Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[Br:17][C:18]1[CH:19]=[C:20]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH2:25])[CH:21]=[CH:22][CH:23]=1.ClCCl>CN(C)C=O.C1CCCCC1.C(OCC)(=O)C.O>[Br:17][C:18]1[CH:19]=[C:20]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:8][CH2:9][O:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[CH:30][CH:31]=2)=[CH2:25])[CH:21]=[CH:22][CH:23]=1
Reactant: BrCCOC1CCCCO1
Reactant: C=C(c1ccc(O)cc1)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccc(OCCOC2CCCCO2)cc1)c1cccc(Br)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Cesium carbonate (4.36 g, 13.4 mmol, 1.2 eq) and 2-(2-bromoethoxy)-tetrahydro-2H-pyran (1.94 mL, 12.8 mmol, 1.2 eq) were added to a solution of 4-[1-(3-bromo-phenyl)-vinyl]-phenol (2.9 g, 10.7 mmol, 1.0 eq) in dry N,N-dimethylformamide (35 mL). The mixture was stirred overnight at 55° C. Dichloromethane (100 mL) and water (50 mL) were then added. The organic phase was washed with water (3×) and dried over sodium sulfate. Evaporation of solvent and purification by flash chromatography (eluent: cyclohexane/ethyl acetate=9:1 then 8:2) gave 2.0 g of desired product as yellow oil (yield 47%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][CH:8]([O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:13]=1)[CH2:9][CH3:10].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:7][CH:8]([O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH:19][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:14][CH:13]=1)[CH2:9][CH3:10]
Reactant: O=C(Cl)C1CC1
Reactant: CCC(C)Oc1ccc(OCCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Oc1ccc(OCCNC(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
At 5° C., 3.4 g of cyclopropanecarboxylic chloride was dripped into a solution of 6.5 g of 2-[4-(1-methylprop-1-yloxy)-phenoxy]-ethylamine and 3.5 g of triethylamine in 100 ml of absolute methylene chloride. After the mixture had been stirred for 8 hours it was poured onto 200 g of ice/water and the resultant solution was adjusted to a pH of 2 with 2N aqueous hydrochloric acid. The aqueous phase was then extracted twice, each time with 50 ml of methylene chloride, and the combined organic phases were washed with saturated sodium carbonate solution and water, and dried over sodium sulfate. After removal of the solvent under reduced pressure and recrystallization from cyclohexane, there was obtained 6.4 g of N-{2-[4-(1-methylprop-1-yloxy)-phenoxy]-ethyl}-cyclopropanecarboxamide (compound no. 2); m.p.: 65°-68° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH:23]=2)[C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH:23]=2)[C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(CC(C)C)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 87.3 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.035 g, 0.079 mmol) and 1M NaOH (0.788 ml, 0.788 mmol) in MeOH (5 mL) was heated at reflux for 4 h. Then, cooled, neutralized with 1M HCl (0.8 mL), concentrated and the residue was taken up in Et2O (25 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give (S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (0.0303 g, 0.069 mmol, 88% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.99-7.96 (m, 1H), 7.85 (dt, J=7.3, 1.4 Hz, 1H), 7.41-7.33 (m, 2H), 6.82 (s, 1H), 5.41 (s, 1H), 3.75-3.56 (m, 1H), 3.05-2.92 (m, 1H), 2.65 (s, 3H), 2.55 (br. s., 1H), 1.29 (s, 9H), 1.09 (d, J=6.7 Hz, 3H), 1.02 (d, J=6.4 Hz, 3H). LCMS (M+H) calcd for C23H29ClN3O3: 430.19. found: 430.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([Br:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([Br:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
N-[4-(benzyloxy)phenyl]-5-bromo-3-nitropyridin-2-amine (28.5 g, 0.071 mmol) and tin (II) chloride dihydrate (160.67 g, 0.712 mmol) were dissolved in 500 mL ethanol under N2 and the reaction mixture heated at reflux (70° C.) for 30 min. Sodium bicarbonate was then added to the cooled mixture until the pH was greater than 9.5, and then the mixture was filtered through celite which was washed with methanol. The combined organic phases were concentrated in vacuo before being re-constituted in CH2Cl2, drying over Na2SO4, and concentration in vacuo to yield N2-[4-(benzyloxy)phenyl]-5-bromopyridine-2,3-diamine. 1H NMR (400 MHz, CDCl3) δ 3.44 (bs, 2H), 5.07 (s, 2H), 6.02 (bs, 1H), 6.97 (dt, 2H, J=5.6, 3.6 Hz), 7.12 (d, 1H, J=2.0 Hz), 7.32 (dt, 2H, J=4.8, 0.4 Hz), 7.34-7.48 (m, 5H), 7.84 (d, 1H, J=2 Hz); MS (ES+): m/z 371[MH+], 372 (35) [MH2+]
Reaction SMILES: Cl.[Cl:2][C:3]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([N+:14]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].[OH-].[Na+]>>[Cl:2][C:3]1[C:10]([NH2:11])=[CH:9][C:8]([NH2:14])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)cc(N)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 194 gm. (0.86 mole) of stannous chloride dihydrate in 475 ml. of concentrated hydrochloric acid is added 27.5 gm. (0.12 mole) of 2-chloro-3,5-dinitrobenzonitrile. The temperature rises to 84° and a solution occurs. The mixture is allowed to cool to room temperature, placed in an ice-bath, cooled to 0° and a cold 50% sodium hydroxide solution is added, with cooling, until the mixture is strongly basic. The gelatinous precipitate is removed by filtration. The precipitate is washed thoroughly (4 times) with portions of ethyl acetate. The combined ethyl acetate washes are used to extract the aqueous filtrate. The combined ethyl acetate extracts are dried over anhydrous MgSO4 and the solvent removed by distillation. The residue is recrystallized from ethanol. There is obtained 11.30 gm. (56%) of colorless needles melting at 181°-82°.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>C1(C)C=CC=CC=1>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc2[nH]ccc2c1)c1ccccc1

Procedure:
0.307 g (1 mmol) of 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 0.400 mg (3 mmol) of 5-amino-indole are refluxed in 10 ml toluene for 1 hour. The mixture is evaporated down in vacuo and the evaporation residue is distributed between EtOac and water. A viscous oil is obtained from the organic phase after drying, filtering and evaporation in vacuo, and this oil is purified by column chromatography on silica gel with the eluant EtOac/petroleum ether (1:1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:34]3[CH:33]=[N:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a white solid. UPLC-MS (condition 1) tR=2.10 min, m/z=475.2 [M+H]+, m/z=473.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.79 (m, 1H) 1.79-1.92 (m, 1H) 2.91 (d, J=11.25 Hz, 1H) 3.19-3.27 (m, 2H) 3.33-3.47 (m, 1H) 3.89 (s, 3H) 4.16-4.25 (m, 1H) 4.83 (d, J=3.42 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.41 (d, J=1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.21 (d, J=1.47 Hz, 1H) 8.30 (d, J=2.69 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([F:20])[CH:5]=1.[CH:21](OCC)=[O:22].Cl>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[CH:8][C:7]([CH:14]([CH:21]=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([F:20])[CH:5]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1cc(OC(C)C)c(Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)c1cc(OC(C)C)c(Cl)cc1F
Reaction time: 0.5 h

Procedure:
Then, 1.1 g of sodium hydride (60% in oil) was suspended in 50 ml of tetrahydrofuran, and the mixture was cooled to 5° C., to which a solution of 7.2 g of ethyl 4-chloro-2-fluoro-5-isopropoxyphenylacetate in 80 ml of tetrahydrofuran was slowly added dropwise. The mixture was stirred for 30 minutes with a gradual temperature increase to room temperature, to which 10 ml of ethyl formate was added at room temperature, followed by stirring for 3 hours. Then, the reaction mixture was cooled to 5° C., to which diluted hydrochloric acid was added. The reaction mixture was concentrated, and the residue was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 8.0 g of ethyl 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-formylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]2[CH3:37])=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]3[CH3:37])=[N:22][CH:23]=2)=[O:8])=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)c1ccc(Br)c(OC(F)(F)F)c1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(NC(=O)c2ccc(Br)c(OC(F)(F)F)c2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 4-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (150 mg, 0.50 mmol, Preparation 52), (R)-tert-butyl 4-(5-aminopyridin-2-yl)-3-methylpiperazine-1-carboxylate (145 mg, 0.50 mmol), and HATU (235 mg, 0.62 mmol) dissolved in DMF (1 mL) was added DIPEA (0.43 mL, 2.48 mmol). The reaction mixture was stirred at RT for 1 h, extracted with EtOAc (80 mL) washed with water (3×20 mL) and brine (20 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (12 g silica gel, 0-40% EtOAc:hexanes over 20 min), to provide the title intermediate (203 mg, 71% yield) as a yellow solid. (m/z): [M+H]+ calcd for C23H25BrF4N4O4 577.10; 579.10. found 579.0.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([NH:41][C:42]([C:44]2[C:49](=[O:50])[N:48]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[CH:47]=[CH:46][N:45]=2)=[O:43])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:12]=[C:13]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:40]=[C:39]([NH:41][C:42]([C:44]2[C:49](=[O:50])[N:48]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[CH:47]=[CH:46][N:45]=2)=[O:43])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:12]=[C:13]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:6]=12
Reactant: COc1ccc(Cn2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(CC3CCNCC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolved tert-butyl 4-((4-(2-fluoro-4-(4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)piperidine-1-carboxylate (43 mg, 0.055 mmol) in DCM (1 mL) and added excess TFA (d 1.48) (0.100 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed, and the crude was partitioned between DCM (15 mL) and aqueous 10% Na2CO3 (20 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford title compound as free-base. Yield 41 mg, 89% purity by HPLC, 97%. LRMS (APCI pos) m/e 678.3 (M+H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)=O.[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:18]([CH3:17])[C:19](=[O:20])[NH:2][C:3]=2[CH3:16])=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(C(=O)C(C)N)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(-c2c(C)[nH]c(=O)n2C)cc1
Reaction time: 0.67 h

Procedure:
2-Amino-4'-n-butylpropiophenone hydrochloride (5.36 g, 22.2 mmol) was suspended in acetone (180 ml) under ice-cooling, and methyl isocyanate (1.61 g, 28.2 mmol) was added thereto. After addition of triethylamine (4.49 g, 44.5 mmol), the mixture was stirred for 40 minutes under ice-cooling. Trifluoroacetic acid (16 ml) was added thereto, and the mixture was stirred for 5 hours at room temperature. The solvent was removed by evaporation under vacuum, and the residue was taken in dichloromethane. The organic mixture was washed successively with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ ethanol=50/1 (v/v)) and recrystalization (hexane-ethyl acetate) to give the title compound. Yield: 3.85 g (71%), m.p. 180°-180.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([N:28]([CH3:27])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
Under nitrogen atmosphere, oxalyl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and chilled (~10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 75 ml of dimethylformamide. After the addition was complete, the reaction was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (~10° C.) solution of N-methylaniline (2.02 g, 0.019 mole), triethylamine (1.88 g, 0.019 mole), and 74 ml of dimethylformamide. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of water and diluted with water until the cloud point. The mixture was seeded annd refrigerated overnight. The solid was collected by filtration and dried under high vacuum. The solid was suspended in dilute sodium bicarbonate, collected by filtration, washed with water, and dried under high vacuum at 50° C. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum first at 56° C., then at 98° C. for 2 days to give 3.0 g (45.7%) of crystals, mp 170°-171° C.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[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.[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([SH:56])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44].O[C@@H]([C@H]1C(=O)N2C(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=C(S[C@@H]3CN(C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H](C4N(C)C(=O)C4)C3)C[C@H]12)C>>[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([S:56][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[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])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44]
Reactant: NC(=O)C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Agent: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)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](C4CC(C(N)=O)N(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (290 mg, 0.49 mmol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer II (280 mg, 0.49 mmol, compound of Reference Example 14) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer II (419 mg, yield: 93.4%).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[S:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1.C1(C)C=CC=CC=1>O>[Br:2][CH2:6][C:7]1[S:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(CO)s1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(CBr)s1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 261.6 %

Procedure:
Phosphorus tribromide (PBr3) (10.45 g) was added dropwise to a mixture of 2-hydroxymethyl-5-nitrothiophene (17.7 g) and toluene (150 ml) and this mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4), after which the solvent was evaporated off. The residual oil was subjected to solica gel column chromatography and eluted with chloroform to yield 2-bromomethyl-5-nitrothiophene (22.43 g, 92%) as an oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:20][CH2:21][CH2:22][OH:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH2:25][C@H](O)C.CCOC(C)=O.Cl>CN1C(=O)CCC1.O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[C:11]([NH:20][CH2:21][C@H:22]([OH:23])[CH3:25])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(NCCO)nc(SCc2ccccc2)n1
Reactant: C[C@@H](O)CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](O)CNc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1
Temperature: 80 °C

Procedure:
To the subtitle product of Example 19 step (0.20 g) in NMP (2 ml) was added (2R)-1-amino-2-propanol (0.46 g) and the reaction was heated at 80° C. for 6 h. To the reaction was added EtOAc (50 ml) and H2O (20 ml). This solution was acidified with aqueous hydrochloric acid. The organic layer separated and washed with H2O (2×20 ml), brine (20 ml) and the organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a solid. This material was purified by reverse phase HPLC (90% to 5% 0.02 M ammonium hydroxide/acetonitrile) to yield the title compound as a solid. Yield: 20 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])(C)(C)[CH3:2].FC(F)(F)C(O)=O.ClC(OCC)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)C1

Procedure:
(S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected with trifluoroacetic acid according to known procedures. After concentration, the amine trifluoroacetate salt was treated with ethyl chloroformate (1 equiv.) and triethylamine (3 equiv.) in methylene chloride to afford (S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C13H17N3O4 (m/e) 279.3, obsd 280.1 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1>CC(O)CCC>[ClH:2].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:27]([F:32])[CH:26]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCCN1CCCC1
Yield: 44.3 %

Procedure:
Using an analogous procedure to that described for Example 15, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (236 mg, 0.6 mmol), (prepared as described for the starting material in Example 31), was reacted with 4-chloro-2-fluoroaniline (80 μl, 0.72 mmol) in 2-pentanol (5 ml) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (124 mg, 42%).