Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC2CCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydrofuran (0.56 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.94 g, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].Cl.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: Cc1ccc(C#N)nc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(CN)nc1C
Reaction time: 8 h

Procedure:
To a solution of compound 3 in Scheme 4-3 (58 mg, 0.44 mmol) in MeOH (5 mL) and 6N HCl (1 mL) was added Pd/C (10 mg) at room temperature, the mixture was filled with hydrogen for three times and stirred overnight. The reaction mixture was filtered through celite and washed with MeOH and the filtrate was concentrated. The residue was concentrated to give compound 4 as a dark brown solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:13][C:14]1[C:15]([NH:26][NH2:27])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]#[N:25])=[CH:19][CH:18]=2.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[C:15]([NH:26][NH:27][C:10](=[O:11])[CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]#[N:25])=[CH:19][CH:18]=2
Reactant: N#Cc1ccc2nc(NN)c(Cl)nc2c1
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C#N)cc2nc1Cl)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (2.15 g, 10 mmol) in 20 ml of dry tetrahydrofuran was added to a solution of 3-chloro-6-cyano-2-hydrazinoquinoxaline (2.0 g, 9 mmol) and dry triethylamine (1.4 ml, 10 mmol) in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature overnight, and filtered. The filtrate was evaporated, and the title compound was isolated as a semisolid residue, which was used in the next step without further purification; 1H-NMR (DMSO-d6): δ 1.26 (t, 6H), 3.09 (d, 2H), 4.10 (quint, 4H), 7.71 (d, 1H), 7.97 (dd, 1H), 8.39 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:41][C:42]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>ClCCl>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:44]([C:43]3[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:42]=3[Cl:41])=[O:45])[CH2:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Clc1cnc2n1CCNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(Cl)cnc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I20) (450 mg, 2.86 mmol) and diethylaminomethyl polystyrene (2855 mg, 9.14 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2,4-dichlorobenzoyl chloride (0.439 mL, 3.14 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford crude product. The product was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford product then by MDAP (High pH method) to afford clean desired product in 350 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[Cl:13][CH2:14][O:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]>>[Cl-:13].[CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N+:8]([CH2:14][O:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CN(C)C(=O)Oc1cccnc1
Reactant: O=C(OCCl)C1CC1
Product: CN(C)C(=O)Oc1ccc[n+](COC(=O)C2CC2)c1
Product: [Cl-]
Reaction time: 3 h
Yield: 92.2 %

Procedure:
3-Dimethylcarbamoyloxypyridine (1.66 g) and chloromethylcyclopropanecarboxylate (2.70 g) were heated to 90° C. with stirring for 3 hrs. The reaction mixture was treated in a similar manner as described in Example 1 to give 2.77 g of 3-(dimethylcarbamoyloxy)-1-(cyclopropylcarbonyloxymethyl)pyridinium chloride as oil. The structure was determined by N.M.R.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11]([NH:13][C:14](/[C:16]/1=[CH:17]\[CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])=[O:12])([OH:3])=[O:2].C>CCO.CCOCC>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:16]([CH2:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14](=[O:15])[NH:13][C:11]1=[O:12])([OH:3])=[O:2]
Reactant: CCCCCC(=O)C/C=C1\C(=O)NC(=O)N1CCCCCCC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CCCCCC(=O)CCC1C(=O)NC(=O)N1CCCCCCC(=O)O

Procedure:
A solution of 1-(6-carboxyhexyl-5-((E)-3-oxooctylidene)hydantoin (3.06 g) in EtOH (60 ml) was stirred with 10% palladised charcoal (200 mg) under hydrogen at room temperature and pressure, absorption of 1 molecular equivalent of hydrogen occurring in 2 hours. The catalyst was filtered, the filtrate was evaporated in vacuo, and the residual gum was set aside to give a mass of colourless crystals. The crystals were suspended in ether (4 ml) and collected, affording pure 1-(6-carboxyhexyl)-5-(3-oxo-octyl)hydantoin, m.p. 84.5°-86°. A stirred suspension of 0.5 g of this compound in water (15 ml) at 0° C. was treated with NaHCO3 (0.36 g) and then, during 3 minutes, with sodium borohydride (54 mg). After 45 minutes, more sodium borohydride (54 mg) was added and, after a further 11/2 hours, the clear solution was set aside at room temperature for 11/2 hours. The solution was then acidified to Congo Red with hydrochloric acid, the liberated carboxylic acid was extracted into chloroform, and the chloroform solution was washed and dried over magnesium sulphate. Evaporation of the solvent afforded 1-(6-carboxyhexyl)-5-(3-hydroxyoctyl) hydantoin as a mixture of diastereomers which was subjected to HPLC (SiO2, CHCl3 /MeOH/HOAc 97.75:1.25:1.0), affording the individual diastereomers as colourless gums, Rf. 0.44 and 0.40 (relative to 0.64 for a marker of the starting oxo-compound) on SiO2 in CHCl3 /MeOH/HOAc 90:5:5.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C@H:15]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl.O>[CH3:10][O:11][CH2:12][O:14][C@H:15]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COCCl
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCO[C@H](Cc1ccc(N2CCOCC2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Diisopropylethylamine (1.15 ml) and chloromethyl methyl ether (0.5 ml) were added to a solution of benzyl (R)-2-hydroxyl-3-(4-morpholinophenyl)propionate (1.5 g) in dichloromethane (15 ml) under ice-cooling and the mixture was stirred at room temperature for 19 hours. This reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (20 ml×3). The organic layer was washed serially with 5% sodium hydrogencarbonate solution (20 ml), water (20 ml) and saturated aqueous solution of sodium chloride (20 ml) in the order mentioned and dehydrated over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography, elution being carried out with hexane-ethyl acetate (1:2, v/v). From the fraction containing the objective compound, the solvent was distilled off under reduced pressure to provide 1.73 g of benzyl (R)-2-methoxymethoxy-3-(4-morpholinophenyl)propionate.
Reaction SMILES: C([O:8]C([NH:11][C@H:12]([C:34]([NH:36][C@H:37]([C:44]([O:46]CC)=[O:45])[CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23]C(OCC3C=CC=CC=3)=O)[CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.C([OH:51])C>C(O)(=O)C.[Pd]>[OH2:8].[OH2:51].[OH2:8].[OH:23][C:20]1[CH:21]=[C:22]2[C:17]([NH:16][CH:15]=[C:14]2[CH2:13][C@@H:12]([C:34]([NH:36][C@H:37]([C:44]([OH:46])=[O:45])[CH2:38][C:39]([OH:41])=[O:40])=[O:35])[NH2:11])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccc(OC(=O)OCc3ccccc3)cc12)NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)N[C@@H](CC(=O)O)C(=O)O
Product: O

Procedure:
32 g (0.05 mol) of the derivative obtained above according to (a) are dissolved in 600 ml of acetic acid and 600 ml of ethanol and the solution is hydrogenated at atmospheric pressure in the presence of 3 g of 5% palladium-on-charcoal. When the absorption of hydrogen has ended, the mixture is filtered, the filtrate is evaporated, the residue is made into a paste again with ether and the product is recrystallized from water. This gaves 86% of the trihydrate of the title derivative of m.p. 190° C. and [α]D =+12.40° (C=1, 0.1N NH4OH). TLC of the product on a Kieselgel plate in the system isopropanol 2/ethyl acetate 2/water 1/acetic acid 0.1 gives a single spot of Rf=0.65.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])C1C=CC=CC=1.[CH:18]([O-])=O.[NH4+]>CO.[Pd]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1
Reactant: O=C[O-]
Reactant: O=C(O)C1CC(O)CCN1Cc1ccccc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C1CC(O)CCN1
Temperature: 25 °C
Yield: 123 %

Procedure:
To a stirred solution of the product of step B (600 mg, 2.4 mmol) in methanol (15 mL) was added 10% palladium on carbon (60 mg) and ammonium formate (1.26 g, 20.0 mmol). The reaction mixture was heated to reflux for 2 h, cooled to ambient temperature then filtered through Celite. The filtrate was concentrated in vacuo to afford methyl 4-hydroxypiperidine-2-carboxylate (470 mg, 95%) as a colorless oil which was carried forward without purification: 1H NMR (CDCl3, 400 MHz) δ 3.76-3.74 (m, 4H), 3.44-3.41 (m, 1H), 3.26-3.21 (m, 1H), 2.70-2.63 (m, 1H), 2.33-2.28 (m 1H), 1.91-1.90 (m, 1H), 1.50-1.40 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])[C:13]3[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=3[S:11]2(=[O:32])=[O:31])=[CH:5][C:4]=1[CH3:33].B(Br)(Br)Br.CCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[OH:2][C:3]1[C:4]([CH3:33])=[CH:5][C:6]([N:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[C:19]([F:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=3[F:24])[C:13]3[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=3[S:11]2(=[O:32])=[O:31])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc(C)c1O
Yield: 57.1 %

Procedure:
To a solution of (115) (0.2 g, 0.42 mmol) in DCM (5 mL) was added boron tribromide (1.0M solution in DCM, 0.46 mL, 0.46 mmol) at −70° C. The resulting mixture was stirred for approximately two h at rt with TLC monitoring (hexane:EtOAc, 1:1). The reaction mixture was poured into saturated aqueous NaHCO3 solution (50 mL), extracted with EtOAc (3×50 mL), and the combined organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by trituration with DCM in pentane (1:9) yielded the title compound (0.11 g, 0.24 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:28]([CH:31]=1)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCCC4)c(C#N)c3)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (40 mg, 0.139 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (35.8 mg, 0.153 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (54.4 mg, 0.167 mmol). The mixture was stirred at 50° C. for 16 h. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to provide the title compound as an off-white foam (57.4 mg). LCMS m/z=485.4 [M+H]+; 1H NMR (400 MHz, CDCl3) α ppm 1.24-1.34 (m, 1H), 1.43-1.53 (m, 4H), 1.50 (s, 9H), 1.80 (dd, J=12.88, 1.26 Hz, 1H), 1.89 (t, J=10.86 Hz, 4H), 2.22-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.44 Hz, 1H), 2.82-2.92 (m, 1H), 2.99 (t, J=3.09 Hz, 1H), 3.65-3.75 (m, 1H), 3.95-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.06 (s, 2H), 6.09 (s, 1H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.08 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Al:5].[H][H]>>[CH3:2][CH:1]([CH3:3])[O-:4].[Al+3:5].[CH3:2][CH:1]([CH3:3])[O-:4].[CH3:2][CH:1]([CH3:3])[O-:4]
Reactant: [H][H]
Reactant: [Al]
Reactant: CC(C)O
Product: CC(C)[O-]
Product: [Al+3]

Procedure:
Aluminum isopropoxide was prepared by refluxing 240 grams of isopropanol (four moles) under a nitrogen atmosphere then adding 27 grams (1 mole) of finely divided aluminum metal. The reaction proceeded with hydrogen evolution. The product was kept in a sealed flask for further testing.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2C=[CH:24][CH:23]=[CH:22][C:19]=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:28]([O:31]CC)(=[O:30])[CH3:29]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:19]=[CH:22][CH:23]=[CH:24][C:29]=2[C:28]([OH:31])=[O:30])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C#N)c(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)O)c(Cl)cn1
Yield: 66.1 %

Procedure:
To a 50 mL round bottom flask was added 2-({5-chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzonitrile (300 mg, 0.850 mmol), and NaOH 1 M solution (10 ml, 10.00 mmol) in 1,4-dioxane (10 mL). The mixture was heated under reflux for 18 hours. Ethyl acetate was added (20 mL) and the layers separated—all product stayed in the water phase. The water phase was neutralized with 6 N HCl, and 40 mL of ethyl acetate were added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. 2-({5-Chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzoic acid (220 mg, 0.562 mmol, 66.1% yield) was isolated as off-white solid and used in the next step without further purification. LCMS (M+H)+=372.1; 1H NMR (400 MHz, MeOD) ppm 1.33 (t, J=7.20 Hz, 4 H) 2.22 (s, 3 H) 4.00 (q, J=7.33 Hz, 2 H) 6.01 (s, 1 H) 6.82 (s, 1 H) 7.06 (td, J=7.52, 1.14 Hz, 1 H) 7.39-7.49 (m, 1 H) 7.49-7.55 (m, 1 H) 7.87-7.94 (m, 1 H) 8.05 (dd, J=7.83, 1.52 Hz, 1 H).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][S:8][C@H:3]12.[OH:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](O)=[O:28]>>[CH2:14]([O:13][C:11]([CH:10]=[CH:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:27](=[O:28])[CH:26]([OH:25])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23](=[O:24])[N:4]2[C:5]=1[C:16]([OH:18])=[O:17])=[O:12])[CH3:15]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCOC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Product: CCOC(=O)C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3ccccc3)[C@H]2SC1

Procedure:
Following the general procedure of Example 9, a salt of tert-butyl 7-amino-3-(2'-ethoxycarbonylvinyl)-3-cephem-4-carboxylate was acylated with the acid chloride derivative of 2-hydroxy-2-phenylacetic acid (mandelic acid), and after ester group removal the title compound was obtained as product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#N)[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-:26].[Na+].[OH2:28].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:28])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O
Reactant: [OH-]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C#N)c3)cs2)cc1OCC
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3cccc(C(=O)O)c3)cs2)cc1OCC

Procedure:
A solution of 16 g of 2-(3,4-diethoxyphenyl)-4-(3-cyanophenyl)thiazole in 120 ml of ethanol and 90 ml of a 40% aqueous sodium hydroxide solution was refluxed for 15 hours with heating. The reaction mixture was mixed with water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml×3). The extract was washed with water (10 ml×3) and subjected to distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 7 g of 2-(3,4-diethoxyphenyl)-4-(3-carboxyphenyl)thiazole.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:18])[C:11](=[O:17])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[CH:19]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[CH:19]1([C:11]([OH:17])([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]([O:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cl[Mg]C1CCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)C1CCCC1

Procedure:
Prepared using the same method as for Intermediate I-14, but from from 20.8 g (0.0784 mol) of of 2-oxo-2-thien-2-ylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester and cyclopentylmagnesium cloride, 0.08 mol (40 ml of a solution 2M in ether). The oil obtained (15.64 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 97:3:0.5 to obtain 8.38 g (32%) of a pure product, mixture of diastereomers: I-15a and I-15b. Structure confirmed by 1H-NMR.
Reaction SMILES: [CH3:1][N:2]([CH2:19][C:20]([OH:22])=[O:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N1C=CN=C1)(N1[CH:29]=[CH:28]N=C1)=O.C(O)C>O1CCCC1>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:29]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 0.75 h
Yield: 134 %

Procedure:
A solution of 0.53 g (1.6 mmol) {methyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic acid in 8 mL anhydrous tetrahydrofuran was treated with 0.32 g (2.0 mmol) 1,1′-carbonyl-diimidazole. After stirring for 45 minutes, 1 mL of ethanol was added. The resulting mixture was then permitted to stir overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed twice with saturated sodium bicarbonate, twice with water, dried over sodium sulfate and concentrated in vacuo. After drying via high vacuum overnight, 0.76 g of the title compound was isolated as a red solid; 1H NMR (CDCl3) δ 1.23-1.29 (m, 3H), 2.59 (t, J=6.15 Hz, 4H), 2.87 (s, 1H), 3.76 (t, J=6.09 Hz, 4H), 3.96 (s, 2H), 4.11-4.18 (m, 2H), 6.89-6.96 (m, 2H), 7.67-7.75 (m, 2H); MS (ES) m/z 355.3 (MH+); HRMS for C16H22N2O5S: 355.1332
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[CH:10][C:8](=[O:9])[N:7]([CH2:13][CH2:14][CH3:15])[C:5]1=[O:6])[CH2:2][CH3:3].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+].Cl>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:20]=[O:21])[C:8](=[O:9])[N:7]([CH2:13][CH2:14][CH3:15])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(N)cc(=O)n(CCC)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Reaction time: 0.17 h
Yield: 146.3 %

Procedure:
1,3-Di-n-propyl-6-aminouracil (30 g) was suspended in lL of water with 41 ml of 20% acetic acid and overhead stirring. Sodium nitrite (9.03 g) in 41 ml of water was added in portions, keeping the solution acidic with 12 ml concentrated hydrochloric acid. A purple precipitate formed. Addition was complete in 10 minutes and the suspension was allowed to stir for 2 hours. The solution was then filtered, and the filtrate was rinsed with water and dried under vacuum to yield 46 g of 1,3-di-n-propyl-5-nitroso-6-aminouracil.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:27].C(OCC)C>O1CCOCC1>[ClH:27].[ClH:27].[NH2:8][C@H:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (R)—(R)-quinuclidin-3-yl 2-((tert-butoxycarbonyl)amino)-2-phenylacetate (0.608 g, 1.687 mmol) in anhydrous dioxane (6 mL) was added 2M HCl in diethyl ether (5.2 mL, 10.4 mmol). The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo to afford the title compound as a white solid (0.564 g, quantitative yield).