Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24].[OH-].[Na+]>>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:30][CH:31]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Butoxy-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C23H30O6 [M+NH4]+: 420, [M+Na]+: 425, [M+H]+: 403.
Reaction SMILES: O=C1C2[C:5](=CC=CC=2)[C:4](=O)[N:3]1[O:12][CH2:13][C:14]1[N:15]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]3[N:24]=[N:25][N:26]=[C:18]3[C:17]=2[N:27]=1.O.NN.[CH2:40](O)C>>[CH3:23][C:20]1[N:19]2[N:24]=[N:25][N:26]=[C:18]2[C:17]2[N:27]=[C:14]([CH2:13][O:12][N:3]=[C:4]([CH3:5])[CH3:40])[N:15]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[C:16]=2[C:21]=1[CH3:22]
Reactant: CCO
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNS(C)(=O)=O)c12
Agent: NN
Solvent: O
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A mixture of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]methanesulfonamide (205 mg, 0.40 mmol), hydrazine hydrate (0.4 mL), and ethanol (4 mL) was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between 1 M aqueous HCl (20 mL) and dichloromethane (10 mL). The aqueous phase was washed with dichloromethane (3×8 mL), then was adjusted to pH 12 with 1 M aqueous sodium hydroxide and was concentrated under reduced pressure. To the residue was added acetone (10 mL) and methanol (10 mL), and the reaction mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The organic layers were combined, washed with saturated aqueous sodium carbonate (3×10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 20-40% CMA in chloroform, where CMA is 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to yield 91 mg of N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}methanesulfonamide as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.O[NH:29][C:30](=[NH:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[O:12][N:37]=[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N=C(NO)c1ccncc1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc(-c2ccncc2)no1

Procedure:
A solution of tert-butoxycarbonylaminoacetic acid (11.0 g, 5.71 mmol) and triethylamine (802 μl, 5.71 mmol) in toluene (30 ml) was cooled to 0° C. and isobutylchloroformate (740 μl, 5.71 mmol) introduced dropwise. The reaction mixture was stirred at 0° C. for 10 min and at rt for 30 min, whereupon N-hydroxyisonicotinamidine (652 mg, 4.76 mmol) and powdered 3 Å molecular sieves (4 g) were added. After heating under reflux for 12 h the reaction was cooled, filtered through celite and the solvent removed in vacuo. The residue was dissolved in EtOAc (200 ml) and washed with water (30 ml) and saturated aqueous NaHCO3 (30 ml), then dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (IH-EtOAc, 2:3) to afford the title compound: RT=2.97 min; m/z (ES+)=277.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][O:21]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:29][C:28]3[NH:27][CH:26]=[C:25]4[C:20](=[O:19])[O:21][CH2:22][CH2:23][C:24]=34)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-(2-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:1][C:2]1[CH:12]=[C:11]([NH:13][C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1N
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)COC)cc1NC(=O)COC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2,4-diaminobenzoate (3.6 g) in pyridine (80 ml) is added dropwise methoxyacetyl chloride (4.0 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue are added water and chloroform. The organic layer is separated and washed with water and then with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the resulting oily substance is dissolved in ethyl acetate-hexane, and the solution is allowed to stand at -30° C. for 6 hours. The precipitated crystals are separated by filtration to give the title compound (6.0 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:13]([CH:12]([F:11])[C:16]([F:19])([F:18])[F:17])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (2.03 g; 11.5 mmoles) and 2,3,3,3-tetrafluoro-propionic acid (1.99 g; 13.6 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (60 mL) and with ethyl acetate (60 mL), then sodium bicarbonate (4.02 g; 47.9 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light orange solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][C:9]2([CH3:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:23][C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(c1ccc(F)c(Cl)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (423 mg, 1 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (380 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=396.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[O:6][N:5]=1.[H][H].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CS(C)=O>[CH3:3][C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:20][CH:22]2[O:24][CH2:23]2)[O:6][N:5]=1
Reactant: BrCC1CO1
Reactant: [H][H]
Reactant: Cc1cc(C=Cc2ccccc2O)on1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C=Cc2ccccc2OCC2CO2)on1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6.44 g of 55% strength sodium hydride in paraffin oil (0.15 mole) are introduced into 200 ml of absolute dimethylsulfoxide and 30 g (0.15 mole) of 3-methyl-5-(2-hydroxy-styryl)-isoxazole, dissolved in 50 ml of dimethylsulfoxide, are added dropwise, at room temperature. When the evolution of hydrogen has ceased, 20.2 g (0.15 mole) of epibromohydrin are added dropwise and the reaction mixture is stirred for 20 hours at room temperature. It is then poured onto 1.5 liters of ice water and the solid residue is filtered off and recrystallized from isopropanol. 26.2 g (68% of theory) of colorless crystals, of melting point 99°-100° C., are obtained.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1CCCCC1>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 51.8 mmol) in dichloromethane (2.00 mL) was added TFA (2.96 g, 2.00 mL, 26.0 mmol, Eq: 501), the reaction mixture turned brown and was stirred at 25° C. for 18 h. The mixture was concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. Product isolated as an off-white solid which was sonicated with cyclohexane decanted and then sonicated again with MeOH, decanted and dried to give clean N-tert-butyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (8 mg, 22.7 μmol, 43.8%). MS (M+H)+=353.1; 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 3.76 (s, 3H), 2.91 (br. s., 2H), 2.64 (br. s., 2H), 1.65-1.84 (m, 4H), 1.45 (s, 9H); LCMS ESI+ TIC MS showed 100% purity, [M+H]+=353.1, [MNa]+=375.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:27]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccnc(-n3ccnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K48) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (32 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[C:3]=1[F:20].[Cl:21]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([Cl:21])=[C:6]([CH:8]=[O:9])[N:5]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=2)[C:3]=1[F:20]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Nc1cc(C=O)nc(-c2ccc(C(F)(F)F)nc2)c1F
Solvent: CC#N
Product: Nc1c(F)c(-c2ccc(C(F)(F)F)nc2)nc(C=O)c1Cl
Yield: 147.5 %

Procedure:
Using the procedure for Example 15, 4-amino-3-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridine]-6-carbaldehyde (200 mg, 0.701 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (76 mg, 0.386 mmol) and CH3CN (7 mL) gave 4-amino-5-chloro-3-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridine]-6-carbaldehyde (182 mg, 69.8%) as a yellow solid: mp 147-149° C.; 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 9.34 (d, J=2.0 Hz, 1H), 8.54 (m, 1H), 7.84 (m, 1H), 5.13 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −68.02, −137.62.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]([OH:14])=[O:13].Br[CH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.Br>C(#N)C>[Br-:10].[C:12]([CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:4]1)([OH:14])=[O:13]
Reactant: BrCCc1cccc2ccccc12
Reactant: O=C(O)CBr
Reactant: Clc1nc[nH]c1Cl
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)Cn1c[n+](CCc2cccc3ccccc23)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-bromoacetic acid (2.15 g, 15.46 mmol) was added to the solution and refluxed for 2.5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(2-bromoethyl)naphthalene (1.73 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C@@:11]1([CH2:25][CH3:26])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[O:23][CH3:24])[CH2:12]1)=[O:10].C(N(CC)CC)C.Cl[C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=1>CS(C)=O>[CH2:25]([C@:11]1([C:9]([N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=2)=[O:10])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[C@H:18]([O:23][CH3:24])[CH2:19][O:20][CH2:21][CH2:22]2)[CH2:12]1)[CH3:26]
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3)CC[C@@H](N[C@@H]2CCOC[C@H]2OC)C1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3c2cc(C(F)(F)F)ccn2)CC[C@@H](N[C@H]2CCOC[C@H]2OC)C1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
To a solution of HCl salt of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl((1S,3R)-1-ethyl-3-((3S,4R)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)methanone (118 mg, 0.33 mmol) in DMSO (2 ml) was added triethylamine (0.15 ml, 1.08 mmol) and the 2-chloro-4-(trifluoromethyl)pyridine (183 mg, 1.01 mmol). The reaction was heated to 120° C. for 15 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (40 mg 26%). LC/MS (M+H)=497.2739 exp, 497.2884 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.25-8.24 (1H), 6.75-6.74 (1H), 6.51-6.45 (1H), 5.13-4.76 (2H), 4.10-4.03 (1H), 3.95-3.90 (1H), 3.72-3.16 (11H), 2.82-2.67 (1H), 2.58-2.36 (1H), 2.06-1.36 (12H), 0.86-0.67 (3H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[CH:14][CH:15](O)[S:16][C@H:11]12)=[O:8].P(Br)(Br)[Br:34].C(OCC)(=O)C.O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Br:34])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CC(O)S[C@H]12
Reactant: BrP(Br)Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Br)CS[C@H]12

Procedure:
To a solution of 19 g. (40 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-2-hydroxy-3-cephem-4-carboxylate in 300 ml of dry DMF was added 15 g. (56mmole) of phosphorus tribromide and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and water and the organic phase was separated and washed repeatedly with water and dried over magnesium sulfate. The dried organic phase was evaporated in vacuo to dryness. The crude reaction product residue weighing about 9 g. was purified by chromatography over 500 g. of silica gel using ethyl acetate-hexane (55:45 v:v) as eluent. The eluate was evaporated to dryness under reduced pressure and the product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-bromo-3-cephem-4-carboxylate was obtained crystalline by triturating the dry residue with diethyl ether.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[N+](=[CH2:22])=[N-]>O1CCOCC1>[C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([O:15][CH3:22])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1

Procedure:
N-Carbobenzyloxy-4-hydroxy-L-proline [12.4 g. (0.047 mole)] is esterified with diazomethane in dioxane-ether as described in JACS, 79, 191 (1957). To avoid freezing of the dioxane the addition of the diazomethane solution is begun at 10° and completed at 0°-2°. The yield of nearly colorless viscous oil is 14.6 g. (100%).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]([CH3:11])[C:8]([NH2:10])=[NH:9].C[O-].[Na+].C([O:17][C:18](=O)[CH2:19][C:20](OCC)=[O:21])C>CO>[CH3:6][N:7]([CH3:11])[C:8]1[N:10]=[C:18]([OH:17])[CH:19]=[C:20]([OH:21])[N:9]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(C)C(=N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CN(C)c1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
136 g (0.5 mol) of N,N-dimethylguanidine sulphate were added to a solution of 162 g (3 mol) of sodium methylate in 1 l of methanol at 0° to 5° C. 160 g (1 mol) of malonic acid diethyl ester were then allowed to run in without cooling and the mixture was stirred for 24 hours at room temperature. The solvent was then distilled off in vacuo and the residue was dissolved in water. The solution was brought to approximately pH 5 by adding glacial acetic acid; it was then cooled to 0°-5° C and the product which had precipitated was filtered off. 75 g (48% of theory) of 2-dimethylamino-4,6-dihydroxypyrimidine were thus obtained in the form of a colorless powder of melting point > 300° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[F:10][C:11]([F:40])([C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:40][C:11]([F:10])([C:30]([F:38])([F:39])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])=[CH:27][CH:28]=2)=[N:19][CH:18]=1
Reactant: C=CCCCCCCBr
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCCCCCCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 8-bromo-1-octene (1.00 g, 5.24 mmol), 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (2.54 g, 5.50 mmol) and cesium carbonate (3.40 g, 10.47 mmol) in acetone (40 ml) was heated under reflux for 12 h, cooled to room temperature, washed with water and the organic layer extracted into ethyl acetate/hexane (3 times). The combined organic extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:22][CH2:23][CH3:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:25][C:26]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:27])[CH2:22][CH2:23][CH3:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CCCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl benzoate (700 mg, 2.1 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 39 (150 mg, 19% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.84-0.99 (m, 5H), 1.20-1.38 (br. m, 3H), 1.41-1.51 (m, 2H), 1.70-1.73 (m, 2H), 1.84-1.89 (m, 4H), 2.11 (tt, J=12, 3.2 Hz, 1H), 2.82-2.91 (m, 2H), 6.61 (t, J=5.6 Hz, 1H), 7.52-7.58 (m, 3H), 7.47 (t, J=6.0 Hz, 1H), 7.95-7.97 (m, 2H), 12.04 (s, 1H). MS (ESI) m/z 400.15 (M+Na)+; 376.16 (M−H)−.