Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16]CO)=[CH:9][CH:8]=1)[CH3:6])=[O:4].[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]CCC#C)(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH2:16][CH2:15][C:14]#[C:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]([CH3:6])[C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: C#CCCOCCCCCCOC(C)=O
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1
Product: CC(=O)OCCCCCCOCCC#Cc1ccc(N(C)C(=O)C(F)(F)F)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 36, using Intermediate 26 in place of Intermediate 33. ES/MS calcd. for C21H27F3NO4+ 414.2. Found m/z=414.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br>CC(N(C)C)=O.O>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH:11]2[CH2:12][CH2:13]2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cc(O)c(Br)c(=O)n1CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-bromo-1-(cyclopropylmethyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.276 g, 1.07 mmol) and K2CO3 (0.148 g, 1.07 mmol) in DMA (4 mL) was added 2,4-difluorobenzyl bromide (0.14 ml, 1.07 mmol). The mixture stirred at room temperature for 1.5 hours. The reaction mixture was diluted in water and extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were combined, and concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (q, 1H), 7.04 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.06 (s, 1H), 4.04 (s, 1H), 2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H); ES-HRMS m/z 384.0392 (M+H calculated for C17H17N2OBrF2 requires 384.0405).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:11](Cl)(=[O:13])[CH3:12]>C(Cl)Cl>[C:2]1([CH2:1][NH:8][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzylamine (98.1 g) in methylene chloride (100 ml) was added an aqueous solution (200 ml) of sodium hydroxide (44 g). While further stirring the mixture, acetyl chloride (78 ml) was added at 15-20° C. over 1 hr. This reaction mixture was stirred at room temperature for 30 min and extracted with chloroform (100 ml×2). The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a white solid (160 g). The obtained solid was crystallized from hexane: ethyl acetate (2:1, 750 ml) to give the title compound (125.7 g) as white crystals, m.p.=61-62° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: O=C(CCl)CCl
Product: Fc1ccc(-c2nc(CCl)cs2)cc1
Yield: 89 %

Procedure:
This compound was synthesized from 4-fluorothiobenzamide and 1,3-dichloroacetone as described in example 39 step 1 (0.65 g, yield 89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.30 (s, 1H), 7.16-7.12 (t, J=8.7 Hz, 2H), 4.75 (s, 2H). MS (ESI) m/z: Calculated for C10H7ClFNS: 227.00. found: 228.0 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)#[N:36]>C(Cl)Cl>[C:35]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:21]2[CH2:22][C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:27][CH:26]=4)=[O:13])[CH:15]=3)[C@@H:20]2[CH:23]([CH3:24])[CH3:25])(=[O:45])=[O:44])=[CH:41][CH:42]=1)#[N:36]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(S(=O)(=O)c2ccc(C#N)cc2)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.8 %

Procedure:
To a solution of (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (6.9 mg, 17.8 μmol) in CH2Cl2 (600 μL) was added triethylamine (5.0 μL, 36.6 μmol) and 4-cyanobenzenesulfonyl chloride (5.4 mg, 26.8 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to yield 4.9 mg of (S)-6-((4-cyanophenyl)sulfonyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide as an HCl salt (13, 46%). LC-MS tR=0.84 min in 1 min chromatography, MS (ESI) m/z 553.5 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.85 (d, J=2.0 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 8.03 (dd, J=2.0 Hz, 8.8 Hz, 2H), 7.86 (m, 4H), 7.60 (d, J=8.4 Hz, 2H), 4.93 (m, 2H), 4.73 (dt, J=1.2 Hz, 16.4 Hz, 1H), 4.66 (s, 2H), 3.19 (q, J=7.6 Hz, 2H), 2.41-2.32 (m, 1H), 1.20 (t, J=7.6 Hz, 3H), 1.00 (d, J=7.2 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:15][CH:9]1[CH2:10][C:11](=[O:24])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH:13]2[CH:14]([O:16][Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19])[CH2:15][CH:9]1[CH2:10][CH:11]([OH:24])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CC(=O)CC1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC2CC(O)CC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of compound 86a (6.9 g, 20 mmol, 1.0 eq) in MeOH (100 mL) was added NaBH4 (1.5 g, 40 mmol, 2.0 eq) slowly at room temperature, then the mixture was stirred at room temperature for 1 h. The mixture was quenched with water (100 mL), extracted with EA (100 mL) two times. The organic layer was combined, dried over Na2SO4 and concentrated to give 8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ol 116b as a colorless oil, 6.24 g, yield: 90%. MS: calc'd (MH+) 348, measured (MH+) 348.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OCc1ccccn1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nnc3cc(C45CCC(CC4)C5)c(OCc4ccccn4)nn23)cc1
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.08 g, 0.25 mM, Example 1, step b) and 2-pyridylcarbinol (0.06 ml, 0.5 mM) in N,N-dimethylformamide (2 ml) under nitrogen was added lithium bis(trimethylsilyl)amide as a 1 mol solution in hexanes (0.375 ml). The reaction was stirred for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-hexane to give the required product (0.050 g, m.p.=166-168° C.). 1H NMR (360 MHz, DMSO) δ1.55 (2H, m), 1.91 (4H, m), 1.97 (2H, m), 2.13 (2H, m), 2.49 (1H, m), 5.77 (2H, s), 7.54 (1H, m), 7.69 (4H, s), 8.00 (1H, t, J=7.6 Hz), 8.28 (1H, s), 8.34 (2H, dd, J=7.6 and 1.5 Hz), 8.80 (1H, m); MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.16; H, 5.59; N, 17.41. C24H23N5O. 0.1H2O requires C, 72.20; H, 5.86; N, 17.54%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1.[CH2:16]([OH:19])[CH2:17][OH:18]>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:18][CH2:17][CH2:16][OH:19])=[O:14])=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: COC(=O)COc1ccc(N=C=O)cc1
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)OCCO)cc1
Temperature: 42 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
(4-Isocyanato-phenoxy)-acetic acid methyl ester 28 (15 g, 72.46 mmol) was added to ethylene glycol (30 ml) at room temperature. The reaction was exothermic and the temperature raised to 42° C. Later the reaction mixture was stirred at room temperature for 16 hours. Water (100 ml) was added and crude 29 was filtered, dried and purified by column chromatography on silica gel using chloroform as eluant to get pure 29 (16.17 g, 82.9%) as a off-white powder. M.p: 85.5-87.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH:7]([C:25]#[N:26])[C:8](=S)[NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.[Hg]=O>[C:1]([O:5][C:6](=[O:27])[C:7]([C:25]#[N:26])=[C:8]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[NH:9][CH2:10][CH2:11][CH:12]([CH3:20])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C#N)C(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: O=[Hg]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)CCNC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.2 %

Procedure:
To a solution of 2-{N-[3,5-bis(trifluoromethyl)phenyl]thiocarbamoyl}cyanoacetic acid tert-butylester (1.12 g, 2.7 mmol, prepared from cyanoacetic acid tert-butyl ester and 3,5-bis(trifluoromethyl)phenylisothiocyanate) in DCM (15 mL) 3-methylbutylamine (1.0 mL, 8.60 mmol), magnesium sulfate (0.5 g) and mercury(II) oxide (2.0 g) were added. The resulting mixture was stirred at room temperature for 14 h, diluted with DCM (30 mL), filtered over Celite, washed with ice-cold diluted hydrochloric acid, with brine (2×20 mL), dried (magnesium sulfate) and concentrated. The residue was crystallized from heptane. 0.29 g (23%) of the title compound was obtained as colourless crystals, mp. 128-129° C. From the mother liquor additional 0.25 g (20%) of product were obtained. 1H NMR (400 MHz, DMSO-d6): δ=0.82 (d, J=7 Hz, 6H), 1.41 (s, 9H), 1.43 (q, J=7 Hz, 2H), 1.57 (nonett, J=7 Hz, 1H), 3.18 (q, br, J=7 Hz, 2H), 7.63 (s, 2H), 7.70 (s, 1H), 8.91 (s, br, 1H), 9.52 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ=21.96, 24.95, 28.02, 37.50, 41.84, 61.55, 79.66, 115.53, 118.67, 119.87, 123.05 (q, J=282 Hz), 130.44 (q, J=33 Hz), 142,11, 160.46, 167.93. Anal. Calcd. for C21H25F6N3O2 (465.44): C, 54.19; H, 5.41; N, 9.03. Found: C, 54.27; H, 5.57; N, 8.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[CH:39].C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:39]#[C:38][C:37]([CH3:41])([CH3:40])[CH3:36])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.15 g, 0.24 mmol) prepared in Example 190c in anhydrous N,N-dimethylformamide (10 mL) was added CuI (3 mg), 3,3-dimethyl-1-butyne (19.7 mg, 2.4 mmol) (Aldrich), and triethylamine (1 mL, 7.2 mmol). The mixture was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium (8.4 mg, 0.012 mmol) (Strem) was added and the reaction mixture was heated at 80° C. under nitrogen for 0.5 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3,3-dimethyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 41 mg, 30%).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[N:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=O.[NH2:24][O:25][CH3:26].Cl>>[CH3:26][O:25][N:24]=[CH:1][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[CH:18][CH:19]=[CH:20][N:21]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: CON
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Agent: Cl
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Yield: 83.3 %

Procedure:
was synthesized as described in Example 22 but using (68) (210 mg, 0.70 mmol) instead of (55) and NH2OMe.HCl (300 mg, 3.6 mmol) instead of NH2OH.HCl. The reaction gave (69) (192 mg, 83%). Mp. 158-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:10][CH2:11][CH:12]([CH3:16])[C:13](Cl)=[O:14])=[O:9])=[CH:4][CH:3]=1.C(SCC(C)C(Cl)=O)(=O)C.C(SCC(C)C([N:35]1[CH2:39][CH2:38][CH:37]=[C:36]1[C:40]([OH:42])=[O:41])=O)(=O)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:10][CH2:11][CH:12]([CH3:16])[C:13]([N:35]2[CH2:39][CH2:38][CH:37]=[C:36]2[C:40]([OH:42])=[O:41])=[O:14])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)SCC(C)C(=O)N1CCC=C1C(=O)O
Reactant: Cc1ccc(C(=O)SCC(C)C(=O)Cl)cc1
Agent: CC(=O)SCC(C)C(=O)Cl
Product: Cc1ccc(C(=O)SCC(C)C(=O)N2CCC=C2C(=O)O)cc1

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 3-[[(4-methylphenyl)-carbonyl]thio]-2-methylpropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in part 1(b) and subjecting the product to the procedure of Example 1 (c), one obtains (±)-4,5-dihydro-1-[3-[[(4-methylphenyl)carbonyl]thio]-2-methyl-1-oxopropyl]-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:11]([CH3:24])=[C:12]([NH:17][C:18]([NH:20][C:21](=[NH:23])[NH2:22])=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[ClH:1].[CH3:24][C:11]1[C:10]([OH:9])=[CH:15][CH:14]=[C:13]([CH3:16])[C:12]=1[NH:17][C:18]([NH:20][C:21](=[NH:22])[NH2:23])=[O:19]
Reactant: Cc1ccc(OCc2ccccc2)c(C)c1NC(=O)NC(=N)N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(O)c(C)c1NC(=O)NC(=N)N
Reaction time: 0.75 h

Procedure:
A mixture of 1-(3-benzyloxy-2,6-dimethylphenyl)-3-amidinourea hydrochloride (17.4 g) and 5% Pd/C (1.0 g) in absolute ethanol (200 ml) containing 50 ml of methanolic HCl is shaken under an atmosphere of H2 (50 psi) for 45 minutes. The reaction mixture is filtered through Celite and the Celite washed with methanol. The filtrate is concentrated in vacuo and the foam taken up in acetonitrile. The acetonitrile solution is concentrated in vacuo and the residue crystallized from methanol/acetonitrile to give, after filtering and vacuum drying, 10.1 grams of the 3-hydroxy phenyl amidinourea hydrochloride salt , M.P. 207°-208° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH3:19]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCBr
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 79 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and ethylbromide (also propyl and pentyl) (373 μL, 549 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetylbutanoic-acid-tert-butylester (250g) (970 mg, 3.97 mmol, 79%) as a slightly yellow oil. Then, 250 g (1.40 g, 5.73 mmol) and 109 mg (0.57 mmol) p-TsOH.H2O were stirred in 18.0 mL benzene according to decarboxylation method A. Kugelrohr distillation gave 486 mg (3.4 mmol, 59%) of 251 g as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[C:5]1[C:10](=[O:11])[CH:9]2[CH2:12][CH2:13][N:6]1[CH2:7][CH2:8]2.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[C:10](=[O:11])[CH:9]2[CH2:12][CH2:13][N:6]1[CH2:7][CH2:8]2
Reactant: O=C1C(=Cc2ccccc2Cl)N2CCC1CC2
Reactant: Br[Mg]c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1Cl

Procedure:
2-(2-Chlorobenzylidene)-1-azabicyclo[2.2.2]octan-3-one (3 g) was dissolved in toluene (30 ml) and placed in a dropping funnel. Phenylmagnesium bromide was dissolved in toluene (15 ml) and stirred under nitrogen. This was cooled in an ice/water bath and the benzylidene solution was added dropwise. After 3 hrs the reaction was quenched with ammonium chloride solution and the aqueous layer extracted with dichloromethane (×4); this was combined with the original toluene layer and dried (MgSO4). The solvent was removed in vacuo and the residue purified by chromatography on silica eluting with 1:1 hexane:diethyl ether which afforded the title compound as a 2:1 mixture of its diastereoisomers:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[CH2:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[C:18]([CH2:22]Cl)=[CH:17][N:16]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH:12]=[CH:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[CH:17][C:18]=2[CH2:22]1)(=[O:11])[CH3:10]
Reactant: ClCc1cnc(Cl)cc1Cl
Reactant: C=Cc1ccc(Cl)cc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccc(Cl)cc21
Yield: 53.9 %

Procedure:
The title compound (70.6 mg, 54%) was prepared from 6C (80 mg, 0.41 mmol) and 41B (80 mg, 0.41 mmol) in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.782 min; LCMS Found: (M+H)+=319.
Reaction SMILES: N1CCC(N)CC1.[N+:8]([C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1)([O-])=O>CO.[Rh]>[NH2:8][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: NC1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Rh]
Agent: NC1CCNCC1
Solvent: CO
Product: Nc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 2 h

Procedure:
Using the procedure of Example 1, piperidin-4-ylamine Compound 21a1 was used in place of Compound 1n2 and carried forward to prepare 1-(4-nitro-benzyl)-piperidin-4-ylamine Compound 21a2. 5% Rh/C (350 mg) was added to a solution of 1-(4-nitrobenzyl)-piperidin-4-ylamine Compound 21a2 (647 mg, 2.75 mmol) in methanol (15 mL). The mixture was hydrogenated at 50 PSI for a period of 2 hrs, then filtered through Celite. The filtrate was evaporated in vacuo to give 1-(4-amino-benzyl)-piperidin-4-ylamine Compound 21a (640 mg) as a light yellow oil. 1H NMR (CDCl3) δ 7.09 (d, J=8.2 Hz, 2H); 6.64 (d, J=8.2 Hz, 2H); 3.62 (br s, 1H); 3.41 (s, 2H); 2.88-2.80 (m, 2H); 2.70-2.58 (m, 1H); 2.07-1.95 (m, 2H); 1.84-1.74 (m, 2H); 1.57 (br s, 2H); 1.47-1.32 (m, 2H); 1.31-1.18 (m, 2H).
Reaction SMILES: Br[C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([O:20][CH3:21])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:8]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:2]=2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 170 °C
Reaction time: 2 h
Yield: 144.1 %

Procedure:
2-Bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde (3.5 gm, 0.0087 mol), anhydrous sodium carbonate (1.125 gm, 0.0106 mol) and palladium (II) acetate (0.19 gm, 0.0008 mol), in dimethylacetamide (15 ml) are heated and stirred under nitrogen at 170° C. for 2 h. Water (90 ml) is added to the cooled reaction mixture. The precipitated solid is collected by filteration and washed with 5% hydrochloric acid followed by water. The product was obtained as a yellow solid (3.4 gm).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1
Reactant: CCc1cccc(CNCC(O)C(Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reaction time: 1.17 h

Procedure:
The slurry of [1-(3,5-difluorobenzyl)-3-(3-ethylbenzylamino)-2-hydroxypropyl]-carbamic acid tert-butyl ester (5.25 g, 0.012 m) in anhydrous dioxane (20 ml) was stirred (magnetic bar) at RT under nitrogen atmosphere in an 250 ml round-bottom flask, immersed in a cold water bath. The solution of hydrogen chloride in dioxane (4M, 32 ml) was added in one portion. The reaction mixture, initially homogenous, became a thick slurry within ca. 20 min. Mixture was stirred for 70 min, and was monitored by the TLC (silica gel plates, 5×10 cm, eluted with ethyl acetate—methanol 95:5 mixture). Ethyl ether (100 ml) was added, precipitated product was filtered off and rinsed with ether (2×50 ml). The filter cake was air-dried for 1 hour then placed in an vacuum oven at 35° C. and the oven evacuated (5 torr). Product was dried to constant mass for 7 hours. Yield was 5.24 g. LC-MS (m/e): 335 (M+1); purity: 100% (254 nm).