Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: O=C1COc2ccc(O)cc2N1
Product: COc1cc2c(Oc3ccc4c(c3)NC(=O)CO4)ncnc2cc1OCCCN1CCCC1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 9), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (170 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.CC1C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-9H-purine (A-1) (1.29 mol, 1 eq) and anhydrous TsOH (0.02 mol, 0.015 eq) in ethyl acetate (1000 mL), 3,4-dihydro-2H-pyran (1.94 mol, 1.5 eq) is added and the resulting mixture is stirred at reflux for 2 h. The reaction mixture is allowed to cool to RT, aqueous Na2CO3 solution (3%, 500 mL) is added and the resulting mixture is stirred for 10 min. The organic layer is separated, washed with water (2×500 mL) and brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate is concentrated in vacuo. The product is dissolved in ethyl acetate (50 mL), and then n-heptane (500 mL) is added. The resulting mixture is stirred at RT for 1 h. The precipitate is collected by filtration, rinsed with heptane (100 mL) and dried in vacuo to afford the product, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (A-2).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ccc(C)cc1
Product: Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)cc1
Yield: 89 %

Procedure:
According to the method described in example S76a, (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate was reacted with p-ethynyltoluene to give the title compound as a black oil (55 mg, 89%). MS ESI 497.3 [M+H]+, calcd for [C26H28N2O4S2+H]+ 497.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1I
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1I
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To 3-chloro-5-iodo-4-methoxybenzoic acid (2.74 g), toluene (27 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.76 mL) were added to the solution, and then the mixture was stirred at 60° C. for 15 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (3.05 g) as a yellow solid.
Reaction SMILES: Cl.[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:31]CC2C=CC=CC=2)=[C:26]([NH:28][CH:29]=[O:30])[CH:27]=1)[OH:21].CO.C(Cl)(Cl)[Cl:42]>CO.[Pd]>[ClH:42].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([NH:28][CH:29]=[O:30])[CH:27]=1)[OH:21]
Reactant: O=CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 22 (in a solution of 40 mg of the compound in 5.8 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (27 mg), whereby the above-identified compound (28.1 mg) was obtained. Rf=0.08 (methanol/chloroform of 1/10).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:4][C:3]=1[O:19][CH3:20].Cl[CH2:22][C:23]1[N:24]=[C:25](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:26][C:27]=1C>>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:6]=[CH:7][C:2]=1[O:1][CH2:22][C:23]1[N:24]=[C:25](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:26][CH:27]=1
Reactant: Cc1oc(/C=C/c2ccccc2)nc1CCl
Reactant: COc1cc(CCCCC2OC(=O)NC2=O)ccc1O
Product: COc1cc(CCCCC2OC(=O)NC2=O)ccc1OCc1coc(/C=C/c2ccccc2)n1

Procedure:
In substantially the same manner as in Working Example 9, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-[(E)-styryl]oxazole to obtain 5-[4-[3-methoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.171-172° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)(=O)=O.[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:18][CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC(CF)C1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (12.5 g, 47 mmol) and 235 mL tetrabutylammonium fluoride (1M solution in THF, 5 equiv.) was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and excess THF was removed on a rotary evaporator. The residue was dissolved in ethyl acetate. The organic phase was washed with sat'd aqueous NaHCO3, washed with water, washed with brine, dried over Na2SO4, filtered and concentrated on a rotary evaporator to give the crude product. This crude product was purified by silica gel chromatography to afford tert-butyl 3-(fluoromethyl)azetidine-1-carboxylate as clear oil (7.5 g). 1H NMR (DMSO-d6): δ 4.52 (dd, 2H), 3.89 (br, 2H), 3.61 (br, 2H), 2.92-2.77 (m, 1H), 1.36 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>N1CCCCC1.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C:26]([C:21]4[N:20]=[CH:25][CH:24]=[CH:23][N:22]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2c(CF)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 66 °C

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (49 mg, 0.12 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (11.5 mg, 0.01 mmol), copper(I) iodide (1.9 mg, 0.01 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (39 mg, 0.25 mmol). The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was re-suspended in acetonitrile (1 mL), whereupon a brown solid precipitated and was collected by filtration to furnish the title compound as a brown solid: 1H NMR (500 MHz, METHANOL-d4) delta 1.99 (3H, s), 5.75 (2H, d, J=47.92 Hz), 7.23 (1H, d, J=5.36 Hz), 7.42 (1H, dd, J=8.28, 1.02 Hz), 7.48 (1H, t, J=4.89 Hz), 7.85 (1H, d, J=8.20 Hz), 8.25 (1H, d, J=4.73 Hz), 8.88 (2H, d, J=4.89 Hz), 9.06 (1H, s); LC-MS: m/z=+390.05 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[SH:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([S:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[N:7]2
Reactant: Clc1ccc2nccn2n1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Sc1ccc2nccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), methyl 2-mercaptobenzoate (1.788 mL, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at 70° C. for 18 hr. To the reaction mixture was added methyl 2-mercaptobenzoate (0.963 mL, 7.0 mmol), and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=90/10→20/80) and precipitated from diisopropyl ether to give the title compound (663 mg, 2.3 mmol, yield 23%) as a white solid.
Reaction SMILES: CO.[Na].[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][NH2:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18](Cl)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[NH:10][CH2:9][C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: NCc1ncc[nH]1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Agent: [Na]
Solvent: CO
Solvent: CC#N
Product: O=c1cnn(-c2ccc(C(NCc3ncc[nH]3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Yield: 16.5 %

Procedure:
Methanol (100 ml) was stirred at RT and sodium (0.09 mol) was added. The mixture was stirred until complete dissolution. (1H-imidazol-2-yl)methanamine (0.045 mol) was added. The mixture was stirred for 30 minutes. NaCl was removed by filtration and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator. 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and acetonitrile (50 ml) were added. The resulting reaction mixture was stirred and refluxed for 20 hours. The solvent was evaporated, the residue was stirred in water, and extracted with CH2Cl2/CH3OH (90/10). The separated organic layer was dried, filtered, and the solvent evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was stirred in CH3CN, filtered off, washed with DIPE, then dried, yielding 1.1 g (16.5%) of (±)-2-[3-chloro-4-[(4-chlorophenyl)[(1H-imidazol-2-ylmethyl)amino]methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 50).
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C(Cl)Cl>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2](=[O:3])[NH:1][CH:4]([CH3:6])[CH3:5])=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)N=C=O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC(=O)NC(C)C)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-Isocyanatopropane (Aldrich, Cat. #141070) (22 mg, 0.25 mmol) was added to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (50 mg, 0.2 mmol) and triethylamine (26 mg, 0.25 mmol) in methylene chloride (2 mL). The reaction was stirred for 1 h. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product, (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(isopropylcarbamoyloxy)phenyl)propanoate (50 mg, 80%) as a white solid. Analytical LCMS (M+H-Boc)+: m/z=281.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH:13]C(OCC2C=CC=CC=2)=O)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO.[ClH:26].CCOCC>[Pd]>[ClH:26].[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH2:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(NNC(=O)OCc1ccccc1)Nc1ccc(O)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NNC(=O)Nc1ccc(O)c(O)c1

Procedure:
A solution of 5.03 g (15.85 mmol) of 2-[[(3,4-dihydroxyphenyl)amino]carbonyl]hydrazinecarboxylic acid, phenylmethyl ester in 250 ml of methanol containing 2.64 ml (31.70 mmol) of hydrochloric acid was hydrogenated in the presence of 0.5 g of 10% palladium on charcoal for 5 minutes. The catalyst was filtered off and the solvent was distilled off in vacuo to leave a solid which was stirred with a few ml of dry ether; yield after drying in vacuo: 3.36 g; melting point 170°-180° C., dec.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[C:23]([C:29]#[N:30])=[CH:24][CH:25]=[CH:26][C:27]=2[F:28])[CH:21]=1>>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([C:29]#[N:30])[C:22]=1[C:20]1[CH:21]=[C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)[CH:17]=[CH:18][C:19]=1[F:31]
Reactant: N#Cc1cccc(F)c1-c1cc(Br)ccc1F
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Product: N#Cc1cccc(F)c1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 31.2 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 5′-bromo-6,2′-difluorobiphenyl-2-carbonitrile (221 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 6,2′-difluoro-5′-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)-biphenyl-2-carbonitrile (65 mg, 31%) as a white solid: δH (360 MHz, CDCl3) 6.99 (1H, dd, J 7 and 6), 7.41-7.51 (2H, m), 7.54-7.60 (1H, m), 7.62-7.69 (3H, m), 7.87 (1H, s), 8.33 (1H, d, J 7); m/z (ES+) 418 (100%, [MH]+).
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[CH2:65][CH2:64][N:63]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[CH2:65][CH2:64][N:63]([C:66]([O:68][CH2:69][C:70]5[CH:71]=[CH:72][C:73]([N+:76]([O-:78])=[O:77])=[CH:74][CH:75]=5)=[O:67])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 76.7 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (255 mg, 0.45 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (240 mg, 0.45 mmol, compound of Reference Example 5) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (297 mg, yield: 78.6%).
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][NH:1]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccc2c1CCCN2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Oc2cccc3c2CCCN3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a solution of 0.15 g (1.01 mmol) 1,2,3,4-tetrahydro-quinolin-5-ol in 10 ml dichloromethane were added 0.17 g (1.40 mmol) phenylboronic acid, 0.25 g (1.36 mmol) copper(II) acetate, a spatula end of 4 Å molecular sieves and 0.57 ml (4.52 mmol) triethylamine. The reaction mixture was stirred at room temperature for 72 h and then filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 34 mg (17%) of the title compound as a pink oil. MS (ISP): 226.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCCCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCCc1ccccc1
Yield: 52.4 %

Procedure:
By the method of part A of Example 1 N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) was condensed with 3-phenylpropylamine (2.7 g.) and the product was purified by high pressure liquid chromatography on silica gel using hexaneethyl acetate (7:3) as the eluant, affording 1-(tert-butyloxycarbonyl)-N-(3-phenylpropyl)-L-prolinamide (3.48 g.).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:5][CH2:6][NH:7][C@@H:8]1[C@@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:25][CH3:26])[CH2:23][CH3:24].[OH-].[Na+]>CO>[C:20]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([O:18][CH3:19])[C@@H:8]([NH:7][CH2:6][CH2:5][C@H:4]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:3]([OH:34])=[O:2])[C:9]2([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:13]=1)(=[O:22])[NH2:21]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a solution of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid methyl ester (12.0 g, 25.4 mmol) in methanol was added 5.0 M NaOH (25 mL) and the reaction mixture was heated at 30° C. for 8 h and then at 25° C. overnight. Most of the methanol solvent was removed by rotary evaporation at 25° C., water (100 mL) and isopropyl acetate (100 mL) was added and the resulting mixture was stirred for 15 min. The bottom two of three layers were extracted with isopropyl acetate (100 mL). Bottom layers were cooled to −5° C. and MeTHF (200 mL) was added and then concentrated HCl (˜15 mL) was added in portions until pH ˜2. Phases were separated, water layer was washed with MeTHF (100 mL) and combined organic layers were dried with Na2SO4. Most of the organic solvent was removed by rotary evaporation, ethyl acetate (200 mL) was added and the volume was reduced to 50 mL. Ethyl acetate (200 mL) was added and the resulting slurry was stirred/triturated at RT for 3 h. Product was filtered under nitrogen and dried under vacuum for 48 h to yield the hydrochloride salt of the title compound (11 g, 98.2% purity) as a white solid. 1H NMR (DMSO-d6): δ(ppm) 0.54 (t, 3H), 0.63 (t, 3H), 0.82 (m, 2H), 1.05-1.3 (m, 6H), 1.45 (m, 1H), 1.55-2.0 (m, 10H), 2.40 (m, 1H), 2.67 (dd, 1H), 3.06 (m, 1H), 3.22 (m, 1H), 3.30 (dd, 1H), 3.41 (s, 3H), 3.45 (dd, 1H), 4.05 (m, 1H), 7.19 (d, 1H), 7.50 (br, 1H), 7.69 (d, 1 h), 7.70 (s, 1H), 7.95 (br, 2H), 9.26 (br, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18]CC)=O)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:22]>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([NH2:22])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)on1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc(C(N)=O)no2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 5-(4-tert-butylphenyl)-3-isoxazolecarboxylate (25 grams) was mixed with 1 liter of concentrated ammonium hydroxide, and the reaction mixture stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into 1 liter of water. The product precipitated and was separated by filtration, yield, 34 grams. The structure of the product was confirmed by NMR.