Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:4][CH:3]=1.[CH3:36][C@@H:37]1[O:39][C@H:38]1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[OH:39][C@@H:38]([CH3:40])[C@H:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:6][CH:7]=1)[CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Reactant: C[C@@H]1O[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O[C@H](C)[C@H](C)O)cc2)c2ccnn12
Yield: 54 %

Procedure:
To a solution of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.92 g) in N,N-dimethylformamide (10 mL) were added trans-2,3-epoxybutane (1.8 mL) and then cesium carbonate (2.0 g), and the mixture was stirred at 100° C. for 15 hr. The mixture was allowed to cool, to the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.57 g, 54%).
Reaction SMILES: CN1CCOCC1.[NH2:8][C@H:9]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[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].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:56]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:57]([C:62]([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60].CC(C)N=C=NC(C)C>CN(C=O)C.O>[NH:56]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH:8][C@H:9]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:71])[CH2:66][CH:67]([CH3:68])[CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 19 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
4-Methylmorpholine (2.53 g, 25 mmol) was added to a solution of H-Lys(Z)-Leu-Leu-OMe·HCl (13.93 g, 25 mmol) in DMF (85.0 g) at 10° C. HOBt (3.38 g, 25 mmol), Boc-Leu-Leu-OH (8.61 g, 25 mmol) and DIC (3.47 g, 27.5 mmol) were added over 30 min at 8-10° C. An additional portion of DMF (5.0 g) was added and the reaction was kept at 8-10° C. for 16 h. The reaction was stirred at 18-20° C. for 3 h, cooled to 5-10° C. and treated with H2O (130.0 g). A solid precipitated at 25° C. which was filtered, washed with H2O and recrystallized from MeOH and H2O to give Boc-Leu-Leu-Lys(Z)-Leu-Leu-OMe (SEQ. ID No. 2) (18.3 g, 86.4%).
Reaction SMILES: [OH:1][CH:2]([CH3:5])[C:3]#[N:4].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=O.[ClH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:9][C:7]1[C:6](=[O:10])[O:1][C:2]([CH3:5])=[C:3]([Cl:12])[N:4]=1
Reactant: Cl
Reactant: CC(O)C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1oc(=O)c(Cl)nc1Cl
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxypropanenitrile (26-1) (5.0 g, 70 mmol, 1 eq) in toluene (60 mL) was added dropwise to a stirring solution of oxalyl chloride (24.6 mL, 281 mmol, 4 eq) in toluene (165 mL) at 0° C. After 30 minutes, the reaction mixture was heated to 90° C. and triethylamine hydrochloride (4.8 g, 35.2 mmol, 0.5 eq) was added. The mixture stirred for 4 hours at the same temperature and then was concentrated in vacuo at 60° C. The resulting mixture was suspended in Et2O (300 mL), filtered washing with Et2O (3×100 mL), and the filtrates were combined and concentrated. Purification by flash chromatography (330 g SiO2, 0-50% EtOAc in hexanes) afforded 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one (26-2) as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[CH3:31])/[S:3]1.[C:35]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[C:14]([CH3:31])=[C:13]([O:12][C:11]3[CH:32]=[CH:33][CH:34]=[C:9](/[CH:8]=[C:4]4/[C:5](=[O:7])[N:6]([CH3:35])[C:2](=[O:1])[S:3]/4)[CH:10]=3)[N:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)NC4=O)c3)c2C)CC1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)N(C)C4=O)c3)c2C)CC1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution (Z)-ethyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (300 mg, 0.0006198 mole) in dimethyl acetamide (10 ml), K2CO3 (171 mg, 0.001239 mole) was added followed by addition of methyl iodide (0.060 ml, 0.0009297 mole) at 0° C. and reaction mixture was stirred at 27° C. for 30 minutes. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. Organic layer was washed with water and brine, dried over sodium sulfate and evaporated on a rotavpour to yield the product as yellow solid (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27].C[O-].[Na+]>CO.O>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([S:26]([NH:27][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=3)[CH:18]=2)=[O:24])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: CC(=O)Oc1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(O)cc4)oc3C)cc2)cc1
Yield: 20.6 %

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester (64 mg) in an analogous manner to that described in Example 2A. The acetic ester intermediate was hydrolysed with sodium methoxide (80 mg) in a mixture of methanol (10 mL) and water (1 mL) for 1 hour. The solution was concentrated in vacuo then partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (starting at 30% acetonitrile and increasing at a rate of 1% per minute up to 98% acetonitrile) to give compound 13 as a white solid (15 mg). LC/MS System C: Rt=3.50 mins, m/z (ES−)=492 (M− for C26H23N2O7S).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>>[S:35]([OH:39])([O-:38])(=[O:37])=[O:36].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: O=S(=O)(O)O
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Product: O=S(=O)([O-])O

Procedure:
7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (4 g) was dissolved in 0.4 N sulfuric acid (40 ml). The mixture was lyophilized to give 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (4.20 g).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)=[C:2]=[O:3].[CH3:12][CH:13]([CH3:36])[CH:14]([NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)[N:26]=1)=[O:21])[C:15]([O:17][CH3:18])=[O:16]>>[CH3:11][C:6]1[CH:5]=[C:4]([NH:1][C:2](=[O:3])[NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:25]3[N:26]=[C:22]([C:20]([NH:19][CH:14]([CH:13]([CH3:36])[CH3:12])[C:15]([O:17][CH3:18])=[O:16])=[O:21])[S:23][CH:24]=3)=[CH:28][CH:29]=2)[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: Cc1ccc(N=C=O)cc1C
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C)c(C)c3)cc2)cs1)C(C)C
Yield: 75 %

Procedure:
The title compound was synthesized analogous to Example 23, using 4-isocyanato-1,2-dimethylbenzene and intermediate 3. Yield: 75%; 1H NMR (DMSO-d6, 300 MHz): δ 8.80 (s, 2H), 8.51 (s, 1H), 8.30 (s, 1H), 8.03 (d, 2H), 7.57 (d, 2H), 7.24 (s, 1H), 7.19 (d, 1H), 7.07 (d, 1H), 4.39 (t, 1H), 3.70 (s, 3H), 2.31 (m, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 0.97 (t, 6H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24]([NH:38][S:35](=[O:37])(=[O:36])[NH:34][CH3:33])=[O:25])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F

Procedure:
The compound was prepared in a similar manner to Example 408 from 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and N-methylsulfamide. LCMS (Method D): RT=4.48 min, m/z: 524.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.46-7.38 (m, 4H), 7.27 (t, J=7.7 Hz, 4H), 7.22-7.08 (m, 3H), 6.95 (d, J=12.7 Hz, 1H), 4.46 (s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.24 (d, J=7.4 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.92-2.79 (m, 1H), 2.53 (d, J=4.9 Hz, 2H), 2.11-1.99 (m, 1H), 1.25 (d, J=7.1 Hz, 1H), 0.93-0.83 (m, 2H), 0.67 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([OH:14])=O)=[CH:5][C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=1.CC[N:17]=C=NCCCN(C)C.Cl.[CH2:27]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:12]([NH2:17])=[O:14])=[CH:5][C:6]2[NH:10][C:9]([N:37]3[CH2:38][CH2:39][CH:34]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:35][CH2:36]3)=[N:8][C:7]=2[CH:11]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc2nc[nH]c2cc1C(=O)O
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCC(Cc4ccccc4)CC3)[nH]c2cc1C(N)=O

Procedure:
6-methoxy-5-benzimidazole carboxylic acid, (1 equivalent) was treated with 1.1 equivalent of EDAC.HCl and 1 equivalent of 4-benzylpiperidine in the presence of a catalytic amount of DMAP in DMF/DCM 1:1 for 3–6 hrs. The reaction mixture was then concentrated and taken up in ethyl acetate. After washing with 5% aq. Sodium carbonate a solution of saturated sodium chloride, the organic layer was dried over anhydrous sodium sulfate and concentrated to give crude material. This crude material was purified by chromatography on silica. M+349, Exp. 349.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[Na+].[Na+].[I-].C[CH:25]=[N+:26]=[CH:27]C>C(Cl)Cl>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:25][N:26]([CH3:27])[CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC=[N+]=CC
Reactant: O=C([O-])[O-]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CON(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4.86 g of dibenzylhydroxylamine, 2.42 g of anhydrous sodium carbonate and 4.22 g of N,N-dimethylmethyleneammoniumiodide in 50 ml of methylene chloride is stirred at room temperature under N2 for 48 hrs. After removal of the insoluble inorganic residue by filtration, the solution is concentrated under reduced pressure. The resulting residue is treated with heptane to extract the product. Removal of the combined heptane extracts affords the product as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=C)[C:5]#[N:6].[O:12]=[O+][O-].[BH4-].[Na+].O>CO>[OH:12][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(C#N)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)ccc1CO
Temperature: -70 °C
Yield: 90 %

Procedure:
3-Methyl-4-vinylbenzonitrile (0.40 g; 2.8 mmol; from step (i) above) was dissolved in 50 mL of methanol and cooled to −70° C. Ozone (2 eq.) was bubbled through, and then 0.20 g (5.3 mmol) of sodium borohydride and 5 mL of water were added and the cooling bath was removed. After 4 h the methanol was evaporated and the residue was partitioned between 1M HCl and ether. The aqueous layer was extracted twice with ether and the combined organic phase was washed with water, dried (Na2SO4) and evaporated to yield 0.37 g (90%) of the desired product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:16][CH:13]([NH:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([CH2:24][CH2:25][CH2:26][Cl:27])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:16][CH:13]([N:14]([CH2:26][CH2:25][CH2:24][C:22](=[O:23])[C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:29][CH:28]=4)[CH2:15]2)[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC(C2)NC3)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc(C23CCCC(C2)N(CCCC(=O)c2ccc(F)cc2)C3)c1
Product: Cl
Yield: 42.2 %

Procedure:
A mixture of 0.8 g of 1-(3-methoxyphenyl)-6-azabicyclo[ 3,2,1]octane, 0.81 g of 3-(4-fluorobenzoyl)propyl chloride, 0.8 g of potassium carbonate, 0.03 g of potassium iodide and 20 ml of toluene is refluxed for 48 hours. After cooling, the mixture is treated in the same manner as described in Example 11. 0.65 g of 1-(3-methoxyphenyl)-6-[3-(4-fluorobenzoyl)propyl]-6-azabicyclo[3,2,1]octane hydrochloride is obtained. M.p. 195° - 196°C(recrystallized from a mixture of ethanol and ether).
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][C:6]([CH3:16])([CH3:15])[CH2:5]1)=[N+]=[N-].O.C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O>[Br:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:15])([CH3:16])[CH2:5][CH:4]2[NH2:1]
Reactant: CC1(C)CC(N=[N+]=[N-])c2cc(Br)ccc2N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(N)c2cc(Br)ccc2N1
Reaction time: 8 h

Procedure:
To a solution of 4-azido-6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinoline (2.29 g, 8.15 mmol), water (6.50 ml, 361 mmol), and THF (20.4 ml, 8.15 mmol) was added triphenylphosphine (2.35 g, 8.96 mmol) in one portion. The resulting mixture was heated to 40 deg C. and stirred overnight. The crude mixture was dissolved with EtOAc and transferred to a sep. funnel containing 0.5 MHCl. The aqueous layer was washed 5×DCM. The aqueous layer was then neutralized with 6N NaOH and washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to provide the desired product. MS m/z: 239 (M−NH2).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.CO.F[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[Br:24]>CN(C)C=O.O>[Br:23][C:20]1[CH:19]=[C:18]([Br:24])[CH:17]=[CH:22][C:21]=1[N:6]1[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=[C:5]1[CH3:4]
Reactant: COC(=O)c1c[nH]c(C)n1
Reactant: Fc1ccc(Br)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccc(Br)cc2Br)c(C)n1

Procedure:
14.1 g of 30% strength sodium methylate solution was added to 10.9 g (0.078 mol) of methyl 2-methylimidazole-4-carboxylate in 100 ml of dimethylformamide; the methanol which formed was removed completely. 38.1 g (0.15 mol) of 1-fluoro-2,4-dibromobenzene was added to the dimethylformamide solution remaining, and the mixture was refluxed for 2 hours. Water was then added, extraction carried out with ethyl acetate and the ethyl acetate phase was washed with water. After removal of the solvent from the organic phase, there was obtained a residue which crystallized on trituration with diisopropyl ether.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][CH2:5][C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:6](=[O:8])[CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:10])=[O:9])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: CN(C)C(=O)CCC(=O)O
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CCC(=O)N(C)C)nc12

Procedure:
From N,N-dimethylsuccinamic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+21.9° (c=1.04, CHCl3), ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:41][C:42]1[N:47]=[C:46](Cl)[CH:45]=[CH:44][N:43]=1.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([C:44]4[CH:45]=[CH:46][N:47]=[C:42]([Cl:41])[N:43]=4)[CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2ccnc(Cl)n2)CC1
Yield: 71.4 %

Procedure:
To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (295 mg) in ethanol (5 ml) were added triethylamine (0.15 ml) and 2,4-dichloropyrimidine (150 mg), and the mixture was stirred under reflux for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) and dried under reduced pressure to give the title compound (263 mg).
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=CC=1)([O-])=O.[NH2:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([NH:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:28]([F:33])[CH:29]=2)[N:24]([CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:23]=1.N1C=CC=CC=1.O>ClCCl>[CH:35]1([NH:34][C:27]2[CH:26]=[C:25]3[C:30]([C:31](=[O:32])[C:22]([NH:21][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[CH:23][N:24]3[CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:29][C:28]=2[F:33])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(=O)CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(CC)n1cc(N)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCNC(=O)Nc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
180 mg of 4-nitrophenyl chloroformate was dissolved in 3.0 ml of dichloromethane, and 140 mg of ethyl 3-aminopropanoate hydrochloride and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and then concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was obtained. 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was dissolved in 2.0 ml of dichloromethane, and 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 120 mg of ethyl 3-[({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}carbonyl)amino]propanoate was obtained.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=[CH:17][CH:16]=2)[C:9]2[CH:14]=CC=C[CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Li])[CH2:23]CC.C1C2CC3C(=CC=CC=3)C=2C=CC=1C=O>C1COCC1.CCCCCC>[CH:22]([C:17]1[CH:16]=[CH:15][C:8]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:9]=2[CH:10]=1)=[CH2:23]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)Cc1ccccc1-2
Reaction time: 2 h

Procedure:
Triphenylmethyl phosphonium bromide (36 gms/0.1 mole) in 500 milliliters of dry THF is treated under nitrogen with 90 milliliters of a 1.1 molar solution of n-butyl lithium in hexane and stirred for 2 hours. A solution of 19.4 gms. (0.1 mole) of fluorene-2-carboxaldehyde in 100 milliliters of THF is added dropwise and the final mixture refluxed for 1 1/2 hours. One liter of hexane is added to the cold solution and the precipitate filtered off. The filtrate is evaporated and the residue chromatographed on alumina (Woehlm neutral) using hexane to give 15 gms. (75% theory) of product. Recrystallization from hexane yields 2-vinylfluorene as colorless plates. The structure of the product is confirmed by nuclear magnetic resonance and elemental analysis.