Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.[Ti+4]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:10](=[O:11])[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: OCCc1ccc(Br)cc1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(NC(=O)OCCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Titanium tetra-tert-butoxide (0.080 mL, 0.21 mmol) was added dropwise to a solution of 3-cyanophenylisocyanate (228 mg, 1.58 mmol) and 2-(4-bromophenyl)ethanol (606 mg, 3.01 mmol) in toluene (10 mL). A precipitate formed immediately and the reaction was stirred for 2 h at rt. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The residual solid was triturated with DCM hexane to give 11A (543 mg, 100%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.95 (t, J=6.81 Hz, 2 H), 4.38 (t, J=6.81 Hz, 2 H), 6.68 (s, 1 H), 7.11 (d, J=8.35 Hz, 2 H), 7.31-7.35 (m, 1 H), 7.38 (t, J=7.91 Hz, 1 H), 7.44 (d, J=8.35 Hz, 2 H), 7.52 (d, J=7.03 Hz, 1 H), 7.76 (s, 1 H).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH3:21]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH4+:21]
Reactant: N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: [NH4+]

Procedure:
While stirring 60 parts of oleic acid at room temperature, a mixture comprising 74.5 parts of 10% aqueous ammonia and 200 parts of water, was dropwise added to obtain an aqueous solution of ammonium oleate having a solid content of 20.2%.
Reaction SMILES: CI.[CH:3]([C:5]1[CH:13]=C(C(O)=O)[C:8]([OH:14])=[CH:7][CH:6]=1)=[O:4].[C:15](=O)([O-])[O-].[Cs+].[Cs+].[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22]>CN(C)C=O>[CH3:15][O:14][C:8]1[CH:7]=[CH:6][C:5]([CH:3]=[O:4])=[CH:13][C:22]=1[C:21]([O:24][CH3:25])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C=O)ccc1OC
Reaction time: 8 h

Procedure:
Methyl iodide (3.6 mL, 0.042 mol, 3.5 eq) was added dropwise to a stirred solution of 5-formylsalicylic acid (2.78 g, 0.017 mol, 1 eq) and cesium carbonate (16.36 g, 0.050 mol, 3 eq) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred overnight, then diluted with ethyl acetate (100 mL) and the organic solution washed with water (100 mL), and brine (4×100 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to a cream coloured powder (2.8 g, 86%). 1H NMR (CDCl3) δ9.92 (s, 1H, O═C—H), 4.01 (s, 3H, CH3), 3.93 (s, 3H, CH3).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([CH3:38])([CH3:37])[CH2:9][C@@:10]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.N1C=CC=CC=1.N>CN(C)C=O>[CH3:1][N:2]([CH3:6])[C:3]([N:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]3[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:37])[CH3:38])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:15][C:14]3=[O:16])[CH3:18])=[CH:24][CH:23]=2)[CH2:26][CH2:27]1)=[O:4]
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@@H](c1ccc(C2CCN(C(=O)N(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylcarbamoyl chloride (26 μL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (120 mg) and pyridine (40 μL) in N,N-dimethylformamide (2 mL) at room temperature. The solution was stirred at room temperature for 5 h, before another portion of dimethylcarbamoyl chloride (26 μL) and pyridine (20 μL) were added. The solution was stirred at room temperature overnight. Then, diluted aqueous ammonia solution was added and the resulting mixture was concentrated under reduced pressure. The residue was purified by HPLC on reversed phase (MeOH/H2O/NH3) to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCOCC1CO1
Product: CCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.7 %

Procedure:
Using the method of Example 5, supra, 1-octyl glycidyl ether (187 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 105 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 366 (M+1, 0.08), 350 (0.08), 244 (100), 222 (5.8), 163 (12), 121 (18): 1H-NMR (CDCl3) δ 7.08 (2H, d, J=8.6), 6.82 (2H, d, J=8.6), 3.79 (1H, m), 3.77 (3H, s), 3.45 (4H, m), 2.92 (1H, broad s), 2.79 (1H, dd, J=11.6 and 4.1), 2.65 (2H, m), 2.55 (2H, m), 1.27 (8H, m), 1.06 (3H, s), 1.04 (3H, s), 0.88 (3H, t, J=6.7); 13C-NMR (CDCl3) δ 158.0, 131.2, 129.9, 113.2, 73.4, 71.6, 68.9, 55.0, 53.3, 46.2, 44.6, 31.7, 29.5, 29.3, 29.1, 26.5, 26.4, 26.0, 22.5, 14.0; FT-IR (film) cm−1 3409 (broad), 1611, 1512, 1245, 1120.
Reaction SMILES: CN.[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[C:24]([BH3-])#[N:25].[Na+].C(O)(=O)C>C1COCC1>[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([CH:9]([NH:25][CH3:24])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
2.0 M methylamine solution in THF (18 mL, 36.0 mmol) was added to a solution of 1-(4-biphenylyl)-2-(4-morpholinyl)ethanone (2.52 g, 8.93 mmol ) in anhydrous THF (20 mL), The reaction mixture was stirred at room temperature for 1 h and then sodium cyanoborohydride (1.68 g, 26.79 mmol) and acetic acid (1 mL) were added. The resulting mixture was stirred at room temperature for 72 h until the starting material was consumed completely. At this point, saturated K2CO3 solution (40 mL) was added to and after stirring for 15 min, the solution was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over Na2SO4 and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield [1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine as an off-white solid(1.40 g, 53%), MS (ES) m/e 296[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:24][NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)NN)ncn2-c2cccc(Cl)c2C1=O
Yield: 108.5 %

Procedure:
50 g (156.4 mmol) of ethyl 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate were stirred at boiling temperature for 6 hours with 90 ml (1.85 mol) of hydrazine hydrate in 500 ml of ethanol. By cooling to -10°, filtering the suspension under suction and drying the crystallizate there were obtained 51.9 g (100%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide of m.p. 287°.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12]/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH2:18][CH2:19][CH3:20])=[CH:6]2)#[N:2].[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=O)#[N:26].C(N(CC)C(C)C)(C)C>C(#N)C>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:21]([F:24])([F:23])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:33]=[CH:34][CH:35]=1)#[N:26]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C#N)c2)n1
Temperature: 150 °C
Yield: 58.9 %

Procedure:
To a solution of (1Z)-2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-cyanobenzoyl chloride (0.204 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.079 g (59% yield) of pure product: MS (ES) m/z 435 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:14](#[N:16])[CH3:15]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:15][C:14]#[N:16])[CH:11]=[CH:12][CH:13]=1
Reactant: COCCOc1cccc(C=O)c1
Reactant: CC#N
Product: COCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(2-methoxy-ethoxy)benzaldehyde gave 3-(3-(2-methoxy-ethoxy)-phenyl)-3-hydroxypropionitrile as yellow oil. Yield (1.4 g, 63%): 1H NMR (400 MHz, CDCl3) δ 7.27-7.32 (m, 1H), 6.95-7.0 (m, 2H), 6.91 (dd, J=8.0, 1.8 Hz, 1H), 5.0 (t, J=6.2 Hz, 1H), 4.12 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.48 (s, 3H), 2.75 (d, J=6.2 Hz, 2H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:40][C@:41]2(C)[CH2:43][O:42]2)(=O)=O)C=CC=1)([O-])=O.CN(C=O)C>O>[C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:40][C@@H:41]2[CH2:43][O:42]2)[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1O)c1ccccc1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1OC[C@@H]1CO1)c1ccccc1
Yield: 98.6 %

Procedure:
To a stirred solution of 4-(benzoylamino)-2-chloro-5-hydroxyphenyl benzoate (103 mg, 0.28 mmol) and [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (73 mg, 0.28 mmol) in DMF (3 mL) cesium carbonate (98 mg, 0.3 mmol) was added. The stirring was continued at ambient temperature over night. The mixture was poured into water and partitioned between water and ethylacetate. The organic phase was washed with water, dried and concentrated in vacuo to give a white solid (117 mg, 98%). The solid was used without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[N:26]1([CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:48]([OH:50])=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C)C=O>[N:51]1([C:48]([C:42]2([C:39]3[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][CH2:32][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:37][CH:38]=3)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:50])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCOCC1)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.5 mmol) was added to a solution of 4-[4-(3-Morpholin-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid hydrochloride (160 mg, 0.4 mmol), morpholine (54 μL, 0.6 mmol) and Hunig's base (180 μL, 1 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between 2M NaOH solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (182 mg, 100%) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 1.93-2.04 (m, 4H), 2.20 (m, 2H), 2.42-2.55 (m, 6H), 3.22-3.43 (br m, 8H), 3.72 (t, 4H), 3.79 (m, 2H), 3.90 (m, 2H), 4.00 (t, 2H), 6.88 (d, 2H), 7.17 (d, 2H). LRMS APCI+ m/z 419 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:21][C:22]([F:25])([F:24])[F:23].[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]3[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=3)=[CH:4][C:3]=2[O:21][C:22]([F:25])([F:24])[F:23])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CCc1cccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2OC(F)(F)F)c1

Procedure:
Compound 37 was synthesized using the procedure above for preparing 13.3 using compound 37.3 and 3-methoxyphenylboronic acid 37.4 (available from Aldrich). MS ESI (neg.) m/e: 445 (M−H). 1H NMR (400 MHz, CD3CN) δ ppm 7.51 (3H, s), 7.38 (1H, s), 7.22 (1H, s), 7.05 (2H, s), 6.98 (1H, s), 6.87 (3H, s), 5.15 (2H, s), 3.81 (3H, s), 2.86 (2H, s), 2.59 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(N)=O)ccc2c1=O
Yield: 69.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.17 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.96 g, 5 mol) and 1-hydroxybenzotriazole ammonium salt (0.76 g, 5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.81 g, 69.8%) as crystals.
Reaction SMILES: [OH2:1].O1C=CC2C([O:11][CH2:12][C@@H:13]([OH:31])CN3CCC(C4SC5C=CC=CC=5C=4C)CC3)=CC=CC1=2.[O:32]1[CH:36]=[CH:35][C:34]2[C:37]([O:41][CH2:42][C@@H:43]([OH:61])[CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[S:55][C:54]5[CH:56]=[CH:57][CH:58]=[CH:59][C:53]=5[C:52]=4[CH3:60])[CH2:47][CH2:46]3)=[CH:38][CH:39]=[CH:40][C:33]1=2.O1C[C@H]1COC1C2CCOC=2C=CC=1>CO>[C:13]([OH:31])(=[O:32])[C:12]([OH:11])=[O:1].[O:32]1[CH2:36][CH2:35][C:34]2[C:37]([O:41][CH2:42][C@@H:43]([OH:61])[CH2:44][N:45]3[CH2:46][CH2:47][CH:48]([C:51]4[S:55][C:54]5[CH:56]=[CH:57][CH:58]=[CH:59][C:53]=5[C:52]=4[CH3:60])[CH2:49][CH2:50]3)=[CH:38][CH:39]=[CH:40][C:33]1=2
Reactant: Cc1c(C2CCN(C[C@H](O)COc3cccc4occc34)CC2)sc2ccccc12
Reactant: O
Agent: c1cc2c(c(OC[C@@H]3CO3)c1)CCO2
Solvent: CO
Product: Cc1c(C2CCN(C[C@H](O)COc3cccc4c3CCO4)CC2)sc2ccccc12
Product: O=C(O)C(=O)O
Yield: 86.1 %

Procedure:
A solution 4-hydroxy-4-(3-methylbenzo[b]thiophen-2-yl)piperidine (0.070 g, 0.303 mmol, prepared in example 11) and (S)-(+)-4-(oxiranylmethoxy)-2,3-dihydrobenzo[b]furan (0.058 g, 0.303 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/1% methanol in dichloromethane) to give the free base of the title compound as a clear colorless oil (0.067 g, 52%). The oxalate salt was prepared to give the title compound. FDMS, m/e=424 (M++1 of free base). [α]D=−9.09 (c=0.44, methanol). C25H29NO3S.C2H2O4
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13]CC)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:20][CH2:19][CH2:18][NH2:21])=[O:13])=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: NCCN
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Product: CC(=O)Nc1ccc(OCC(=O)NCCN)cc1

Procedure:
In a similar manner using 23.7 g. of ethyl 4-acetamidophenoxyacetate and 60 ml. of ethylenediamine as starting materials there is obtained β-(4-acetamidophenoxyacetamido)ethylamine, m.p. 210°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:27]=[C:28]([N:30]5[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]5)[CH:29]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Reactant: NC1CCCC1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(NC5CCCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.2 mmol) and cyclopentylamine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A yellow solid (13 mg); Mp: 88-90° C.; 1H NMR (300 MHz, CDCl3) δ 0.98(d, J=6.6 Hz, 3H), 1.23-1.87(m, 13H), 2.77-2.85(m, 2H), 3.76(d, J=12.3 Hz, 2H), 4.08-4.15(m, 1H), 5.15(bs, 1H), 6.04(s, 1H), 6.76(d, J=12.3 Hz, 1H), 6.98(d, J=8.4 Hz, 1H), 7.26-7.30(m, 2H), 7.49-7.55(m, 2H), 7.87-7.97(m, 3H), 8.07-8.11(m, 1H), 8.20(s, 1H);
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=2)[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=2)[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:3]1[CH2:1][CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: CCC(=O)c1c(CC)[nH]c2cc(C(=O)OC)ccc12
Product: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C(=O)OC)ccc12

Procedure:
Methyl 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carboxylate (278 mg) was prepared from methyl 2-ethyl-3-propionylindole-6-carboxylate (215 mg) and 2-chlorobenzyl bromide (0.24 ml) in a similar manner to that of Example 1.
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:16]=[CH:17][C:18]3[C@H:23]([CH2:24][CH2:25][OH:26])[O:22][CH2:21][CH2:20][C:19]=3[CH:27]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O>>[CH3:28][S:29]([O:26][CH2:25][CH2:24][C@H:23]1[C:18]2[CH:17]=[CH:16][C:15]([N:14]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:27][C:19]=2[CH2:20][CH2:21][O:22]1)(=[O:31])=[O:30]
Reactant: OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21

Procedure:
2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethanol was reacted with methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, to yield 2-{(1S)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].O.CC(=O)OCC.C[N:36](C=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:36])[CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc(Cc2cccc(F)c2C)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccccc2)c(Cc2cccc(F)c2C)cn1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound of step 4 (6.748 g, 20.00 mmol) in 60 ml of anhydrous DMF under a nitrogen atmosphere at 0° C. was added sodium hydride (60% in mineral oil, 0.960 g, 24 mmol) in small portions. After stirring for 10 min at 0° C., the mixture was allowed to warm to room temperature over 15 min. After cooling to 0° C. again, 0-(2,4-dinitro-phenyl)-hydroxylamine (cf. C. Legault et al., J. Org. Chem. 68 (2003), 7119; P. H. Boyle et al., ARKIVOC (2003) (vii), 67; 4.779 g, 24.00 mmol) was added in small portions and the mixture was stirred at room temperature for 1 h. Water (250 ml) and EA (250 ml) were added and the organic phase was washed twice with 125 ml each of a 1 N sodium hydroxide solution and 125 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel, first eluting with cyclohexane/DCM (40:60, then 20:80, then 0:100), then with DCM/EA (97.5:2.5, then 95:5) to give 6.33 g of the title compound as a beige solid melting at 87-88° C.