 ml of benzoyl chloride in 100 ml of anhydrous acetone is added dropwise, at room temperature, to a suspension of 51 g of potassium thiocyanate in 300 ml of anhydrous acetone. When the addition is complete, the reaction mixture is refluxed for 5 minutes. A solution of 85 ml of 2-diethylaminoethylamine in 100 ml of methylene chloride is added slowly to the resulting hot solution, with vigorous stirring, so as to keep the mixture under reflux. When the addition is complete, the mixture is stirred for 1 hour at room temperature, the solvents are then evaporated off and the residue is taken up in iced water. Extraction is carried out twice with 200 ml of methylene chloride and the solution is dried over magnesium sulfate. The solvent is evaporated off to dryness and the oily product obtained is purified by chromatography on a silica column. Impurities of low polarity are removed by elution with an 80/20 (vol/vol) methylene chloride/ethyl acetate mixture. The expected product is then obtained by elution with a 95/5 (vol/vol) methylene chloride/methanol mixture.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](O)[CH:15]=1)[NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH3:2].[CH2:22]([O:29][CH2:30][CH2:31][N:32]([CH2:46][CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](B(O)O)=[CH:38]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:37]2[CH:36]=[CH:35][C:34]3[C:39](=[CH:40][CH:41]=[CH:42][C:33]=3[N:32]([CH2:46][CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:31][CH2:30][O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:38]=2)[CH:15]=1)[NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH3:2]
Reactant: OB(O)c1ccc2c(N(CCOCc3ccccc3)CCOCc3ccccc3)cccc2c1
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCOCc4ccccc4)CCOCc4ccccc4)cccc3c2)c1)NC(=O)C(F)(F)F

Procedure:
3-[5-Bis[2-(benzyloxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester was synthesized in a similar manner to Example 49 from N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester and 5-bis[2-(benzyloxy)ethyl]amino-2-naphthaleneboronic acid.