Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:27](=[O:30])[CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[N:21]=[CH:22][C:23]([CH:27]([OH:30])[CH2:28][CH3:29])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OCc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
In a nitrogen atmosphere at −78° C., 2.71 M n-BuLi/hexane solution (18.8 mL) was dropwise added to a THF solution of 2-(benzyloxy)-5-bromopyridine (12.2 g, 46.2 mmol) synthesized according to the method described in a reference (J. Org. Chem., 1995, Vol. 60, p. 1408), and stirred at −78° C. for 1 hour. At −78° C., propionaldehyde (4.3 mL) was dropwise added, and stirred at −78° C. for 30 minutes and then at room temperature for 3 hours. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried with magnesium sulfate and concentrated. This was purified by silica gel column chromatography to obtain the intended compound (7.15 g, 64%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(C)CC3)cc2)cc1
Yield: 57 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol) and 4-hydroxy-1-methylpiperidine (691 mg, 6.00 mmol) were dissolved in 50 mL of anhydrous tetrahydrofuran. This solution was stirred and triphenylphosphine (1.57 g, 6.00 mmol) and diethylazodicarboxylate (DEAD) (6.00 mmol) were added. The resulting solution was allowed to stir at room temperature for 18 hours. The solvent was removed under reduced pressure and the resulting mixture is flash chromatographed (eluent: 7:3 ethyl acetate:methanol) to give 834 mg of the title compound. Yield: 57%. MS(FD) 488(M+). EA calculated for C29H29NO4S: C, 71.43; H, 5.99; N, 2.87. Found: C, 71.14; H, 5.93; N, 2.61.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[C:24]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[C:24]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=4)=[O:30])[CH:25]=[CH:26][CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of N-(3-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}phenyl)-6-methylpyridine-2-carboxamide (14.6 g, 27.5 mmol), trifluoroacetic anhydride (31 mL) and tetrahydrofuran (300 mL) was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (200 mL) and 4M aqueous sodium hydroxide solution (80 mL) were added to the residue, and the mixture was stirred at 60° C. for 24 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (2.22 g, 22%) as a pale-brown solid.
Reaction SMILES: [OH:1][CH:2]([C:20]1[N:21]=[CH:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]=1[CH3:25])[CH:3]1[C:18](=[O:19])[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][CH3:17])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3>C(O)(=O)C.O>[OH:1][CH:2]([C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25])[CH:3]1[C:18](=[O:19])[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][CH3:17])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCCc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: CC(=O)O
Solvent: O
Product: CCCc1c2n(c3ccccc13)C(=O)C(C(O)c1nc[nH]c1C)CC2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
a solution of 8,9-dihydro-7-[(hydroxy) (5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]-indol-6(7H)-one (1.65 g) in a mixture of acetic acid and water (4:1, 90 ml) was stirred at 60° C. for 4 hours. After evaporation of the solvent, the residue was diluted with as aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crystalline residue was suspended in a mixture of methanol and chloroform and filtered to give one isomer of 8,9-dihydro-7-[(hydroxy) (5-methyl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]indol-6(7H)-one with an upper Rf value in silica gel thin layer chromatography (TLC) (6% methanol-chloroform) (0.27 g), which was designated as the isomer A. The filtrate was evaporated and purified by silica gel column chromatography (6% methanol-methylene chloride). The fractions eluted first contained the isomer A and the fractions eluted later contained another isomer of 8,9-dihydro-7-[(hydroxy) (5methyl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]indol-6(7H)-one with a lower Rf value in TLC, which was designated as the isomer B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]2[CH2:28][CH2:29][NH:30][C:11]([C:8]1[CH:7]=[C:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: Cn1cc(CCN)c2cc(Cl)ccc21
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(CCNC(=O)c2cc(Cc3cccc(F)c3)on2)c2cc(Cl)ccc21
Yield: 36.8 %

Procedure:
A solution of 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine (0.060 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.039 g (36%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=2)[N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])=[CH:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:8]4=[N:9][CH:10]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:48])=[O:47]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCNCC4)cc3)nc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 2,2-Dimethyl-1-[2-(4-piperazin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.10 g, 0.203 mmol) in dichloromethane was added 0.042 mL of diisopropylethylamine (0.031 g, 0.244 mmol) and the reaction mixture was subsequently cooled to 0° C. Methane sulfonyl chloride (0.019 mL; 0.028 g, 0.244 mmol) was added via syringe and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted 3 times with dichloromethane. Combined organics were dried over MgSO4, filtered and conc in vacuo. Silica gel chromatography (15→65% EtOAc/hexanes over 30 minutes) afforded 0.1014 g (87% yield) of 1-[2-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil. MS (E/I): 572 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]([CH3:18])[CH3:17]
Reactant: Oc1ccccc1Br
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
A mixture of 2-bromophenol (23.2 mL, 0.20 mol), potassium carbonate (33.2 g, 0.24 mol) and 2-bromopropane (28.0 mL, 0.30 mol) in dimethylformamide (200 mL) was stirred in a preheated oil bath (60° C.) for 5 h. The cooled reaction mixture was then partitioned between ether and water. The layers were separated and the aqueous phase was extracted with ether. The combined organic solution was washed with copious amounts of water, 3N aqueous NaOH, dried (MgSO4), filtered and concentrated in vacuo to furnish 39.3 g (91%) of XIV as a pale yellow oil which was carried on without further purification. The structure was supported by GC/MS and 90 MHz 1H NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](Cl)=[O:53])=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:52](=[O:53])[CH2:51][C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Reaction time: 0.5 h

Procedure:
Prepared using General Procedure 7: To a stirring solution of 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (70 mg, 0.12 mmol) in DCM (2 mL) was added TEA (0.042 mL, 0.31 mmol) and 2-(4-methoxyphenyl)acetyl chloride (0.85 mL, 0.171 mmol). Additional TEA (0.042 mL, 0.31 mmol) and 2-(4-methoxyphenyl)acetyl chloride (0.85 mL, 0.171 mmol) were added and the reaction stirred for 30 min to yield 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-5. The crude reaction mixture was concentrated to 1.0 mL volume and carried onto the next step without further purification. LCMS-ESI (m/z) calculated for C43H50N2O8: 722; no m/z observed, tR=3.24 min (Method 3).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:11]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH2:11]1
Reactant: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a Parr hydrogenation bottle was added N-(2-{[(3R)-1-(cis -2-azidocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.745 g, 1.70 mmol), dissolved in methanol (20 mL), followed by the addition of 10% Pd/C (0.15 g). This mixture was hydrogenated at 50 psi for 3 h. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.70 g of N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS (EI) calcd: (M+H)+=413.2; found: 413.3.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[S:11])[S-:10])[CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C.Cl[CH2:20][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>C(#N)C>[OH:26][C:21]1([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][S:11][C:9](=[S:10])[N:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: CC(C)CC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: Cc1cccc(N2C(=S)SCC2(O)CC(C)C)n1
Reaction time: 2 h
Yield: 59.8 %

Procedure:
The procedure of Example 4 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (28.5 g) and 1-chloro-4-methylpentan-2-one (13.4 g) in anhydrous acetonitrile (200 cc) at a temperature between 20 and 25° C. The reaction is continued for 2 hours at 20°-25° C. After recrystallisation of the product from diisopropyl ether (390 cc) and filtration of the boiling solution, there is obtained 4-hydroxy-4-isobutyl-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (16.8 g) melting at 95° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([CH3:22])[CH2:13][O:14]CC2C=CC=CC=2)=[C:4]([C:25]#[N:26])[C:3]=1[CH3:27].[H][H]>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([CH3:22])[CH2:13][OH:14])=[C:4]([C:25]#[N:26])[C:3]=1[CH3:27]
Reactant: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)COCc2ccccc2)c1C#N
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)CO)c1C#N
Yield: 50.3 %

Procedure:
N-(4-Bromo-2-cyano-5-fluoro-6-hydroxy-3-methylphenyl)-2,2-dimethyl-3-[(phenylmethyl)oxy]propionamide (I-105) (5.82 g, 13.37 mmol) was dissolved in ethyl acetate (120 ml), carbon-held palladium catalyst (5% wet, 580 mg) was added, followed by vigorously stirring at room temperature under atmospheric pressure of hydrogen for 18 hours. After the reaction, the insoluble matter was separated by filtration through Celite, the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (2.32 g, 50%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][C:43]([CH3:59])([CH3:58])[C:44]([NH:46][NH:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=1)=[O:45]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][C:43]([C:44](=[O:45])[NH:46][NH:47][C:48](=[O:57])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([CH3:58])[CH3:59])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 36.9 mg (0.121 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride (55 mg) (0.093 mmol) are dissolved in 7 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours a further 18.4 mg (0.060 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are added. After a further 24 hours the solvent is removed at room temperature in a high vacuum and the residue is treated with water. The precipitated product is filtered off, washed well with water and dried at room temperature in a high vacuum. There are obtained 37 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[F:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O>C(#N)C>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][F:13])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: FCCOc1ccc(CCl)cc1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COCc2ccc(OCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
Sodium hydride (0.32 g; 60% in oil) was suspended in 30 ml of dry acetonitrile, and 1.1 g of 4-methoxybenzyl alcohol was added. The mixture was stirred at 50° to 60° C. for 30 minutes. Then, 1.5 g of 4-(2-fluoroethoxy)benzyl chloride was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (50 g) column chromatography (developing solvent: a 9:1 mixture of benzene and ethyl acetate) to give 1.6 g of 4-(2-fluoroethoxy)benzyl 4-methoxybenzyl ether.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=1>[Pd].C(O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc[nH]2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Yield: 99.2 %

Procedure:
A mixture of tert-butyl 4-(1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.5 g) and palladium on carbon (10%, 1 g) in ethanol (150 mL) was hydrogenated at 30 psi overnight. The catalyst was removed by filtration through celite and the filtrate was evaporated to give tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (7.5 g).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH2:12][CH3:13])=[CH:20][CH:19]=2)=[CH:26][CH:25]=1
Reactant: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)O)cc1
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of 4-[1-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-propoxy]-benzoic acid methyl ester (0.048 g, 0.11 mmol) in ethanol (3 mL) is added sodium hydroxide (5.0N, 0.11 mL, 0.54 mmol) and stirred for four hours, acidified with 1.0 N HCl and extracted ethyl acetate three times. Organic layers are dried with sodium sulfate, filtered and concentrated under reduced pressure to provide 0.04 g (0.1 mmol, 89%) of title compound.
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH:5]=1>O1CCCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][CH:13]([OH:14])[CH3:1])[CH:5]=1
Reactant: C[Mg]Br
Reactant: O=CCCCc1cccnc1
Solvent: C1CCOC1
Product: CC(O)CCCc1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of methylmagnesium bromide (0.75 mL of a 3M solution (diethyl ether) in 3.5 mL dry tetrahydrofuran) at 0° C. was added a solution of 4-pyridin-3-yl-butyraldehyde (133 mg in 1 mL tetrahydrofuran) and the mixture at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (71 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])[N:6]=1)=[O:4].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:21])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(-c2cc(F)c(Cl)cc2F)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc(F)c(Cl)cc2F)nc(N)c1Cl
Temperature: 40 °C
Yield: 49.9 %

Procedure:
6-Amino-2-(4-chloro-2,5-difluorophenyl)pyrimidine-4-carboxylic acid methyl ester (0.090 g, 0.3 mmol) and N-chlorosuccinimide (0.05 g, 0.37 mmol) were combined in 10 mL acetonitrile and heated at 40° C. for 18 hours. The reaction mixture was concentrated and the product purified by column chromatography (ethyl acetate/hexane gradient) to yield the title compound as an off-white solid (0.050 g, 50% yield): 1H NMR (CDCl3): δ 7.85 (dd, 1H), 7.22 (dd, 1H), 5.62 (br s, 2H), 4.01 (s, 3H).