Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[C:29]([N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=2)[C:33]1=[O:37])(=[O:31])[CH3:30]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 77.6 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.17 g) described in Preparation Example 254 and 1-acetylimidazolidin-2-one (0.38 g) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.00 g) was obtained.
Reaction SMILES: [CH2:1]([CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.[OH-].[Li+]>>[CH2:1]([CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCc2[nH]c(C(=O)OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCC1CCc2[nH]c(C(=O)O)cc21
Yield: 78.7 %

Procedure:
The title compound was synthesized from methyl 4-propyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (95 mg, 0.46 mmol) and lithium hydroxide monohydrate (77 mg, 1.83 mmol) according to General Procedure 7. The crude product was dried onto Silica gel and was purified by flash chromatography (0-80% EtOAc/Heptane) to give 70 mg of 4-propyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (7) as a light yellow solid (79%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.96 (t, J=7.03 Hz, 3H), 1.36-1.56 (m, 4H), 1.92-2.03 (m, 1H), 2.52-2.76 (m, 3H), 2.87-2.96 (m, 1H), 6.61 (s, 1H); LCMS-MS (ESI−) 192.2 (M−H); HPLC (UV=100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][C@@H:22]([CH2:32]O)[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:54]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][C@@H:22]([CH2:32][Cl:54])[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c3c(cc(OCc4ccccc4)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2c3c(cc(OCc4ccccc4)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3CCl
Reaction time: 2 h
Yield: 91.4 %

Procedure:
256.5 mg (0.57 mmole) of methyl (1S)-5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate and 297.4. mg (1.13 mmole) of triphenylphosphine were dissolved in 6 ml of anhydrous dichloromethane, 0.33 ml (3.40 mmole) of carbon tetrachloride was added to the resulting solution, and the resulting mixture was stirred under argon atmosphere in the dark for 2 hours. The solvent was evaporated from the reaction mixture to give a residue, which was then purified by silica gel column chromatography using an eluate of hexane:ethyl acetate (4:1), followed by crystallization from hexane to give 245.3 mg of methyl (1S)-5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate. Yield, 92%. NMR (CDCl3) δ: 1.58 (9H, s), 3.56 (1H, t, J=9.8 Hz), 3.88-3.97 (2H, m), 3.93 (3H, s), 4.09 (1H, m), 4.19 (1H, m), 5.22 (2H, s), 7.08 (1H, d, J=2.0 Hz), 7.39-7.50 (5H, m), 7.81 (1H, brs), 9.03 (1H, s). [α]D25 =-29.3° (c 0.18, methanol).
Reaction SMILES: O.[NH2:2][NH2:3].[NH:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O>CO>[NH:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([NH:2][NH2:3])=[O:11]
Reactant: COC(=O)c1ccc[nH]1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc[nH]1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
Hydrazine monohydrate (31.0 g, 620 mmol) was added to a mixture of methyl 1H-pyrrole-2-carboxylate (10 g, 77.5 mmol) and methanol (100 ml) followed by stirring at 65° C. for 15 h. The mixture was evaporated and the product was isolated as a crystalline solid.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.[C:38]([NH:46][C@H:47]([C:52](O)=[O:53])[CH2:48][CH:49]([CH3:51])[CH3:50])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:38]([NH:46][C@H:47]([C:52]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:53])[CH2:48][CH:49]([CH3:50])[CH3:51])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: NCC1CCCN1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)NCC1CCCN1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
EDCl (23 mg), HOBt (16.2 mg) and triethylamine (15.2 μL) were added to a chloroform (1 mL) solution of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoylleucine (0.12 mL), and the resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), washed with a 2 M aqueous solution of NaOH (0.75 mL×2), filtered through a PTFE membrane, thereby dried and concentrated to provide 2-[(N-benzoylleucyl)aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 344) (74 mg, quantitative). The purity was determined by RPLC/MS (85%). ESI/MS m/e 442 (M++H, C23H32ClN3O2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:18][CH2:19][CH:20]1[O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH:20]3[O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]3)[CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN1CC(CCCl)OC1=O
Reactant: COc1ccc(N2CCNCC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCO
Product: COc1ccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)cc1OC
Yield: 42 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.3 g (0.015 mol) of 1-(3,4-dimethoxyphenyl)piperazine, 2.5 g (0.015 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 5.3 g (0.05 mol) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 mL of 1-butanol gave 2.2 g (42%) of white solid, mp 90°-92° C. (2-propanol).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([CH2:30][C:31]3[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=3)[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([CH2:30][C:31]3[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:33][CH:32]=3)[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C#N)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)Nc3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of methyl [4-({{4-[(4-butylphenyl)ethynyl]benzyl}[(4-cyanoanilino)-carbonyl]amino}methyl)phenoxy]acetate (65 mg) in MeOH/THF (2 ml, (1/1)) was added an aqueous solution of NaOH (2 mL, 1N). The reaction mixture was stirred at rt for 3 hrs. Then an aqueous solution of HCl (7 mL, 1N) was added and extracted with. Et2O (2×7 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure to give 48 mg of the title compound as a yellow powder. HPLC, Rt: 5.2 min (purity: 75.0%). LC/MS, M+(ESI): 572.4, M−(ESI): 570.4. 1H NMR (DMSO-d6) δ: 7.70 (m, 5H), 7.51 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.28-7.16 (m, 6h), 6.89 (d, J=8.7 Hz, 2H), 4.64 (s, 2H), 4.56 (s, 2H), 4.51 (s, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.55 (m, 2H), 1.28 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[NH2:13]N.O.NN>>[NH2:13][CH:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)=NC1CCCC=21
Reactant: NN
Solvent: O
Product: NC1CCC2N=c3ccccc3=C12

Procedure:
In Scheme 1, Step C, the phthalimide group of the tetrahydrocyclopenta[b]indole of formula (2) is cleaved with hydrazine or hydrazine hydrate to provide an aminotetrahydrocyclopenta[b]indole of formula (3) using conditions as described by M. Alajarín, et al (Eur. J. Org. Chem. 2002, 4222-4227). The reaction proceeds in a solvent mixture of tetrahydrofuran/ethanol in a ratio of about 5.5/1 by volume at a temperature of 0 to 50° C., preferably at about room temperature, for 4 to 72 hours. The resulting phthalhydrazide is removed by filtration and the product isolated by concentration of the filtrate. It may be purified by chromatography using techniques known in the art.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=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.[CH2:44]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[C:59](=[O:73])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=2)[N:65]=1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH2:44]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH2:56][CH:55]1[C:59](=[O:73])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:67]=[CH:68][C:69]([NH:72][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[CH:70][CH:71]=2)[N:65]=1)=[O:53])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-Chlorobenzoic acid (0.017 g, 0.11 mmol), HATU (0.042 g, 0.11 mmol), and DIEA 0.09 mL, 0.67 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. (S)-2-[4-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (FW=422.5096 , 0.029 g, 0.054 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered to afford the crude product. The mixture was filtered and separated by reverse phase HPLC (20-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1 TFA). The combined fraction was evaporated to dryness to furnish the desired product. MS: 562.1(M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[NH:40]1[CH:39]=[C:38]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:42]=[N:41]1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc(-c3cn[nH]c3)c2)cn1)N1CCN(C2CCOCC2)C1=O
Temperature: 80 °C
Yield: 49.6 %

Procedure:
A mixture of Example C1 (0.15 g, 0.359 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.077 g, 0.395 mmol), and K2CO3 (0.198 g, 1.436 mmol) in 4:1 dioxane/water (5 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.041 g, 0.036 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, allowed to stand at RT and the resulting solid collected via filtration to afford N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (80 mg, 48%). 1H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1 H), 10.96 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.32 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 8.02 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.32 (d, J=2.4 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 3.91-3.80 (m, 5 H), 3.40 (m, 4 H), 1.71 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 450.2 (M+H+).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH3:28])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[ClH:20].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH3:28])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 152.1 %

Procedure:
7-{2-(2-Formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid (anti isomer, 0.4 g.) was suspended in methanol (15 ml.). Conc. hydrochloric acid (0.16 g.) was added to the suspension and the mixture was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with a mixed solvent of methanol and diethyl ether (1:1), and dried to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid hydrochloride (anti isomer, 0.31 g.), m.p. above than 250° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:18]
Reactant: N#Cc1ccccc1F
Reactant: Oc1cnc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1Oc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
After 0.27 g of 3-hydroxyquinoline was dissolved in N-methyl-2-pyrrolidone, 0.087 g of sodium hydride (60% oil dispersion) was added under ice-cooling, and the mixture was stirred for 30 minutes. At the same temperature, 0.27 g of 2-fluorobenzonitrile was added and then the mixture was stirred for 6 hours at room temperature. After the reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with saturated saline solution, the resultant was dried with magnesium sulfate. After the solvent was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain 0.37 g of 3-(2-cyanophenoxy)quinoline (Compound Number 62).
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@:14]3([CH3:38])[C@@H:23]2[CH2:22][CH2:21][C@H:20]2[C@@:15]3([CH3:37])[CH2:16][CH2:17][C@@:18]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:19]32)[C:10]1([CH3:40])[CH3:39]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:2]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@:14]3([CH3:38])[C@@H:23]2[CH2:22][CH2:21][C@H:20]2[C@@:15]3([CH3:37])[CH2:16][CH2:17][C@@:18]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:19]32)[C:10]1([CH3:40])[CH3:39])(=[O:3])[CH3:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 59.8 %

Procedure:
Ac2O (about 0.93 ml, 9.87 mmol) was added to a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (Betulinic acid, about 0.3 g, 0.657 mmol) and DMAP (about 0.167 g, 1.32 mmol) in pyridine (about 15 ml) at about 0° C. then the reaction mixture was slowly warmed to room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture poured in to ice water and extracted with EtOAc and washed with water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 10% EtOAc in hexane) to afford title compound as a off white solid. Wt: 0.196 g; Yield: 59.8%; 1H NMR (300 MHZ, CDCl3): δ 4.74 (s, 1H), 4.61 (s, 1H), 4.50-4.44 (m, 1H), 3.02-2.97 (m, 1H), 3.01-2.12 (m, 2H), 2.04 (s, 3H), 1.99-1.92 (m, 2H), 1.69 (s, 3H), 1.68-1.57 (m, 6H), 1.56-1.32 (m, 10H), 1.31-1.01 (m, 5H), 0.97, 0.93 (2s, 6H), 0.85 (Brs, 9H); Mass: [M−1] 497 (100%); IR (KBr, cm−1): 3296, 2945, 1736, 1694, 1464, 1368, 1247, 1196, 1161, 1024, 980, 884, 777, 543; M.R: 283.7° C.-290.1° C.; HPLC: 97.17%.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C@H:8]([C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C@H:8]([C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][CH3:27])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH2:9][O:10][CH3:30])=[CH:4][CH:3]=1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](CO)OCc3ccc(Br)cc3)CC2)nc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](COC)OCc3ccc(Br)cc3)CC2)nc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.), stirred solution of the product of step F (0.70 g, 1.52 mmol) in THF (6 mL) was added NaHMDS (1.6 mL of 1.0 M solution in THF, 1.60 mmol) dropwise. Upon stirring at −78° C. for 15 min the mixture was warmed to 0° C. when MeI (0.43 g, 3.04 mmol) was added. The cold bath was removed and the mixture was stirred at RT for 3 h before being quenched with a saturated aqueous solution of NH4Cl. The solution was extracted with Et2O (×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 5:1 hexane:ethyl acetate) to yield the title compound. MS (ESI) m/z 474/476 [M+H]+.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:28][CH2:27][CH2:26][S:25]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:8]2([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=3)[S:28][CH2:27][CH2:26][S:25]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCCC2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C2(C3CCCCCC3)SCCS2)c1

Procedure:
Compound 12 was prepared from Compound 8 using the same procedure as described above for Compound 9. Yield 3.60 g (79.2%) as an oil. Rf=0.56 (hexane:ethyl acetate 92:8); IR (neat) 2925, 1206, 1067, 832, 693 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.32 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.31–3.10 (m, 4H), 2.40–2.32 (m, 1H), 1.96–1.30 (m, 12H). 13C NMR δ 160.38, 148.94, 106.52, 98.48, 81.99, 70.21, 55.60, 51.27, 45.22, 39.34, 32.82, 29.80, 28.04, 27.77; MS: (ESI, Pos.) m/z 361 ([M+23]+).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16]([NH2:18])=[CH:15][C:14]([CH3:19])=[N:13][C:12]=3[S:11][C:10]=2[CH2:20][CH3:21])[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:18][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]3[S:11][C:10]([CH2:20][CH3:21])=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:22])[CH3:1])[CH:4]=4)[C:17]=23)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCc1sc2nc(C)cc(N)c2c1-c1cccc(N(C)C)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc2nc(C)cc(NS(=O)(=O)c3ccc(Cl)cc3)c2c1-c1cccc(N(C)C)c1

Procedure:
Following general method outlined in Example 1, starting from 3-[3-(dimethylamino)phenyl]-2-ethyl-6-methylthieno[2,3-b]pyridin-4-amine (60 mg, 0.193 mmol) (Description 29) and 4-chlorobenzenesulfonyl chloride (81 mg, 0.385 mmol), the title compound (7.1 mg) was isolated as a TFA salt. LCMS (B) m/z: 486 [M+1]+, Rt 3.03 min.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1
Reactant: O=c1c2ccccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CN(C)CCNc1ccc([N+](=O)[O-])c2sc3ccccc3c(=O)c12
Yield: 85.6 %

Procedure:
A solution of 9.3 g (0.105 mole) of N,N-dimethylethylenediamine in 35 ml of xylene was added dropwise over ten minutes to a stirred mixture of 1-chloro-4-nitrothioxanthone (24.5 g, 0.084 mole) and K2CO3 (12.2 g, 0.088 mole) in 350 ml of xylene. The mixture was heated for one hour at 70°, an additional 1.8 g (0.088 mole) of N,N-dimethylethylendiamine was added, and heating was continued for an additional hour. The mixture was cooled and the solid was collected, washed with cold xylene, petroleum ether, dried, triturated with water, and dried in vacuo at 70° to give the product (24.7 g) as a yellow solid, mp 177°-179°.