Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:58][CH2:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:59])[CH3:52])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CN(C)CCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCCCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 30 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (210 mg, 0.58 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (242 mg, 0.63 mmol) and 4-dimethylaminobutyl amine (139 mg, 1.2 mmol); (67 mg, 30% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.4 (m, 2H), 3.3–3.6 (m, 4H), 2.3 (s, 6H), ES-MS (m/z) 377 [M+1]+.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[CH2:7][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCCCN
Product: CCCCNCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional 1 hour. At the end of this period, the excess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 17.0 g (90.9 percent) of N-butylglycine tert-butyl ester, B.P. 76°C/4 mmHg.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:21]1([SH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(N(CC)CC)C.O1CCOCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH2:17][CH:16]([S:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: SC1CCCCC1
Reactant: CC(=O)Oc1cc(N2C(=O)CCC2=O)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(N2C(=O)CC(SC3CCCCC3)C2=O)ccc1C(=O)O
Reaction time: 4 h

Procedure:
8.24 g. (0.03 mole) of 1-(3-acetoxy-4-carboxyphenyl)-pyrroline-2,5-dione are dissolved in 80 ml. of dioxane and 3.6 ml. (0.03 mole) of cyclohexane-thiol are added. Two drops of triethylamine catalyst are then added dropwise to the reaction mixture and the mixture is kept at 80°-90° C. for 4 hours. The solvent is distilled off in vacuo. As a residue an oily 1-(3-acetoxy-4-carboxy-phenyl)-3-cyclohexylthio-pyrrolidine-2,5-dione is obtained. The product is dissolved in a mixture of 30 ml. of glacial acetic acid and 30 ml. of acetic anhydride and under cooling with icy water and stirring 14.4 ml. (0.15 mole) of a 30% hydrogen peroxide solution are added dropwise. The cooling is ceased and the reaction mixture is allowed to warm up to 30° C. The mixture is the cooled again with icy water to 0° to 5° C. and stirred at this temperature for 5 hours. The reaction mixture is allowed to stand overnight. The next day the pure solution is poured on ice and the precipitated product is filtered and washed with water to remove acid. M.p.: 155°-158° C. Yield: 6.7 g. (52.9%). After recrystallization from 50% ethanol the product melts at 160°-161° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH2:28])=[O:27])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:52]CC1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH:28][OH:52])=[O:27])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: NC(=O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NO)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a 25° C. solution of 3(S)-N-(tert-butyldiphenylsilyl)oxy-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (35 mg) in 2 mL of THF was added 0.060 mL of 2M tetrabutylammonium fluoride in THF. After 30 minutes, the solution was partitioned between 1 M pH 7 phosphate buffer and ethyl acetate. The aqueous layer was extracted once with ethyl aceate, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with hexane and the resulting solid was collected by filtration to yield 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-N-hydroxy-tetrahydro-2H-1,4-thiazine-3-carboxamide (22 mg). 1H NMR (CDCl3): δ9.69 (bs, 1H), 7.24 (d, 2H, J=8.82 Hz), 7.51 (d, 2H, J=8.46 Hz), 7.05 (t, 4H, J=9.37 Hz), 6.69 (s, 1H), 4.57 (s, 1H), 4.02 (d, 1H, J=12.5 Hz), 3.28-3.12 (m, 2H), 2.50 (d, 1H, J=12.87 Hz), 1.61 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:60][Si:61]([C:64]#[CH:65])([CH3:63])[CH3:62]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:3][C:2]=2[C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH2:9][CH2:10]1)=[O:27])[CH3:24]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(C#C[Si](C)(C)C)c1
Temperature: 120 °C
Yield: 15.6 %

Procedure:
To a solution of N-{3-bromo-4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-phenyl}-2-ethyl-butyramide (66 mg, 0.12 mmol) in DMF (1.5 mL) was added CuI (1.3 mg, 0.01 mmol), triphenylphosphine (73 mg, 0.28 mmol), diethylamine (220 μL, 2.1 mmol), trimethylsilylacetylene (22 μL, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (5.0 mg, 0.01 mmol). This solution was heated in a focused microwave reactor at 120° C. for 5 min, after which the solution was concentrated and purified by reverse phase HPLC to provide N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-trimethylsilanylethynyl-phenyl}-2-ethylbutyramide (10.5 mg, 16%). This compound (18 mg, 0.03 mmol) was dissolved in MeOH and treated with K2CO3 (9.0 mg, 0.06 mmol). After 1 h, the solids were filtered off, the filtrate concentrated, and the product purified by reverse phase HPLC to afford the title compound (10 mg, 63%). MS: 489.4.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:19][N:18]([CH3:20])[C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)=[O:17]
Reactant: CN(C)C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1CCCN1
Yield: 99 %

Procedure:
In 86 ml of ethanol was dissolved 4.3 g of compound (88) and after adding thereto 210 mg of 10% palladium-carbon, the mixture was stirred vigorously for 90 minutes in a hydrogen stream. After filtering off the catalyst, ethanol was distilled off under reduced pressure to provide 2.19 g of crude (S)-N,N-dimethyl-2-pyrrolidinecarboxamide (89).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([Cl:23])=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:26]1([C:29]#[CH:30])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[Cl:23][C:4]1[S:3][C:2]([C:30]#[C:29][CH:26]2[CH2:28][CH2:27]2)=[N:6][C:5]=1[CH2:7][O:8][N:9]=[C:10]([C:17]1[N:21]([CH3:22])[N:20]=[N:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CC1CC1
Reactant: Cn1nnnc1C(=NOCc1nc(Cl)sc1Cl)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1nnnc1C(=NOCc1nc(C#CC2CC2)sc1Cl)c1ccccc1
Reaction time: 0.05 h
Yield: 84.6 %

Procedure:
To a stirred solution of N-[(2,5-dichloro-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.15 g, 0.406 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added Cyclopropylacetylene (0.029 g, 0.447 mmol, 1.1 eq.) followed by N-ethyldiisopropylamine (0.209 g, 1.62 mmol, 4 eq.), Copper Iodide (0.015 g, 0.081 mmol, 0.2 eq.) and Tetrakis(triphenylphosphine)palladium (0.046 g, 0.041 mmol, 0.1 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 180 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[5-chloro-2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.137 g, 71% yield, 78:5 mixture of stereoisomers) as a yellow viscous oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:14]C)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1cccc2c1CC(c1ccccc1)C=C2CN
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NCC1=CC(c2ccccc2)Cc2c(O)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-Aminomethyl-5-methoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (0.5 g, 1.7 mmol), from Step 2, was suspended in 16 mL of methylene chloride and boron tribromide (5.8 mL of a 1 M solution of BBr3 in methylene chloride) was added dropwise while the reaction mixture was being cooled (to -78° C.) in a dry ice/acetone bath. The reaction mixture was warmed to 0° C. and stirred for 0.5 h, then again cooled to -78° C. in a dry ice/acetone bath. Methanol (2.5 mL) was added dropwise to the reaction mixture, which was then allowed to warm to ambient temperature and concentrated in vacuo. Methanol was added to the residue and the solution was reconcentrated. The residue was dissolved in a small amount of methanol and chromatographed on a silica gel column eluted with ethyl acetate:formic acid:water (18:1:1, v/v/v) to give the formic acid salt of 1-aminomethyl-5-hydroxy-3-phenyl-3,4-dihydronaphthalene, m.p. 102°-104° C.; 1H NMR(d 6-DMSO) δ2.68 (dd, 1H), 3.06 (dd, 1H), 3.6-3.8 (m, 1H), 3.77 (s, 2H), 6.1 (m, 1H), 6.77 (d, 1H), 6.83 (d, 1H), 7.04 (t, 1H), 7.15-7.35 (m, 5H), 8.36 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([OH:9])=[O:8].[CH2:25](O)[CH3:26]>C(OCC)(=O)C>[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][CH2:25][CH3:26])=[O:8]
Reactant: CCO
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
3.9 cm3 of thionyl chloride are added to a stirred suspension of 7.9 g of (2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid (Nε-CBZ-D-lysine) in 120 cm3 of anhydrous ethanol cooled to a temperature in the region of −25° C. The mixture is stirred for 3 hours at this temperature and is then allowed to warm to about 20° C. After leaving for 3 days, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 200 cm3 of ethyl acetate and the resulting solution is washed with aqueous sodium carbonate solution and then with aqueous sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)-carbonyl]amino}hexanoate are obtained in the form of a pale yellow oil. (αD20=−11.7±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=3)[CH2:8][N:7]([CH3:19])[C:6]=2[CH:20]=1.[Mn]([O-])([O-])(=O)=[O:22].[Ba+2]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=3)[C:8](=[O:22])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(=O)Nc1cc2c(cn1)CN(C)c1cc(Cl)ccc1-2
Reactant: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cn1)c(=O)n(C)c1cc(Cl)ccc21
Temperature: 45 °C
Yield: 89.3 %

Procedure:
To a stirred solution of N-(8-chloro-6-methyl-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (0.6 g, 1.199 mmol) in DCM (20 mL) at rt was added barium manganate (1.536 g, 5.99 mmol) in three portions and the reaction was heated at 45° C. for 60 h. After the completion of reaction, the reaction mixture was diluted with DCM (70 mL) and passed through diatomaceous earth (Celite®). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH as an eluant) to yield N-(8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (0.4 g, 1.071 mmol, 89% yield) as an off white solid. LC/MS (ESI) m/e 302.1 [(M+H)+, calcd for C15H13ClN3O2 302.1]; LC/MS retention time (method C): tR=1.88 min; HPLC retention time (method A); tR=8.82 min; HPLC retention time (method B): tR=7.99 min; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.24 (s, 1H), 8.92 (s, 1H), 8.26 (d, J=8.80 Hz, 1H), 7.69 (d, J=2.00 Hz, 1H), 7.48 (dd, J=2.00, 8.80 Hz, 1H), 3.68 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:25]3[C:26]([F:28])=[CH:27][C:22]([Br:21])=[CH:23][N:24]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: Fc1cc(Br)cnc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(Br)cc3F)CC2)CC1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
2d (0.22 g, 0.71 mmol), 3-bromo-6-chloro-5-fluoro-pyridine (0.2 g, 0.95 mmol) and diisopropylethylamine (0.2 mL, 1.2 mmol) in 2 mL of DMSO were heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash LC(0 to 30% EtOAc+0.1% triethylamine in hexane) to afford 46a (92 mg, 28% yield): HPLC, LC-MS 457.1 (MH).
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1>O1CCOCC1.O.CCOCC>[CH:11]([C:9]1[CH:10]=[C:5]([CH3:4])[N:6]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([O:16][CH3:17])=[O:15])[N:8]=1)=[O:2]
Reactant: O=[Se]=O
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(C)n1)C(OC)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](Oc1nc(C)cc(C=O)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Selenium dioxide (8.5 g, 76 mmol) is dissolved in a solution of dioxane (238 mL) and water (40 mL) at 55-60° C. To the solution of selenium dioxide, the compound of Example 9 (20 g, 51 mmol) is added and then the reaction mixture is heated at reflux for 10 hr. The reaction mixture is cooled to room temperature, diluted with ether (200 mL) and filtered. The filtrate is concentrated at reduced pressure on a rotary evaporator and then extracted with ethyl acetate (2×100 mL) to yield the crude title compound. MS m/z 406.9 (M+.+1).
Reaction SMILES: Cl[Mg][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].[C:10]([CH:12]1[CH2:14][CH:13]1[C:15](N(OC)C)=[O:16])#[N:11].[Cl-:21].[NH4+]>C(OCC)C.O1CCCC1>[Cl:21][C:3]1[CH:8]=[CH:7][C:6]([C:15]([CH:13]2[CH2:14][CH:12]2[C:10]#[N:11])=[O:16])=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Cl[Mg]c1ccccc1
Agent: [Br-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC1CC1C(=O)c1ccc(Cl)cc1

Procedure:
3.5 ml (3.50 mmol) of a 1N solution of chlorophenylmagnesium bromide in diethyl ether were introduced into 5 ml of THF at RT under argon, a solution of 490 mg (3.18 mmol) of the compound from Example 73A in 5 ml of tetrahydrofuran was added, and the mixture was heated under reflux for 2 h. Saturated aqueous ammonium chloride solution was added, two extractions with diethyl ether were carried out, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. 714 mg of the title compound with a purity of 54% (59% of theory) were obtained and were reacted without further purification.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(=O)([O-])O.[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>O.CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 947 mg of (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylic acid in 180 ml of water was added 7.8 ml of 0.1 N aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 2 hours to form a solution, which was then frozen. The frozen solution was dissolved in 12 ml of dry DMF, mixed with 0.36 ml of iodomethyl pivalate under the atmosphere of argon at −30° C., and stirred for 1.5 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted with 100 ml of ethyl acetate, and washed with 100 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a total volume of 5 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol 10:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 576 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[S:16][CH:17]=[CH:18][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35].O>C(Cl)Cl>[NH:15]1[C:9]2[C:8]3[S:16][CH:17]=[CH:18][C:7]=3[N:6]([C:4]([C:3]3[CH:19]=[CH:20][C:21]([NH:23][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:32]=4[F:31])=[CH:22][C:2]=3[Cl:1])=[O:5])[CH2:12][CH2:11][C:10]=2[CH:13]=[N:14]1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 129.6 %

Procedure:
To an ice bath cooled mixture of 345 mg of 6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride under argon is added 417 μl of triethylamine followed by a solution of 482 mg of 2-fluoro-5-chlorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give 650 mg of the desired product as a solid residue. To a solution of 500 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 1.51 ml of 1N NaOH. The reactants are stirred at room temperature for 18 hours. The reaction mixture is neutralized with 1N HCl and evaporated in vacuo to a residue which is diluted with 50 ml of chloroform and washed with water, brine and dried (Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrte is evaporated in vacuo to a residue which is crystallized from ethyl acetate containing ethyl alcohol. The collected solid is dried to give 215 mg of the desired product as an off white solid, m.p. 282°-288° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[CH3:31][PH:32](=[O:34])[CH3:33]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]2[CH:27]=[CH:26][C:25]([P:32]([CH3:33])([CH3:31])=[O:34])=[CH:24][CH:23]=2)[N:3]=1)[CH3:11]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC(Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[PH](C)=O
Product: CC(Oc1nc(-c2ccc(P(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine, 4-bromophenylboronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 454 (M+H)+.