Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].Br[C:4]1[S:5][C:6]2[C:11]([NH:12][C@H:13]([CH3:16])[CH2:14][OH:15])=[N:10][C:9]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:8][C:7]=2[N:26]=1.Cl.[CH3:28]O>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:9]1[N:10]=[C:11]([NH:12][C@H:13]([CH3:16])[CH2:14][OH:15])[C:6]2[S:5][C:4]([O:1][CH3:28])=[N:26][C:7]=2[N:8]=1
Reactant: [OH-]
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(Br)sc12
Reactant: CO
Agent: Cl
Agent: [K+]
Product: COc1nc2nc(SCc3ccccc3F)nc(N[C@H](C)CO)c2s1
Reaction time: 24 h

Procedure:
Potassium hydroxide (27 mg) was added to a solution of the product of example 32 step d) (0.1 g) in MeOH (10 ml). The mixture was stirred for 24 h before neutralising to pH 7 with 2M HCl solution. The volatiles were removed in vacuo and the product used directly in the following step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=[CH:5]2.[CH3:15][NH2:16]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:16][CH3:15])=[O:14])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: CN
Product: CNC(=O)c1cccc2cc(O)ccc12

Procedure:
Prepared from 6-hydroxy-1-naphthoic acid and methylamine using the method of preparation 57 to give the title compound as a pale orange solid.
Reaction SMILES: C(C1NC2C(C=1)=[C:9]([O:12]C)[CH:8]=[CH:7]C=2)C.C([Li])(CC)C.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1[CH3:35])=[O:25])([CH3:22])([CH3:21])[CH3:20].CON(C)C(=O)CC>C1CCCCC1.C1COCC1>[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1[CH2:35][C:9](=[O:12])[CH2:8][CH3:7])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCc1cc2c(OC)cccc2[nH]1
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
2-Ethyl-4-methoxy-1H-indole. A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to -60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(4-fluorobenzyloxy)ethyl]piperidine (257 mg, 0.76 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (1.0 mL, 2.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(4-fluorobenzyloxy)ethyl]piperidine (150 mg, 83% yield) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][C@@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: C[C@@H](N)c1ccccc1
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccc3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 2.5 g, 7.5 mmol) and (R)-(+)-alpha-methylbenzylamine (2 eq, 1.82 g, Aldrich) in CH3CN (30 ml) was heated at 60° C. for 2 h. The mixture was extracted with DCM. The organic phase washed with saturated aqueous sodium hydrogen carbonate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue taken up in diethyl ether. The precipitate was filtered off and dried under vacuum to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-N-[(1R)-1-phenylethyl]-4-quinolinamine (2.5 g) which was used without purification in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:25])=[C:7]([C:16]([I:24])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:18]=1[I:19])[C:8]([N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH3:11])=[O:9])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O)([O-:28])=[O:27].O1CCCC1>CN(C)C=O>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:14][C:13](=[O:15])[CH2:12][N:10]([C:8](=[O:9])[C:7]1[C:6]([I:25])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:16]=1[I:24])[CH3:11])([O-:28])=[O:27]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N(C)CC(=O)O)c1I
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N(C)CC(=O)Oc2ccccc2[N+](=O)[O-])c1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.85 g (10 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-sarcosine and 1.7 g (12.2 mMol) o-nitrophenol are dissolved in 15 ml N,N-dimethylformamide. 60 ml tetrahydrofuran is added to this solution which is then cooled down to 0° C. 2,5 g (12 mMol) N,N-dicyclohexylcarbodiimide is added. The reaction runs for 2 hours at 0° C. and overnight at room temperature. The precipitate (N,N'-dicyclohexylurea) is filtered off, washed with 10 ml N,N-dimethylformamide, the tetrahydrofuran is distilled, the solution kept in the refrigerator overnight and then the dicyclohexylurea is again filtered off. The organic solution is added dropwise to 250 ml ether, the precipitate is decantered, dissolved with 25 ml N,N-dimethylformamide and added to water dropwise. The precipitate is filtered, washed with saturated sodium bicarbonate solution and water and dried. Yield: 5.4 g (67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]=[N+]=[N-])[CH:13]([OH:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([C:28](=[O:45])[CH2:29][CH:30]([CH2:34][S:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:36])[C:31](O)=[O:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:31](=[O:32])[CH:30]([CH2:34][S:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:36])[CH2:29][C:28]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:45])[C:13](=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: [N-]=[N+]=NC1CCCN(C(=O)OCc2ccccc2)CC1O
Product: O=C(NC1CCCN(C(=O)OCc2ccccc2)CC1=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1

Procedure:
The crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester was coupled to 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid and oxidized, as described above, to yield 4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic acid benzyl ester; 1H NMR: (DMSO) 8.46–8.42 (m, 1H), 7.44–7.24 (m, 10H), 5.18–5.04 (m, 2H), 4.52–4.33 (m, 4H), 4.04–3.76 (m, 2H), 3.58–3.30 (m, 11H), 3.11–3.03 (m, 1H), 2.96–2.78 (m, 1H), 2.72–2.57 (m, 1H), 1.84–1.55 (m, 4H); MS: (M+H)+ 600.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[CH3:11][C:12]1([CH3:24])[CH2:17][O:16][C:15]2([CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[O:14][CH2:13]1>>[CH3:11][C:12]1([CH3:24])[CH2:13][O:14][C:15]2([CH2:18][CH2:19][CH:20]([O:23][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=3[O:9][CH3:10])[CH2:21][CH2:22]2)[O:16][CH2:17]1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Reactant: COc1c(Cl)ccnc1C
Product: COc1c(OC2CCC3(CC2)OCC(C)(C)CO3)ccnc1C
Yield: 75 %

Procedure:
Preparation was carried out analogously to Example 43 from 4-chloro-3-methoxy-2-methylpyridine and 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol. Yield: 75%; M.p.: 90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[S:25][C:24]([C:26]#[N:27])=[CH:23][C:22]=1[CH3:28]>>[CH3:28][C:22]1[CH:23]=[C:24]([C:26]#[N:27])[S:25][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(c1cccs1)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo4-methylthiophene-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.26 (s, 1H), 7.83 (s, 1H), 7.56 (dd, J=4.9, 1.1 Hz, 1H), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 4.23 (d, J=15.9 Hz, 1H), 4.13 (d, J=15.9 Hz, 1H), 2.19 (s, 3H), 2.03 (s, 3H); MS (ES) m/z 381 (M+H)+; Anal. Calc. For C20H16N2O2S2: C, 63.14; H, 4.24; N, 7.36. Found: C, 62.85; H, 4.16; N, 7.09.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)#[N:2].[CH3:14][O:15]C(Cl)Cl>ClCl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH:7]=2)[CH:14]=[O:15])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C2(C#N)CC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClCl
Solvent: ClCCl
Product: COc1ccc(C2(C#N)CC2)cc1C=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To a stirred solution of Compound 1 (2.0 g, 11.6 mmol) in dry CH2 Cl2 (50 ml) was added TiCl4 (5.7 ml, 52.0 mmol) with cooling (-10° C.). After 15 min., to this was added a solution of dichloromethyl methyl ether (2.0 g, 17.3 mmol) in dry CH2Cl2 (5 ml) dropwise. The reaction mixture was stirred at same temperature for 10 min. and then at room temperature for 1 h. The mixture was poured into ice-water and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product (2.36 g) as a yellow solid. The crude product was recrystallized from hexane-ethyl acetate to give Compound 2 (2.04 g, 88%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[S:5])[CH3:4].FC(F)(F)S(O[C:15]1[C:20](C)=C[CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[C:16]=1C)(=O)=O.[CH3:28]N(C=O)C>>[CH3:20][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[C:4]([CH3:28])[C:3]=1[SH:5]
Reactant: CN(C)C=O
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(C)=S
Agent: [H-]
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(C)c1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred suspension of 570 mg (60% in oil) (14.2 mmol) of sodium hydride in 9 mL of DMF under atmospheric nitrogen at 0° C. was added dropwise 1.64 mL of ethyl thioacetate. After stirring at room temperature for 1 h, it was cooled to 0° C. A solution of 2 g (7.5 mmol) of 2,6-dimethyl-3-nitro-phenyl trifluoromethanesulfonate in 6 mL of DMF was introduced. After stirring at-0° C. for 20 min. it was partitioned between ethyl ether and 3N HCl. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The resulting residue was purified by chromatography using 5% ethyl acetate: hexanes to provide 1.2 g (60%) of 2,6-dimethyl-4-nitro-thiophenol. 1H NMR (CDCl3): 2.43 (s, 3H), 3.67 (s, 1H), 7.93 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:27]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Fc1ccc(C=Cc2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1
Reaction time: 3 h
Yield: 41 %

Procedure:
The compound of Example 2 (0.7 g, 1.8 mmol), 4-fluorostyrene (1 g, 2.6 mmol), palladium acetate (0.03 g, 0.013 mmol) and tri-o-tolyphosphine (0.03 g, 0.01 mmol) were heated to 100°-120° C. in dimethylformamide (20 mL). After 3 h, palladium acetate (0.03 g, 0.013 mmol) was added and heating was continued for 2 h. The cooled reaction mixture was extracted with diethylether (50 mL) and water (100 mL). The diethylether solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel using hexanes/ethyl acetate (6:1) as eluent. The product was isolated as a solid (0.28 g): m.p.: 154°-156° C. 1H NMR (CDCl3, 200 MHz) δ 7.5-7.0 (m,13H), 5.5 (m,1H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[C:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-:20].[Na+]>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:15]2[CH2:16][CH2:17][C:18](=[CH:10][C:9]3[CH:12]=[CH:13][C:6]([O:20][CH2:1][CH:2]4[O:4][CH2:3]4)=[CH:7][CH:8]=3)[C:14]2=[O:19])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1
Reactant: O=Cc1ccc(OCC2CO2)cc1
Reactant: [OH-]
Reactant: O=C1CCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C(=Cc2ccc(OCC3CO3)cc2)CCC1=Cc1ccc(OCC2CO2)cc1
Reaction time: 0.5 h

Procedure:
A solution of p-glycidyloxybenzaldehyde (40 g; prepared according to Method A) and cyclopentanone (9.4 g) in ethanol (40 g) was added over 1 hour to a stirred solution of sodium hydroxide (2.25 g) in a mixture of water (45 g) and ethanol (40 g), keeping the temperature at 25° to 30° C. On complete addition the mixture was stirred at 25° to 30° C. for a further 30 minutes, then water (100 g) was added and the mixture was stirred for 15 minutes. The precipitate was filtered off, washed with water and ice-cold ethanol, and dried at 60° C. in vacuo to give 1,3-bis(p-glycidyloxyphenylmethylidene)cyclopentan-2-one. The yield was 40 g (88% of theory) and the product had an epoxide content of 4.43 equivalents per kilogram, the theoretical value being 4.95 equivalents per kilogram. The N.M.R., I.R., and UV spectra of the product were consistent with the above structure.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.[Cl:40]CCl>>[ClH:40].[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(F)cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ccc(-c3ccc(F)cc3)cc2)cs1)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-[(4-{2-[(4′Fluorobiphenyl-4-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (300 mg) obtained in Example 256-3 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1). The obtained compound was dissolved in diethyl ether (4 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give the title compound (199 mg) as a white solid.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=2[O:2]1.CC(C)=O.[I-:16].[Na+]>CCOCC>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][I:16])=[CH:4][C:3]=2[O:2]1
Reactant: [I-]
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: ICc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
11.65 g 3,4-methylenedioxybenzyl chloride in 128 ml of abs. acetone are treated with 49.7 g of sodium iodide, and this mixture is stirred at RT for 2.5 h under argon and while excluding light. The reaction mixture is diluted with 1.5 l of ether, and this mixture is washed with 10% sodium thiosulfate solution (600 ml) and saline. The title compound is obtained after drying over sodium sulfate and removing the solvent. It is recrystallized from ether/hexane. m.p.: 51° C. TLC Rf (hexane:ethyl acetate, 4:1)=0.43. 1H-NMR (360 MHz, CDCl3): 6.93-6.77(m, 2H), 6.77-6.64(m,1H), 5.95(s, 2H), 4.44 (s,2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[C@H:34]([CH3:35])[CH2:33][N:32](C(OC(C)(C)C)=O)[C@@H:31]([CH3:43])[CH2:30]2)[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:30][C@@H:31]([CH3:43])[NH:32][CH2:33][C@@H:34]2[CH3:35])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@@H](C)NC[C@@H]3C)c2C1

Procedure:
To a solution of racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.227 g, 0.389 mmol) and DCM (3 mL) at rt was added TFA (1 mL). After 25 min an additional 0.5 mL aliquot of TFA was added. After 1 h more the reaction was concentrated under reduced pressure to give 2-(2,6-dimethylphenyl)-4-((trans)-2,5-dimethylpiperazin-1-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as a TFA salt. MS (ESI+) m/z 484.4 (M+H)+
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1
Reactant: [H][H]
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCCCc1ccc2c(c1)OCO2)N1CCCCC1
Yield: 78.5 %

Procedure:
Piperine (2 g, 7 mmol) was hydrogenated in ethanol (50 ml) over 5% Pd-C under a pressure of hydrogen at 10 psi for 30 mins to give tetrahydropiperine (1.59 g, 78% yield) as an oil2. Tetrahydropiperine (RV-C02)
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.Cl.N[C@@H:37]([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[C@@H:38]([OH:48])[CH:39]([OH:47])[CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][CH:40]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:39]([OH:47])[CH:38]([OH:48])[CH2:37][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Reactant: CCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: -15 °C

Procedure:
25.6 mg of L-N-[(2S or R)-2-ethylsulfonylmethyl-4-methylpentanoyl]norleucine was dissolved in 0.5 ml of dry DMF, and a dry DMF solution of 30.8 mg of triethylamine, 25.2 mg of DPPA and 38.5 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was added thereto at -15° C. under stirring. The mixture was stirred at the same temperature for one hour and at room temperature overnight. The reaction solution was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain 21.7 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-2-ethylsulfonylmethyl-4-methylpentanoyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH3:3].[CH2:6]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[C:25]3[C:20](=[C:21]([F:27])[C:22]([Cl:26])=[CH:23][CH:24]=3)[N:19]([C:28](=[NH:31])[NH:29][OH:30])[C:18]=2[CH3:32])[CH:11]=1)[CH3:7]>N1C=CC=CC=1>[CH2:6]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[C:25]3[C:20](=[C:21]([F:27])[C:22]([Cl:26])=[CH:23][CH:24]=3)[N:19]([C:28]3[N:31]=[C:1]([CH2:2][CH3:3])[O:30][N:29]=3)[C:18]=2[CH3:32])[CH:11]=1)[CH3:7]
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(C(=N)NO)c3c(F)c(Cl)ccc23)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3noc(CC)n3)c3c(F)c(Cl)ccc23)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Propionyl chloride (0.042 mL, 0.48 mmol) was added to a solution of 3-[6-Chloro-7-fluoro-1-(N-hydroxycarbamimidoyl)-2-methyl-1H-indol-3-ylsulfanyl]-benzoic acid ethyl ester (0.12 g, 0.24 mmol) in pyridine (2 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for overnight, then cooled to room temeperature and subjected to standard aqueous workup. The crude residue was purified on silica gel (0-60% EtOAc in hexanes) to afford the title compound.