Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>Br>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCCN2CCN2CCOCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(C2CCCN2CCN2CCOCC2)cc1
Temperature: 110 °C
Yield: 66.1 %

Procedure:
To a suspension of pentane washed sodium hydride (80% oil dispersion, 2.51 g) in dry dimethylformamide (50 ml) was added 2-(4-methoxyphenyl)pyrrolidine (6.74 g) in dimethylformamide (80 ml), followed by N-(2-chloroethyl)morpholine hydrochloride (7.23 g) and potassium iodide (0.05 g) at ambient temperature. The solution was heated at 110° C. for 1.5 hrs, cooled to ambient temperature, and quenched with saturated aqueous ammonium chloride solution. The mixture was distilled through a Kugelrohr apparatus. The residue was diluted with water and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate (4 times). The combined organic extracts were washed with brine, dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/1% methanol/ethyl acetate). The appropriate fractions were collected and concentrated to afford 3.99 g (34.6%) of 1-[2-(4-morpholinyl)ethyl]-2-(4-methoxyphenyl)pyrrolidine. 1-[2-(4-Morpholinyl)ethyl]-2-(4-methoxyphenyl)pyrrolidine (3.75 g) was dissolved in 48% hydrobromic acid (35 ml) and warmed at 110° C. for 5 hrs. The reaction mixture was cooled, neutralized with saturated sodium bicarbonate solution and extracted into dichloromethane (6 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography. The appropriate fractions were collected and concentrated to afford 2.36 g (66.0%) of product. The analytical sample was recrystallized from ether/petroleum ether and had mp 107°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])[N:3]=1.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.CS(C)=O>N1C=CC=CC=1>[Br:23][C:24]1[S:28][C:27]([S:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:19])=[O:18])[N:3]=2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C(N)=O)c1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Br)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
3-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 12) (22 mg, 0.07 mmol) was dissolved in pyridine (1.6 mL) and added to 5-bromo-2-thiophenesulfonyl chloride (27 mg, 0.1 mmol). The reaction mixture was shaken at room temperature for 5 min and then stood overnight at room temperature. DMSO (0.2 mL) was added to the reaction mixture and purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (4.6 mg, 12%) LCMS (System A) RT=1.04 min, ES+ve m/z 521/523 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:20]([O-:22])=[O:21])=[CH:9][C:10]([CH2:17][C:18]#[N:19])=[C:11]([CH3:16])[C:12]=1[N+:13]([O-:15])=[O:14])[CH2:4][CH3:5])[CH3:2].[OH-:23].[K+]>C(O)(C)(C)C>[CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:20]([O-:22])=[O:21])=[CH:9][C:10]([CH2:17][C:18]([NH2:19])=[O:23])=[C:11]([CH3:16])[C:12]=1[N+:13]([O-:15])=[O:14])[CH2:4][CH3:5])[CH3:2]
Reactant: [OH-]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(CC#N)c(C)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(CC(N)=O)c(C)c1[N+](=O)[O-]
Yield: 55.1 %

Procedure:
A sample of {5-[(1-ethylpropyl)amino]-4,6-dinitro-o-tolyl}acetonitrile (4.25 g; 0.014 mol) is added to warm t-butanol (40°-45° C.; 50 ml) followed by finely powdered potassium hydroxide (9.0 g; 0.16 mol). Additional t-butanol (20 ml) is added, and the reaction mixture heated at the reflux overnight. The reaction mixture is then cooled, diluted with 200 ml salt solution, and filtered to give 2.5 g (55%) of an orange solid, melting point 192°-194° C. A sample is recrystallized from methanol for analysis, melting point 194°-196° C.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.N[C:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=C[NH:17][N:16]=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:17]3[N:16]=[CH:15][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccncc3)ccnc12

Procedure:
A mixture of 3.52 g. of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 50 ml. of glacial acetic acid is refluxed for 15 hours. The solvent is removed and the residue worked up as for Example 53 to give 3.0 g. of crystals, m.p. 209°-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)C(C)Cl
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(C)Oc1ccccc1Br
Temperature: 80 °C
Yield: 89 %

Procedure:
60 g (347 mmol) of 2-bromophenol, 57.43 g (416 mmol) of potassium carbonate, 57 g (347 mmol) of potassium iodide, 600 ml of dimethylformamide and 4.34 g (416 mmol) of 3-chloro-2-butanone are introduced into a 1 liter three-necked flask equipped with a reflux condenser. The mixture is heated to 80° C. for 16 hours. 1500 ml of water are added and then extraction is carried out with ethyl acetate (3×400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2×500 ml), dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent, 9/1 cyclohexane/ethyl acetate). 75.07 g (yield: 89%) of 3-(2-bromophenoxy)-2-butanone are obtained (yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Cc1ccc(CCBr)cc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(C)cc3)CC1)O2
Yield: 89.7 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (253 mg, 0.749 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-methyl-benzene (0.23 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-methyl-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (282 mg) as a light brown solid.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([F:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[CH2:22]([Mg]Br)[CH3:23]>>[CH2:22]([CH:12]1[C:11]2[C:10]3[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[C:16]([F:18])[C:15]=2[CH2:14][CH2:13]1)[CH3:23]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)N1CCc2cc(F)c3c(c2CC1)C(=O)CC3
Product: CCC1CCc2c(F)cc3c(c21)CCNCC3

Procedure:
Example 8 was prepared in a similar fashion to Example 4, except Intermediate 5 was used as the starting material and ethylmagnesium bromide (3M in diethyl ether) was used instead of cyclopropylmagnesium bromide (Example 4, step (a)). 1H NMR (300 MHz, CDCl3) δ 6.62 (d, 9.3 Hz, 1H); 3.11-3.06 (m, 1H); 2.96-2.87 (m, 10H); 2.22-1.97 (m, 2H); 1.51-1.31 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); MS: ESI (positive): 234, (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]=[CH2:14])[O:8][C@:7](/[CH:19]=[CH:20]/[CH:21]3[CH2:23][CH2:22]3)([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:24]=1.[N+](=[CH2:27])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]3[CH2:27][CH2:14]3)[O:8][C@:7](/[CH:19]=[CH:20]/[CH:21]3[CH2:23][CH2:22]3)([C:15]([F:16])([F:17])[F:18])[C:6]=2[CH:24]=1
Reactant: C=C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 73 mg of rel-(3S,5S)-trans-7-chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 42) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and he filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 47 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 31 mg: mp 143-144°; HRMS: Calcd. for C18H16NO2F3Cl (M-H)- : 370.0822. Found: 370.0801.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:40]/[O:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)/[C:37](O)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:76][CH:77]1[C:107](=[O:108])[N:79]2[C:80]([C:91]([O:93][CH:94]([C:101]3[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=3)[C:95]3[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=3)=[O:92])=[C:81](/[CH:84]=[CH:85]/[CH2:86][O:87][C:88](=[O:90])[CH3:89])[CH2:82][S:83][C@H:78]12>C1COCC1>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:40]/[O:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)/[C:37]([NH:76][CH:77]2[C:107](=[O:108])[N:79]3[C:80]([C:91]([O:93][CH:94]([C:95]4[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=4)[C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=4)=[O:92])=[C:81](/[CH:84]=[CH:85]/[CH2:86][O:87][C:88](=[O:90])[CH3:89])[CH2:82][S:83][C@H:78]23)=[O:38])[N:35]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)OC/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)OC/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 1-hydroxybenzotriazole (223 mg, 1.44 mmol) and (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (1.06 g, 1.44 mmol) in THF (14 ml) was added DCC (300 mg, 1.44 mmol) and the mixture was stirred for 1 hr at 5° C. Diphenylmethyl 7-amino-3-[(E)-acetoxy-1-propenyl]-3-cephem-4-carboxylate (670 mg, 1.44 mmol) was added to the mixture. After stirring for 4 hr at ambient temperature, the reaction mixture was filtered, diluted with ethyl acetate (50 ml) and washed with water. Concentration of the organic layer gave an oil, which was chromatographed on a column of silica gel. Elution with toluene-ethyl acetate (10:1) gave 1.607 g (99%) of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(E)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate as an amorphous powder. IR νmax (KBr) cm-1 1770, 1730. 1H NMR (CDCl3) δ 2.0 (3H, s, OAc), 3.33 (2H, s, 2-H), 4.54 (2H, ABq, CH2OAc), 5.04 (1H, d, J=5 Hz, 6-H), 6.0 (1H, m, vinyl-H), 6.02 (1H, dd, J=5 & 7 Hz, 7-H), 6.40 (1H, s, thiazole-H), 6.82 (1H, d, J=15 Hz, vinyl-H), 7.00 (1H, s, Ph2CH), 7.3 (25H, s, Ph).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@H:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[C:45](=[O:47])[CH3:46].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[C:45]([C:31]1[CH:32]=[CH:33][C:34]([C:2]2[N:7]=[C:6]([C@H:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:16]([CH3:27])[CH:15]=3)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:35][C:30]=1[O:29][CH3:28])(=[O:47])[CH3:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(C)=O
Reactant: CCCC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCC[C@@H](Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(C)=O)c(OC)c2)n1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.11 mmol) was dissolved in DME (0.76 mL) and then treated with 1-[2-(methyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (41 mg, 0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and then a solution of Na2CO3 (49 mg, 0.46 mmol) in water (0.42 mL). The resulting mixture was then placed under nitrogen and heated at 80° C. for 18 h. The solvents were the removed under vacuum (Genevac) and the residue purified by mass directed autoprep HPLC) to give the title compound as an oil (39 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.[C:26](O)(=[O:28])[CH3:27]>>[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C@H:7]2[CH2:8][CH2:9][C@H:4]([NH:3][C:26](=[O:28])[CH3:27])[CH2:5][CH2:6]2)[CH2:13][CH2:14]1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccccc3)CC2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccccc3)CC2)CC1

Procedure:
From {1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-phenyl-methanone dihydrochloride (138 mg) and acetic acid (23 mg) by procedure C. Yield: 85 mg (66%). White solid. 357.3 ([M+H]+).
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])(O)=[O:2].S(Cl)([Cl:23])=O>ClCCl.CN(C=O)C>[N:8]1([C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:7][CH2:6][O:5][CH2:4][C:1]1=[O:2]
Reactant: O=C(O)COCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1

Procedure:
290 mg (1.02 mmol) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid in 100 ml dichloromethane are combined with 0.186 ml (2.55 mmol) thionyl chloride and 2 drops of DMF and refluxed for one day. After evaporation of the solution i. vac. it is evaporated with toluene and the residue is further reacted without any more purification.
Reaction SMILES: N(OCCC(C)C)=O.[CH:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2N)[CH2:11][CH2:10]1.[I:19]CI>C1COCC1.[Cu](I)I>[CH:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[I:19])[CH2:11][CH2:10]1
Reactant: ICI
Reactant: Nc1cnccc1C1CC1
Agent: I[Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Ic1cnccc1C1CC1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
Isoamyl nitrite (2.62 gm, 22.38 mmol) was added to the stirred solution of 4-cyclopropylpyridin-3-amine (1.0 g, 7.46 mmol) in dry THF (15 mL) under argon atmosphere. This was followed by the addition of diiodomethane (3.0 mL, 22.38 mmol) and copper iodide (1.42 g, 7.46 mmol). The resulting mixture was refluxed at 80° C. for 1 hour. The reaction mixture was cooled, filtered and the filtrate was partitioned between ethyl acetate and water. The organic layer was concentrated to yield the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 600 mg of the product (34% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: Fc1ccc(Nc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(N(CCN2CCCC2)c2nccs2)cc1

Procedure:
A solution of 1.0 g (5.2 mmol) of N-(4-fluorophenyl)thiazol-2-amine in 25 mL of THF was treated with 10.3 mL (10.3 mmol) of a 1.0 M solution of NaHMDS in THF and 0.88 g (5.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride and heated at reflux for 18 h. The reaction mixture was poured into 250 mL of EtOAc and extracted thrice with 1 M aqueous HCl. The combined acidic extracts were brought to pH 12 with a 10% (w/v) solution of Na2CO3 and extracted five times with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography eluting with a linear gradient of neat EtOAc to 20% MeOH in EtOAc to deliver the desired compound. MS (M+H)+ 292.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:15]([O:19][C:20]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)[N:24]=[C:23]1[NH2:33])=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.Cl.C[N:46](C)[CH2:47][CH2:48][CH2:49][N:50]=[C:51]=[N:52]CC>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[NH:52][C:51]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[N:24]=[C:23]1[NH2:33])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)n1cc(CCCC(=O)O)nc1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)Nc2ncccn2)nc1N
Temperature: 25 °C

Procedure:
General EDC/HOBt procedure: 2-amino-4-(3-carboxy-propyl)-imidazole-1-carboxylic acid tert-butyl ester 22 (100 mg, 0.371 mmol), 1-hydroxybenzotriazole (100 mg, 0.742 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (142 mg, 0.742 mmol) were dissolved in anhydrous DMF (3 mL). The appropriate amine coupling partner (1.48 mmol) was then added and the solution was stirred at ambient temperature until completion was evident by TLC analysis. The reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was successively washed with water (3×10 mL), a 10% aqueous solution of citric acid (2×10 mL), sat. NaHCO3 (2×10 mL), and brine (10 mL) before being dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography (2-10% MeOH/CH2Cl2) to afford the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>O>[CH:6]1[C:7]2[C:2](=[N:1][C:12]3[C:11]([N:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccccc1
Solvent: O
Product: c1ccc2nc3ccccc3nc2c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
195.4 gms of calcined and protonated ZSM-5 was added to a mixture of 156.3 gms of 25% aqueous TMA(OH) and 195 ml of deionized water. The solution was ion exchanged for three hours at 40° C. using a hot water bath. The slurry was filtered and the filtrate was set aside for future loadings and ion exchange. The filter cake was subjected to further drying in a vacuum desiccator that was equipped with a nitrogen purge. The drying in the vacuum desiccator was at 35° C. and maintained at that temperature for several hours (48 hours or less) for complete removal of the moisture. The dried material was treated with 216.3 gms of 25% aqueous TMA(OH) for a 20% target loading of TMA(OH). The resulting slurry was dried in a rotary evaporator set-up for several hours until it was moist dry. The rotary evaporator was run at 35° C. and 4 to 35 mm Hg. The dried material was transferred to a flat dish and placed in a vacuum desiccator with an inert gas purge. The vacuum desiccator is maintained at 40° C. and drying was allowed for several hours (48 hours or less). The resulting dried material was not hard, and easy to grind and consisted of what appears to be one phase when ground. A coupling reaction test based on reacting aniline and nitrobenzene failed to produce phenazine.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)Nc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), phenyl isocyanate (8.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/00/1 (v/v) as eluent.