Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[CH:10]=O.O.[NH2:13][NH2:14]>>[NH:13]1[C:2]2[C:3](=[CH:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=2)[CH:10]=[N:14]1
Reactant: N#Cc1ccc(F)c(C=O)c1
Reactant: NN
Solvent: O
Product: N#Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
4-Fluoro-3-formylbenzenecarbonitrile (4.6 g, 30.85 mmol) was suspended in 20 mL of hydrazine mono-hydrate and the reaction mixture was stirred at room temperature for 48 hours. The title compound was isolated by filtration as a white solid, was washed with small portions of distilled water, and was dried in a vacuum (3.6 g, 81% yield). The same protocol was used to convert 3.5 g of 4-fluoro-3-formylbenzenecarbonitrile to the title compound and resulted in the isolation of 1.9 g of white solid (80% yield): 1H NMR (CDCl3) δ 10.45 (br s, 1H), 8.20 (d, 1H), 8.19 (d, 1H), 7.6 (s, 1H); ES-MS 250 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[NH:19][CH:18]=2)=[CH:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2]>N.CO.[Pd]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:14]1[CH2:13][CH2:12][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:16][CH2:15]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of compound 118 (0.55 g, 1.427 mmol) in 2 M NH3 in methanol (10 mL) was treated with Pd—C (0.05 g) and flushed with hydrogen gas. The reaction was stirred at room temperature overnight (16 h) under hydrogen atmosphere (balloon pressure). The solution was filtered through a celite bed using methanol washes (2×10 mL). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 2.5:97.5) to obtain compound 119 (0.43 g, 84%) as a solid in 2:3 ratio of diastereomers. 1H NMR (DMSO-d6) δ: 0.99, 1.07 (2t, 3H, J=7.2, 6.6 Hz), 1.37-1.51 (m, 11H), 1.63-1.78 (m, 4H), 2.01-2.18 (m, 2H), 2.98-3.04 (m, 1H), 3.11-3.17 (m, 2H), 3.68-3.80 (m, 1H), 4.52 (brs, 2H), 6.44-6.47 (m, 1H), 6.66-6.70 (m, 1H), 6.86-6.88, 6.99-7.06 (2m, 2H), 10.23, 10.27 (2s, 1H); ESI-MS m/z (%): 380 (M+Na, 6), 358 (MH+, 5), 302 (100), 258 (54); ESI-HRMS calculated for C21H32N3O2 (MH+), Calculated: 358.2507; Observed: 358.2489.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([C:17]#[C:18][CH3:19])[C:11]=1[NH2:20].O.CCOC(C)=O>CN1C(=O)CCC1>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]2[C:11]=1[NH:20][C:18]([CH3:19])=[CH:17]2)=[O:21]
Reactant: CC#Cc1cc(Cl)cc(C(=O)OC)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Cl)cc2cc(C)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a cold (−10° C.) solution of t-BuOK (30 mg, 0.27 mmol) in 4 ml NMP was added a solution of 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (46 mg, 0.21 mmol) in NMP (2 ml). The reaction mixture was slowly warmed to rt and stirring was continued for 1 h. Water and EtOAc were added and organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 5-chloro-2-methyl-1H-indole-7-carboxylic acid methyl ester (25 mg, 54%) as a light yellow solid. MS (ISP) 222.3 (M+H)+.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1COCC1.BrC(Br)C>[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)=[O:13]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: CN1CCC(Cl)CC1
Agent: CC(Br)Br
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cc(I)ccc2F)CC1
Temperature: 70 °C
Yield: 52.6 %

Procedure:
A stirred suspension of Mg turnings (3.82 g, 157 mmol) in dry THF, under N2, was treated with 2-3 drops of dibromoethane, followed by slow addition of freshly-distilled 4-chloro-N-methylpiperidine (7.00 g, 52.4 mmol) in THF. The reaction mixture was heated at 70° C. for 3 h, cooled to room temperature, added to 2-fluoro-5-iodobenzoyl chloride (10.1 g, 35.6 mmol) in THF at −78° C., warmed to room temperature over 1 h and concentrated in vacuo. The resultant residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 concentrated in vacuo. This residue was purified by chromatography (0-10% CH2Cl2 in CH3OH as eluent) to provide the title compound (6.50 g, 53%), characterized by HNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg), 4-fluorophenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH3:45][C:46]1[CH:47]=[C:48]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[C:49](=[O:52])[NH:50][N:51]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:56]2[CH2:57][CH2:58][CH:53]([C:48]3[C:49](=[O:52])[NH:50][N:51]=[C:46]([CH3:45])[CH:47]=3)[CH2:54][CH2:55]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2c(F)cccc2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C2CCNCC2)c(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4c(F)cccc4F)Cn4c(CC(F)(F)F)cnc43)CC2)c(=O)[nH]n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
Triethylamine (22 μL, 0.16 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (15 mg, 0.04 mmol) and 4-nitrophenyl chloroformate (19 mg, 0.043 mmol) in tetrahydrofuran (5 mL) at 0° C. After 30 min, 6-methyl-4-piperidin-4-ylpyridazin-3(2H)-one (15 mg, 0.08 mmol), triethylamine (22 μL, 0.16 mmol) and chloroform (5 mL) were added and the mixture was heated to 50° C. After 30 min, the reaction mixture was allowed to cool to ambient temperature. Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (15 mg). MS 565.2346 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.CCOC(C)=O>C(Cl)Cl.CCCCCCC.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][N:20]3[C:30]3[CH:31]=[C:26]([CH3:25])[CH:27]=[CH:28][CH:29]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CSc1n[nH]c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CSc1nn(-c2cccc(C)c2)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-(3-methylsulfanyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (63 mg, 0.18 mmol) and 3-methyl phenyl boronic acid (50 mg, 0.36 mmol) in CH2Cl2 (1.5 mL) were added TEA (0.051 mL, 0.36 mmol) and Cu(OAc)2 (33 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was loaded onto a silica-gel column and chromatography (gradient eluent heptane to 50% EtOAc in heptane) to yield 4-(3-Methylsulfanyl-1-m-tolyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as colorless film stuck on flask wall.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[CH2:20]=O>C(O)=O>[CH3:20][N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: C=O
Reactant: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Solvent: O=CO
Product: CN(Cc1cccc(Cl)c1)c1ccc(C(=O)O)nc1
Reaction time: 24 h

Procedure:
The mixture of 10 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester, 13 ml of 35% aqueous formaldehyde and 13 ml of formic acid is stirred at the steam bath for one day. It is evaporated, the residue boiled with 100 ml of methanol, until dissolution, the solution filtered hot and the filtrate cooled. The precipitate formed is collected and recrystallized from methanol, to yield the 5-(N-methyl-N-m-chlorobenzylamino)-pyridine-2-carboxylic acid melting at 138°-140°.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:8]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Clc1ccc2scc(CN3CCN(c4ccccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 1-(2-pyridinyl)piperazine were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.15 (m, 2H), 3.49 (m, 6H), 3.75 (s, 2H), 6.61 (dd, 1H, J=7.5, 4.5 Hz), 6.80 (d, 1H, J=8.7 Hz), 7.40 (dd, 1H, J=8.7, 1.5), 7.52 (m, 1H), 7.70 (s, 1H), 8.00 (d, 1H, J=8.7 Hz), 8.08 (m, 2H). MS (DCI/NH3) m/z 344.0 (M+H)+. Anal. Calcd for C18H18N3SCl: C, 62.87;H, 5.28; N, 12.22. Found: C, 62.71;H, 5.23; N, 12.26.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC2CCNCC2)cc1

Procedure:
Starting materials: 1-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.).
Reaction SMILES: Cl[C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:38]1([CH3:47])[CH:43]=[CH:42][CH:41]=[C:40]([C:44](Cl)=[O:45])[CH:39]=1.C(=O)(O)[O-].[Na+].C(Cl)[Cl:54]>>[Cl:54][CH:4]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1)[C:44](=[O:45])[C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH3:47])[CH:39]=1)[C:3]1[CH:20]=[CH:21][C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:23][CH:2]=1
Reactant: ClCCl
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N(c2ccc(OCCN3CCCC3)cc2)C(Cl)c2ccc(OC3CCCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (100 mg, 0.232 mmol) and triethylamine (0.100 mL, 0.696 mmol) in methylene chloride was added to m-toluenecarbonyl chloride (72 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 549.1 (M+1)+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.Cl.C(O[C:22](=N)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.Cl.[OH-].[Na+]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]1[NH:13][C:12]2[CH:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH3:28]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850, mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Reaction SMILES: [C:1]([CH:4]1[N:9](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:8][CH2:7][N:6]([C:23]([C@@H:25]2[CH2:29][C@H:28]([S:30][C:31]3[C@H:32]([CH3:55])[C@@H:33]4[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]4[C:35]=3[C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[CH2:27][N:26]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:24])[CH2:5]1)(=[O:3])[NH2:2].[ClH:69]>O1CCCC1.O>[ClH:69].[C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:23]([C@@H:25]2[CH2:29][C@H:28]([S:30][C:31]3[C@H:32]([CH3:55])[C@@H:33]4[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]4[C:35]=3[C:36]([OH:38])=[O:37])[CH2:27][NH:26]2)=[O:24])[CH2:5]1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C(N)=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C(N)=O)C4)C3)[C@H](C)[C@H]12

Procedure:
2.33 g of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-carbamoyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 25 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 2.7 ml of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 2.33 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 160 mg of the title compound, as a powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]1([S:18]([NH:21][C:22](=[NH:25])SC)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:12]1([S:18]([NH:21][C:22]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])=[NH:25])(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)NS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=N)NS(=O)(=O)c1ccccc1
Yield: 20.4 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.93g.) and N-benzenesulphonyl-S-methylisothiourea (8.0g.) in acetonitrile (100 ml.) was heated under reflux for 24 hours. Concentration, followed by chromatographic purification on a column of silica gel with benzene-methanol (10:1) and recrystallisation from aqueous ethanol and then acetonitrile afforded N-benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.5 g.) m.p. 149°-150°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])#[N:16].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1/[CH:4]=[CH:5]/[CH:6]=[C:17]([C:15]#[N:16])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=CC=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C/C=C/c1cc([N+](=O)[O-])ccc1Cl

Procedure:
15 g (70 millimoles) of 2-chloro-5-nitrocinnamaldehyde (mp. 115°-117° C.) and 10 g (0.1 mole) of methyl cyanoacetate in 200 ml of toluene were heated under a water separator in the presence of 1 g of ammonium acetate and 1 ml of acetic acid until water no longer distilled over. The product crystallized out on cooling. After the usual working up procedure, 58% of the product of melting point 193°-194° C. remained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.[N+:16]([O-])([O-:18])=[O:17].[NH4+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc2c(=O)c(C#N)c[nH]c2c1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2[nH]cc(C#N)c(=O)c2cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a suspension of 10 g (49.6 mmol) of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile in 160 ml of trifluroacetic anhydride was added 6 g (74.9 mmol) of ammonium nitrate over a period of 3 hours. The mixture was stirred an additional two hours. Excess anhydride was removed at reduced pressure at 45° C. The residue was stirred with 500 ml of water. The solid was collected and washed with water. The solid was dissolved in 1000 ml of boiling acetic acid and the solution was treated with decolorizing charcoal. The mixture was filtered and concentrated to a volume of 300 ml. Cooling gave a solid which was collected giving 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-3-quinolinecarbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 246.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cc(C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To 5-trifluoromethyl-2(1H)-pyridone (10.0 g, 61.3 mmol) and sodium acetate (5.25 g, 64 mmol) in acetic acid (100 ml) was added bromine (3.3 ml, 63 mmol) and the solution stirred at 80° C. for 2 hrs. After concentration in vacuo, the residue was suspended in saturated sodium bicarbonate solution (500 ml) and extracted with ethyl acetate (2×50 ml). The extracts were dried (MgSO4) and concentrated to give the product as a tan solid (14.22 g, 58.8 mmol, 96% yield).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product in 99% yield as a white solid: 1H NMR (400 MHz, CDCl3) δ8.05-8.03 (m, 2H), 7.68-7.66 (m, 2H), 7.65-7.63 (m, 2H), 7.47 (t, J=7.6 Hz, 2H), 7.38 (tt, J=7.2 1.6 Hz, 1H), 7.14 (t, J=8.4 Hz, 1H), 6.69 (t, J=2.4 Hz, 1H), 6.61 (dd, J=8.0, 2.8 Hz, 1H), 6.54 (dd, J=7.6, 2.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.37 (s, 3H), 1.56 (s, 6H).