Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:27]([SiH:30]([CH:32]([CH3:34])[CH3:33])Cl)([CH3:29])[CH3:28]>>[C:1]1([C:7]#[C:8][CH2:9][O:10][SiH:30]([CH:32]([CH3:34])[CH3:33])[CH:27]([CH3:29])[CH3:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: OCC#CC1=CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CC(C)[SiH](OCC#CC1=CCCCC1)C(C)C
Yield: 52.7 %

Procedure:
3-Cyclohexenylprop-2-yn-1-ol (61) (1.236 g, 12.86 mmol), triethylamine (1.30 g, 12.85 mmol), dimethylaminopyridine (0.152 g, 1.267 mmol) and diisopropylchlorosilane (1.918 g, 12.73 mmol) were used to yield compound 7e (1.680 g, 6.71 mmol, 52.7%) as a colorless, clear oily substance after purification by flash chromatography: Rf 0.85 (hexanes/Et2O, 4:1); 1H NMR (500 MHz, CDCl3) δ 6.08 (h, J=1.8 Hz, 1H, H-5), 4.48 (s, 2H, H-1), 4.20 (s, 2H, H-10), 1.98-2.17 (m, 4H, H6-9), 1.49-1.71 (m, 4H, H6-9), 0.96-1.12 (m, 14H, H-11, 12). 13C NMR (300 MHz, CDCl3) δ 134.8 (C-5), 120.3 (C-4), 87.1 (C-2/3), 84.4 (C-2/3), 54.3 (C-1), 29.0 (C6-9), 25.6 (C6-9), 22.2 (C6-9), 21.5 (C6-9), 17.3 (C-12), 17.2 (C-12), 12.3 (C-11); HRMS calcd for C15H26NaOSi (M+Na)+ 273.1651. found 273.1639.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([Cl:19])[CH:11]=2)=[N:6]1)[CH3:4].[CH3:20][C:21]1[NH:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Cl:19][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@@H:3]([CH3:4])[CH2:2][NH:1][C:26]([C:24]3[N:25]=[C:21]([CH3:20])[NH:22][CH:23]=3)=[O:27])[N:6]=2)[CH:17]=[C:16]([F:18])[C:13]=1[C:14]#[N:15]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Yield: 8.2 %

Procedure:
(S)—N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.0 g, 3.59 mmol) and 2-methyl-1H-imidazole-4-carboxylic acid (0.498 g, 3.95 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 8.2%. 1H-NMR (400 MHz; DMSO): δ 1.45 (d, 3H), 2.27 (s, 3H), 3.50-3.74 (m, 2H), 4.62-4.77 (m, 1H), 7.02 (d, 1H), 7.45 (s, 1H), 7.88-8.04 (m, 4H), 12.11 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17]CCO2)=[C:9]([F:18])[CH:8]=1.[CH:19]1([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33]COC)=[CH:29][CH:28]=2)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>C1COCC1>[C:19]1(=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:17])=[C:9]([F:18])[CH:8]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Fc1cc(Br)ccc1C1OCCO1
Reactant: COCOc1ccc(C(=O)C2CCCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.8 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 1.33 mL, 2.13 mmol) was added dropwise to 88 (503 mg, 2.04 mmol) dissolved in anhydrous THF (25 mL) at −78° C. The reaction mixture was stirred for 20 min and 87 (460 mg, 1.85 mmol), dissolved in THF (25 mL), was added dropwise. The mixture was warmed slowly to RT and stirred overnight. Water (150 mL) was added and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting crude oil was taken up in a mixture of EtOH (10 mL) and 12 M HCl (2 mL) and refluxed for 2 h. Removal of solvent and flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 200 mg (35%) of 89 as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.60 (br s, 6H), 2.23 (m, 4H), 6.00 (s, 1H), 6.79 (d, J=8.2 Hz, 2H), 6.89-6.95 (m, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 10.28 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCCCCC>C(O)C.[Zn]>[F:24][C:22]([F:23])([F:25])[C:18]1[CH:17]=[C:16]([S:13]([CH2:12][CH2:11][S:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CCCCCC
Product: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 76 %

Procedure:
1.31 g (20 mmol) zinc was added to a solution of 1.96 g (5.0 mmol) 3-nitro-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]ethyl-sulfanyl]pyridine in ethanol (45 ml) and the mixture was cooled to 0° C. 200 ml (0.2 M, 40 mmol) of an aqueous NH4Cl solution were added at this temperature and then the mixture was heated for 30 min at 90° C. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and neutralised with NaHCO3. It was then extracted with EE and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) of the residue yielded 1.38 g (3.8 mmol, 76%) [2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:29])([C:17](=[CH:26][CH2:27][OH:28])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:29])([C:17](=[CH:26][CH2:27][O:28][CH3:34])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCO)CCC12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCOC)CCC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3-Benzyloxy-2-ethyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-ylidene)-ethanol (0.62 g, 1.5 mmol) in 10 ml dry THF was cooled to 0° C. under nitrogen. NaH (0.08 g, 2 mmol of NaH 60% dispersion in mineral oil) was added portion wise and the solution stirred for 30 minutes before CH3I (0.19 ml, 3 mmol) was added dropwise. The solution was then allowed to warm to room temperature and stirred for 18 hours. After addition of water (20 ml) the organics were extracted with ethylacetate. The organic layer was washed with water, brine, dried over MgSO4 and the solvents were evaporated under vacuum. The crude oil was purified by chromatography (hexane/ethylacetate 20/1) to give 3-benzyloxy-2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene, 0.59 g (91%), as a colourless oil; 1H NMR (CDCl3, 270 MHz): 0.84 (s, 3H, CH3), 1.24 (t, J=7.4 Hz, 3H, CH3), 1.26-1.66 (m, 6H), 1.82-2.02 (m, 3H), 2.20-2.51 (m, 3H), 2.70 (q, J=7.4 Hz, 2H, CH2), 2.87 (m, 2H, H6), 3.36 (s, 3H, CH3O), 3.94 (m, 2H, CH2OMe), 5.06 (s, 2H, CH2Ph), 5.27 (m, 1H, CHCH2OH), 6.66 (s, 1H, ArH), 7.15 (s, 1H, ArH), 7.31-7.48 (m, 5H, Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH:19]([F:21])[F:20])=[N:14]1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:22])[C:15]([CH:19]([F:20])[F:21])=[N:14]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1cc(-n2nc(C(F)F)[nH]c2=O)c(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(C)Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A stirred mixture of 4.0 g (0.012 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one and 4.1 g (0.03 mole) of potassium carbonate in 160 mL of acetone was heated at reflux for 0.5 hours then cooled to about 50° C. Methyl iodide, 8.4 g (0.06 mole), was added and the mixture stirred at 45° for one hour then at reflux for one hour. The mixture was cooled to room temperature and evaporated under reduced pressure to leave an oil. This oil was partitioned between methylene chloride and water. The organic phase was washed with a 10% aqueous sodium hydroxide solution and then dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to leave an oil. This oil solidified when stirred with petroleum ether and upon filtration provided 2.6 g of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4 -triazol-5-(1H)-one (mp 95°-97° C).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[CH2:23]([N:26]=[C:27]=[S:28])[CH2:24][CH3:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[S:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CCCN=C=S
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)NCCC
Yield: 66.7 %

Procedure:
Using the general method of Example 150, 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with propyl isothiocyanate (560 mg, 5.55 mmol) to provide 1.34 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthiourea as a crystalline solid, m.p. 144.5-145.5° C. Analysis: Calculated for C21H30N6S. 0.56H2O: %C, 61.72; %H, 7.68; %N, 20.56; Found: %C, 61.72; %H, 7.67; %N, 20.56.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:2]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[CH:31][CH:32]=1
Reactant: CCN(CC)CCNCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (245 mg, 0.99 mmol) was added to a solution of N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine (235 mg, 0.98 mmol) and N,N-diisopropylethylamine (0.54 mL, 2.94 mmol) in DCM (2 mL). The reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was quenched with saturated NH4Cl (2 mL) and extracted with DCM (2×5 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (200 mg, 45%). 1H NMR (CDCl3, 400 MHz) 7.32 (d, J=8.4 Hz, 2 H), 7.19 (d, J=8.4 Hz, 2 H), 4.42 (s, 2 H), 3.45-3.40 (m, 4 H), 3.25-3.20 (m, 4 H), 3.18 (t, J=6.8 Hz, 2 Hz), 2.56 (t, J=6.8 Hz, 2 H), 2.49 (q, J=7.2 Hz, 4 H), 1.46 (s, 9 H), 0.99 (t, J=7.2 Hz, 6 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[CH3:29][O:30][NH2:31].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1[NH:31][O:30][CH3:29]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Reactant: CON
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CONc1nc(Nc2ccc(C#N)cc2)nc(Oc2c(C)cc(C#N)cc2C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a pressure vessel was added 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile (0.00064 mol), tetrahydrofuran (3 ml), O-methylhydroxylamine (0.06 g), tetrahydrofuran and NaOH 1N (0.00067 mol). The reaction mixture was stirred for 3 days at room temperature, then for 1 day at 75° C., for 1 day at 90° C. and for 2 days at 110° C. To O-methylhydroxylamine (0.60 g) was added tetrahydrofuran (4 ml) and NaOH 50% (0.00719 mol). The liquid was decanted into the reaction flask and the reaction mixture was heated at 110° C. for 3 days. The solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated NaHCO3 solution and water, dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN, filtered off and dried, yielding 0.15 g of 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-(methoxyamino)-2-pyrimidinyl]amino]benzonitrile (51%); mp. 185-186° C. The sample was dried (0.2 mm Hg, 80° C., 16 hours) (comp. 48).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:23]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>CO.[Pt]>[NH2:23][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:13]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Yield: 80 %

Procedure:
A suspension of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (3.89 g, 10 mmol) in methanol (80 ml) containing 10% platinum on activated carbon (50% wet) (389 mg) was hydrogenated at 1.8 atmospheres pressure until uptake of hydrogen ceased. The mixture was filtered and the volatiles were removed by evaporation. The residue was dissolved in water (30 ml) and adjusted to pH10 with a saturated solution of sodium hydrogen carbonate. The mixture was diluted with ethyl acetate/ether (1/1) and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate/ether and the organic layers were combined. The organic layers were washed with water, brine, dried (MgSO4), filtered and the volatiles were removed by evaporation. The resulting solid was triturated in a mixture of ether/petroleum ether, filtered, washed with petroleum ether and dried under vacuum at 60° C. to give ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (2.58 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]([C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[O:16][CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:17]([O:16][C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[C:12]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=3[N:1]=2)[CH2:18]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C1
Reactant: Nc1cccc(C(=O)O)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)O)cccc3[nH]2)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
A mixture of 2,3-diaminobenzoic acid (1; 350 mg, 2.3 mmol), tert-butyl 3-(2-formylphenoxy)pyrrolidine-1-carboxylate (30; 670 mg, 2.3 mmol) and Na2S2O5 (568 mg, 1.3 mmol) in DMF (30 mL) was stirred at 90° C. for 18 h. The mixture was cooled to room temperature. The mixture was diluted with water (100 mL), stirred for 1 h, filtered, and washed with water. The filter cake was dried under vacuum to afford 822 mg of the titled compound 31 (84%). MS (ESI) calcd for C23H25N3O5: 423.18; found: 424 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:31]=[CH:30][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)=[CH:28][CH:27]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: OCCC1CCCCC1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)cc2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{4-[2-{4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCOc1cccc(O)c1
Temperature: 90 °C
Yield: 34 %

Procedure:
A mixture of 11 g of resorcinol, 8.8 g of methyl 5-bromopentanoate, and 13.8 g of potassium carbonate in 150 mL of dimethylformamide was heated in an oil bath at 90° C. for 24 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether providing the title intermediate in 34% yield, NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22]N(C)C)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1([C:40]2[NH:41][C:42]([NH2:45])=[N:43][N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)(=O)C.C(O)C>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][N:43]4[N:44]=[C:40]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:41]=[C:42]4[N:45]=3)=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC(C)(O)C2)cc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1

Procedure:
A mixture of 2 (270 mg, 0.6 mmol) and 5-Phenyl-4H-[1,2,4]triazol-3-ylamine (96 mg, 0.6 mmol) in acetic acid (1 mL) and ethanol (4 mL) was heated under reflux for 6 hours.
Reaction SMILES: [CH3:1][N:2]1C2C(=CC=CC=2)C=C1CNC.[CH2:14]1[C:18]2=[C:19]([CH:26]=O)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:17]2[CH2:16][CH2:15]1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][NH:2][CH2:26][C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[N:17]2[CH2:16][CH2:15][CH2:14][C:18]=12
Reactant: O=Cc1c2n(c3ccccc13)CCC2
Reactant: CNCc1cc2ccccc2n1C
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c2n(c3ccccc13)CCC2
Yield: 54 %

Procedure:
According to the procedure of Preparation 40 (c), except substituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde (0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]1[CH2:32][O:31][CH:30]2[CH:25]([CH2:26][CH2:27][NH:28][CH2:29]2)[O:24]1>C1C=CC=CC=1>[CH2:23]1[CH2:32][O:31][CH:30]2[CH:25]([CH2:26][CH2:27][N:28]([C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:29]2)[O:24]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C1CC2OCCOC2CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC2OCCOC2C1
Reaction time: 8 h

Procedure:
To a stirred solution of 24 parts of diphenylacetyl chloride in 250 parts by volume of benzene is added 15 parts of solid sodium carbonate and 16.4 parts of 4-(ethylenedioxy)piperidine. The resultant mixture is refluxed for about 29 hours, left overnight at room temperature, and filtered. The filtrate is washed twice with 10% hydrochloric acid, twice with saturated sodium bicarbonate solution and once with brine. The filtrate is then dried over magnesium sulfate, concentrated and recrystallized from cyclohexane to afford 4-(ethylenedioxy)-1-(diphenylacetyl)piperidine, melting at about 136°-137° C. This compound has the following structural formula ##STR20##
Reaction SMILES: [CH3:1][S:2][CH:3]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)[C:4]([NH:6][CH:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14]OC(=O)C)[CH2:12][S:13][C@H:8]12)=[O:5].[SH:29][C:30]1[S:31][C:32]([CH3:35])=[N:33][N:34]=1.C(=O)(O)[O-].[Na+].O>P([O-])([O-])([O-])=O>[CH3:1][S:2][CH:3]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)[C:4]([NH:6][CH:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][S:29][C:30]3[S:31][C:32]([CH3:35])=[N:33][N:34]=3)[CH2:12][S:13][C@H:8]12)=[O:5]
Reactant: CSC(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CSC(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1ccco1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
7-[α-Methylthio(2-furyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (341 mg), 128 mg of 2-mercapto-5-methyl-1,3,4-thiadiazole and 68 mg of sodium bicarbonate were dissolved in 10 ml of a 0.1M phosphate buffer (pH 6.4), and the solution was stirred at 60° C. for 7 hours, and then at room temperature for 14 hours. Then, 10 ml of water was added, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid to a pH of 2, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. Petroleum ether was added to the residue, and it was powderized. By filtration, the final product was obtained.