Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[N:10]([CH:12]([C:14](=[O:38])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:32](=[O:37])[NH:33][CH:34]([CH3:36])[CH3:35])[CH2:29][CH:30]([OH:31])[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[NH4+].[OH-]>C(#N)C.CO>[CH2:1]([O:8][C:9](=[O:39])[N:10]([CH:12]([C:14](=[O:38])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:32](=[O:37])[NH:33][CH:34]([CH3:35])[CH3:36])[CH2:29][CH:30]([O:31][C:48](=[O:49])[NH:47][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:24]12)=[O:22])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Reactant: O=C=NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CC(C)NC(=O)N1CC(OC(=O)NCc2ccccc2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
A solution containing 57 (280 mg, 0.51 mmol) and benzyl isocyanate (350 μL, 2.83 mmol) in acetonitrile (500 μL) was warmed to reflux. After 12 h, the reaction mixture was cooled to ambient temperature, diluted with MeOH, and treated with aqueous NH4OH (30%, 5 mL). The solution was concentrated in vacuo and the residue was dissolved in EtOAc, washed successively with 1N HCl, water, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 50-100% MeOH/water containing 0.1% HOAc over 20 min; Flow: 40 mL/min). The pure fractions were combined and concentrated to afford 58 as a white solid (250 mg, 72%). Mass spectrum, m/z [679.3] (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[N:11]2[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1-phenethyl-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (668 mg, 7.5 mmol) and NaOMe solution (12 mL, 6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 27 mg of the title compound as a yellow solid. MS: (+) m/z 458.30 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(CBr)c1Cl
Reaction time: 8 h
Yield: 47.2 %

Procedure:
2-chloro-1-methyl-3-nitrobenzene (1 g, 5.8 mmol) was dissolved in CCl4 (10 mL), then N-bromosuccinimide (2.28 g, 12.8 mmol) and benzoyl peroxide (846 mg, 3.5 mmol) were added. The mixture was stirred overnight at reflux. The solid was removed by filtration, and the filtrate was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified on silica gel using 30% hexane/AcOEt to afford 1-(bromomethyl)-2-chloro-3-nitrobenzene (686 mg, 47% yield); 1H NMR (400 MHz, CDCl3): δ 4.64 (s, 2H), 7.42 (t, J=7.9 Hz, 1H), 7.67 (dd, J=1.6 Hz, J=7.9 Hz, 1H), 7.75 (dd, J=1.6 Hz, J=7.9 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[F:26][C:27]([F:37])([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:32]3([OH:35])[CH2:33][CH2:34][N:29]([CH2:28][C:27]([F:26])([F:36])[F:37])[CH2:30][CH2:31]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=C1CCN(CC(F)(F)F)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CCN(CC(F)(F)F)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].Cl[Sn](Cl)(Cl)Cl.[I:20]I>ClCCl>[I:20][CH2:3][CH:2]1[CH2:1][C:4]2[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=2[O:14]1
Reactant: II
Reactant: C=CCc1cc(C(F)(F)F)ccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(c1)CC(CI)O2
Yield: 43.1 %

Procedure:
To a solution of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol (4 g, 20 mmol) in dichloromethane (50 ml) was added SnCl4 (2.6 g, 10.0 mmol, 0.5 eq) dropwise and iodine (5.03 g, 19.8 mmol, 1 eq) with stirring for 6 h at room temperature. The reaction mixture was diluted with dichloromethane (200 ml) and quenched by the addition of water (100 ml). The organic layer was separated and the pH value of the aqueous layer was adjusted to ˜8 with aqueous sodium bicarbonate. The aqueous layer was extracted further with dichloromethane (3×100 ml). The organic layers were combined, washed with aqueous Na2S2O4 (5%, 100 ml) to remove remaining iodine, dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran as colorless oil (2.8 g, 43%); 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J=5.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 4.91-5.00 (m, 1H), 3.34-3.48 (m, 3H), 3.05-3.12 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.[C:27](O)(=[O:31])[C@H:28]([CH3:30])[OH:29]>>[OH:29][C@@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:31]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)[C@H](C)O)C3)ccc1-2

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene free base 235 and L-(+)-lactic acid were reacted to give 323 isolated as an off-white solid after freeze-drying (42 mg, 29%). LCMS: RT=10.71 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.40-8.33 (1 H, m), 7.90 (1 H, s), 7.10 (1 H, t, J=6.16 Hz), 6.99 (1 H, d, J=8.83 Hz), 5.91-5.83 (1 H, m), 4.62-4.36 (5 H, m), 4.21 (3 H, m), 4.18-4.08 (1 H, m), 3.93-3.84 (1 H, m), 3.40 (2 H, t, J=5.01 Hz), 1.61 (6 H, d, J=6.62 Hz), 1.34 (3 H, d, J=6.57 Hz)
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:16]I>>[CH3:16][N:3]1[CH2:4][CH2:5][CH2:6][C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Product: CN1CCC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-methyl-2-oxopiperidin-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (Example 7) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 100% ethyl acetate, to provide compound (2c) in 31% yield.
Reaction SMILES: C(OC([CH:6]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=[O:27])=O)C.CC(O)=O.Cl.[OH-].[Na+]>O>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([N:10]2[CH2:11][CH2:12][CH2:6][C:7](=[O:27])[C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]2=3)(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
To the mixture of 5-Oxo-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester thus obtained, were added AcOH (2.4 l), conc.HCl (800 ml) and H2O (240 ml). The mixture was heated at reflux for 5 h and poured into ice water. The pH was adjusted to about 7-8 by adding diluted aqueous NaOH. The mixture was extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, concentrated, and the residue was crystallized from the mixture (4:1 n-hexane:AcOEt) to give 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (278 g, 60%) as a white powder.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[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.C([O-])([O-])=O.[Cs+].[Cs+].[C:27]1([C:33]2[O:37][N:36]=[C:35]([C:38]3[O:42][N:41]=[C:40]4[C:43]5[C:48]([CH2:49][CH2:50][C:39]=34)=[CH:47][C:46]([CH:51]=[CH2:52])=[CH:45][CH:44]=5)[C:34]=2[C:53]([F:56])([F:55])[F:54])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[C:1]1([C:7](=[N:14][CH:15]([CH2:52][CH2:51][C:46]2[CH:47]=[C:48]3[C:43](=[CH:44][CH:45]=2)[C:40]2=[N:41][O:42][C:38]([C:35]4[C:34]([C:53]([F:55])([F:56])[F:54])=[C:33]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[O:37][N:36]=4)=[C:39]2[CH2:50][CH2:49]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of ethyl 2-(diphenylmethyleneamino)acetate (236 mg, 0.882 mmol), Cs2CO3 (144 mg, 0.441 mmol), 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 100 mg, 0.245 mmol), and anhydrous DMSO (0.6 mL) was purged with nitrogen for 5 min. and then sealed in a 1 dram vial. The mixture was stirred at 50° C. for 2 h. The mixture was cooled, diluted with water (15 mL) and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (12 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (140 mg, 0.207 mmol, 85% yield) as a sticky liquid. The compound had an LC/MS M+1=676.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1cc2cc(Br)ccc2o1
Reactant: CCCC[B-](F)(F)F
Agent: [K+]
Product: CCCCc1ccc2oc(C=O)cc2c1
Yield: 89.5 %

Procedure:
The compound was synthesized as in Example 3.1, using 5-bromo-2-formylbenzofuran (500 mg, 2.22 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (546 mg, 3.33 mmol) in place of hexylboronic acid to give 5-butyl-2-formylbenzofuran (402 mg, 90%). Used without further characterization.
Reaction SMILES: Cl.C([O:4][C:5](=[O:17])[CH2:6][NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C.C([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])(OCC1C=CC=CC=1)=O>>[NH2:28][C@H:29]([C:31]([N:7]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][C:5]([OH:4])=[O:17])=[O:32])[CH3:30]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNC1CCc2ccccc21
Agent: Cl
Product: C[C@H](N)C(=O)N(CC(=O)O)C1CCc2ccccc21
Yield: 60 %

Procedure:
By reacting 13 g of (indan-1-yl)glycine ethyl ester hydrochloride with 11.6 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 8.0 g of L-alanyl-N-(indan-1-yl)glycine as colorless amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Yield: 96.8 %

Procedure:
100.00 g (0.50 mol) of 5-chloro-2-nitrobenzoic acid were mixed with 72.20 g (0.61 mol) of thionyl chloride and the mixture was heated under reflux for 2 h. The excess thionyl chloride was removed in vacuo. 106.50 g (ca. 98%) of crude 5-chloro-2-nitro-benzoyl chloride were obtained as an oil.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=CC=[CH:45][CH:44]=1>C(O)CCC>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:48]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH2:43][CH2:44][CH3:45]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.0 gram of p-toluenesulfonic acid monohydrate in 10 ml of n-butyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 3 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 50 ml of ethyl ether and 50 ml of petroleum ether were added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine n-butyl ester di(p-toluenesulfonate) in 95% yield: mp. 160°-164° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2.[OH:24]O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSCc3ccco3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)Cc3ccco3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-furylmethyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH2:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1ccc(N)cn1
Product: CCOC(=O)C(=CNc1ccc(CC)nc1)C(=O)OCC

Procedure:
A mixture of 5-amino-2-ethylpyridine (17.6 g) and diethyl ethoxymethylenemalonate (23.25 g) was heated on a steam bath for 2.5 hours. The mixture was cooled in ice. The solid formed was ground up in petroleum ether, b.p. 60°-80° C. and then filtered to give diethyl 2-(6-ethyl-3-pyridylaminomethylene)malonate, m.p. 55°-57° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([C:23]4O[C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[OH:31][CH2:30][CH2:32][NH:33][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([C:23]4[N:33]([CH2:32][CH2:30][OH:31])[C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1ccc(-c2nnc(C)n2CCO)cc1OCc1csc2c(C(=O)NCCO)cncc12
Temperature: 160 °C

Procedure:
A mixture of 3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester and 3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid methyl ester (0.08 g, 0.20 mmol) (from Example 36 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The reaction mixture was purified by C18 column chromatography eluting with acetonitrile/water to give 3-{5-[4-(2-hydroxy-ethyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield: 37.0 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1>Cl.[Pt](=O)=O>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Agent: O=[Pt]=O
Agent: Cl
Product: CCOC(=O)c1cc(O)c2c(n1)CCCC2
Reaction time: 72 h

Procedure:
To a solution of ethyl 4-hydroxy-2-quinolinecarboxylate (2.18 g, 10.0 mmol) in 80 mL of concentrated hydrochloric acid was added platinum (IV) oxide. The mixture was subjected to hydrogenation in a Parr shaker apparatus under 50 lbs of H2 for 72 h. The reaction was filtered and concentrated in vacuo to provide ethyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate that gave a mass ion (ES+) of 222.0 for [M+H]+.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.O>CS(C)=O>[OH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of ethyl 4-fluorobenzoate (16.5 g, 98.1 mmol) and piperidin-4-ol (10.0 g, 98.8 mmol) in DMSO (20 mL) was heated at 120° C. under nitrogen for 48 hours. The mixture was cooled to room temperature, poured into water (400 mL), and the solids were filtered off, washed with water, followed by hexane, to afford ethyl 4-(4-hydroxypiperidin-1-yl)benzoate (20.0 g, 82%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:41]=[CH:40][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:41][CH:40]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1
Reactant: O=C(O)Cn1cncn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 108, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.38 (d, 2H), 7.03-6.85 (m, 6H), 6.73-6.64 (m, 2H), 5.08 (d, 1H), 5.02 (d, 1H), 4.76 (d, 1H), 3.78-3.72 (m, 1H), 3.31 (t, 1H), 3.00-2.68 (m, 3H), 2.56 (dd, 1H), 1.82-1.72 (m, 1H). MS (EI) for C28H23F4N5O3 found 554 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1F
Reactant: OC1CCN(Cc2ccccc2)CC1
Product: Cc1ccccc1OC1CCN(Cc2ccccc2)CC1

Procedure:
By following the manipulative procedure described in Example 1(a), 21.0 g of 1-benzyl-4-piperidinol and 24.0 g of o-fluorotoluene produces a yellow oil fraction which boils at 161°-163° C., 0.09 mm. This oil solidifies slowly upon standing and is recrystallized from petroleum ether (b.p. 30°-60°) to give white crystals of 1-benzyl-4-(o-tolyloxy) piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(Cl)(Cl)Cl.Cl.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
3 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one and 6.4 g of barium hydroxide octahydrate were added with vigorous stirring to 60 ml of chloroform and 10 ml of water. A solution of 3.2 g of 2-(dimethylamino)-ethyl chloride-hydrochloride in 5 ml of water was added dropwise to the above mixture in the course of 5 minutes. Stirring was continued for 24 hours at room temperature and then for 8 hours at 40°. After cooling to room temperature the aqueous phase was separated and discarded and the chloroform was removed under vacuum. Petroleum-ether (40°-60°) was added to the viscous residue which induced crystallisation. The precipitated crystals were filtered off and dried under vacuum to yield 3.63 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-5-(2'-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one; m.p. 88°; [α]D22 +169 (C=0.25 CH 3 OH).