Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN1C(=O)CCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:7]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)ccn2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
Compound 39 (391 mg, 1.00 mmol) was dissolved in NMP (10 mL), and 1-methylpiperazine (1.11 mL, 10.0 mmol) was added thereto, followed by stirring overnight at 150° C. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1) to afford the entitled Compound 41 (22.2 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.[C:19]([CH2:23][C:24](Cl)=O)([CH3:22])([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(OCC)(=O)C.O>[CH:16]1([CH2:15][N:14]2[C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:9])=[O:10])=[CH:7][C:2]=3[N:1]=[C:24]2[CH2:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][CH2:17]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E, 113 mg, 0.38 mmol) in ethyl acetate (3 mL) was added tert-butylacetyl chloride (58 μL, 0.42 mmol) at room temperature. After stirring for 1 h, p-toluenesulfonic acid monohydrate (72 mg, 0.38 mmol) was added and the mixture was stirred under reflux for 3 h. Water (5 mL) and aqueous ammonia (0.5 mL) were added and the mixture was extracted with ethyl acetate (15 mL×3) and washed with brine (5 mL). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by pTLC (hexane:ethyl acetate=1:1 then dichloromethane:methanol=10:1 as eluent) to give colorless oil (74 mg), which was recrystalized from ethyl acetate and hexane to afford the title compound (28 mg, 21%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[NH2:19][NH2:20]>C(O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N+:19]=[N-:20])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Solvent: CCCO
Product: COc1ccc(C(=[N+]=[N-])c2ccc(OC)cc2)cc1

Procedure:
25 grams (0.1 moles) of p,p'-dimethoxybenzophenone, which was purchased from the Aldrich Chemical Company, was dissolved in 50 ml of n-propanol and with solution was treated with 20 grams of hydrazine, which had been freshly distilled over sodium hydroxide pellets. The mixture was then refluxed for a total of 12 hours, after which the solvent (n-propanol) and excess hydrozine were removed at reduced pressure. The residual crude hydrazone was recrystallized from ethanol and had a melting point of 85° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1
Yield: 35 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-methoxybenzene. Yield 35%, colorless gel (195 mg, 35%). 1H NMR (DMSO-d6, 400 MHz): □s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.71 (s, 3H), 4.48 (s, 2H), 5.18 (s, 2H) 6.87 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 8.18 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[N:39][CH:38]=[CH:37]3)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][N:39]([CH3:44])[CH2:38][CH2:37]3)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cnccc3c2)C1
Reactant: CI
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4)cc3)ccc2C1

Procedure:
In an analogous manner to that previously described, by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate with methyl iodide in chloroform and subsequently reducing with sodium borohydride in methanol there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate, which was used in the next step as the crude product without further characterization.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH:13]1([CH:16]([NH2:19])[CH2:17][CH3:18])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CC#N>[CH:13]1([CH:16]([NH:19][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH3:18])[CH2:15][CH2:14]1
Reactant: CCC(N)C1CC1
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1cc[nH]c(=O)c1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Part A. A mixture of 4-chloro-3-nitro-2-pyridone (2.0 g, 11.4 mmol), 1-cyclopropylpropyl amine hydrochloride (1.5 g, 11.4 mmol) and N,N-diisopropylethylamine (4.8 ml, 27.4 mmol) in CH3CN (50 ml) were stirred at 25° C. for 16 h and at reflux for 4 h. After cooling it was stripped in vacuo, and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The insolubles were separated, washed with H2O and EtOAc and vacuum dried 1.51 g. The filtrate layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The Combined extracts were washed with brine, dried over MgSO4, filtered and concd. in vacuo. The residue was washed with EtOAc (2×) and vacuum dried, to give 0.69 g, yellow solid. Combined wt. of 4-(1-cyclopropylpropyl)amino-3-nitro-2-pyridone 2.20 g, 81% yield. 1H NMR(300 MHz, dmso d6): 11.19 (1H, br), 8.94 (1H, d J=8.8 Hz), 7.33 (1H, t J=6.9 Hz), 6.03 (1H, d J=7.7 Hz), 3.18-3.24 (1H, m), 1.60-1.74 (2H, m), 1.03-1.11(1H, m), 0.91 (3H, t), 0.40-0.60 (1H, m), 0.20-0.39 (1H, m).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18]C(=O)OC(C)(C)C)[CH:16]=2)[NH:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=2)[C:31]=1[F:47])=[O:27]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:31]=1[F:47])=[O:27])=[C:9]2[Cl:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Cl)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(N)cc4c3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl (3-chloro-2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate (0.030 g, 0.050 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.021 g, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.98-12.29 (m, 1H), 8.80-9.68 (m, 2H), 8.53-8.63 (m, 1H), 7.78-7.85 (m, 1H), 7.39-7.57 (m, 5H), 7.31-7.39 (m, 1H), 7.09-7.20 (m, 1H), 4.41-4.89 (m, 2H). ES MS: m/z 503 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N[CH2:23][C@H]1CCCN1CC>>[CH2:2]([N:1]1[CH2:6][CH2:5][CH2:23][C@@H:7]1[CH2:8][NH:9][C:10]1[C:18]2[O:17][CH:16]=[CH:15][C:14]=2[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1)[CH3:3]
Reactant: O=[N+]([O-])c1cc(NCCN2CCOCC2)c2occc2c1
Reactant: CCN1CCC[C@@H]1CN
Product: CCN1CCC[C@@H]1CNc1cc([N+](=O)[O-])cc2ccoc12
Yield: 100 %

Procedure:
The title compound was prepared according to the procedure described for Intermediate 27 using (R)-2-aminomethyl-1-ethylpyrrolidine. Yield: 100%, HPLC purity=90%, m/z=290 (M+H)+.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([Cl:23])[C:16]([Cl:24])=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[C:25](OCC)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>>[S:34]([OH:37])(=[O:36])(=[O:35])[CH3:33].[Cl:23][C:17]1[C:16]([Cl:24])=[C:15]2[C:14]3=[C:19]([C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[N:13]3[CH:27]([CH3:28])[CH2:26][C:25]2=[O:29])[CH:18]=1
Reactant: C/C=C/C(=O)OCC
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: CS(=O)(=O)O
Product: CC1CC(=O)c2c(Cl)c(Cl)cc3c4c(n1c23)CCNCC4

Procedure:
Following the general procedure of Example 41, making non-critical variations but starting with 3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, using ethyl crotonate in step 7, and using methanesulfonic acid for the salt formation, the title compound was obtained (mp 225-230° C. [dec.]). 1H NMR (d-DMSO) δ 8.94, 8.12, 4.97, 3.48-3.20, 3.13, 2.77, 2.30, 1.20; IR (drift) 3029, 2979, 2849, 2792, 1683, 1481, 1410, 1312, 1214, 1196, 1184, 1161, 1145, 1040, 775 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH:32][C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=1)=[O:17])=[CH:27][CH:26]=2)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)c1cc2cc(NC(=O)c3cccc(-c4cc(Cl)cc(Cl)c4)n3)ccc2[nH]1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (58) (42 mg, 0.21 mmol) using Method D to give the crude product.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C>CN(C=O)C>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:15]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(Br)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J=17.7 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 5.11 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.89 (d, J=0.9 Hz, 1H), 11.00 (s, 1H).
Reaction SMILES: [P:1](O)([OH:4])([OH:3])=[O:2].[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:14])[NH2:13])[CH3:11])[OH:8].[P:15]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:18][P:19]([OH:22])([OH:21])=[O:20])(=[O:17])[OH:16].C(N[C@H](C(O)=O)CS)(=O)C>>[P:15]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:18][P:19]([O:21][P:1]([OH:4])([OH:3])=[O:2])([OH:22])=[O:20])(=[O:16])[OH:17].[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:13])[NH2:14])[CH3:11])[OH:8]
Reactant: O=P(O)(O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CN(CC(=O)O)C(=N)N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 37 °C

Procedure:
With reference to the FIGURE there is described, schematically, a mechanical system for continuous analyses of a large number of serum samples. Such devises are well-known, e.g., the Technicon AAII by Technicon Corp., Tarrytown, N.Y. In the FIGURE, the serum sample is placed in sample tray 1 which delivers the sample through line 3 to unified pumping head 5 at a rate of 0.32 cc/min. Simultaneously a mixture of creatine phosphate, adenosine diphosphate, Mg++ and N-acetylcystein is monitored (0.60 cc/min.) through line 7 into pumping head 5 and air is monitored through line 9 at a rate of 0.32 cc/min. N-acetylcysteine (N-Ac) is required as a CPK activator. The air and CP/ADP/N-Ac/Mg++ streams are mixed in coil 11 and subsequently combined with sample stream 3. The unified stream is passed through heater bath 13 wherein the stream is heated to about 37° C. Thereafter the heated stream is passed into the upper chamber 15 of dialyzer 16. Any CPK present in the sample catalyzes reaction between the CP and ADP to produce ATP and creatine. The ADP, ATP and creatine diffuse through membrane 17 into the second chamber 19 of dialyzer 16. The second chamber of the dialyzer also contains NAD/glucose/Mg++ mixture injected into the system through line 21 (1.00 cc/min.) via pumping head 5. The NAD/glucose/Mg++ mixture is mixed with air injected via line 23 (0.32 cc/min.) through pumping head 5. The NAD/glucose/Mg++ air stream procedes via line 25 into dialyzer chamber 19 and is combined with ATP from the upper chamber 15. Thereafter the unified stream is passed through line 31 through coiled tube 33 and flow cell 41. Thereafter the sample is passed through line 51 and pumping head 5 to a waste receptable.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4]CCCCCCCCCCCC.C(Cl)(=O)CCC.C(Cl)(=O)CCCCCCCCCCCCCCC>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCC(=O)Cl
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2′-deoxyguanosine, substituting the appropriate amount of butyryl chloride for palmitoyl chloride, and isolating as follows: evaporating the solvent after 72 hours, triturating the resulting material in 1:1 diethyl ether-ethyl acetate, and recovering the product by filtration.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][N:3]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N+:22]([O-:24])=[O:23])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cccnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2cccnc2c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a cold (5°) solution of 2,4-diamino-5-(7-methoxy-5-quinolylmethyl)pyrimidine (0.28 g, 1.0 mmol) in concentrated sulfuric acid (2 mL) was added dropwise 90% nitric acid (0.10 g, 1.4 mmol). After stirring at 5° for 30 min, the reaction was poured onto ice and the resulting solution taken to pH 3 with 5N sodium hydroxide. The tan solid that separated was collected then boiled in water and filtered to remove insolubles. The filtrate was taken to pH 8 with 1M sodium carbonate to precipitate the title compound (0.14 g, 42%); mp>270° dec. Anal. Calcd for C15H14N6O3 : C, 55.21; H, 4.32; N, 25.75. Found: C, 55.02, H, 4.10; N, 25.41.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][O:7][C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:4][CH2:3]1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][O:7][C:6]1=[O:9]
Reactant: CC1CCN(Cc2ccccc2[N+](=O)[O-])C(=O)OC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1CCN(Cc2ccccc2N)C(=O)OC1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
6-Methyl-3-(2-nitrobenzyl)-[1,3]-oxazepan-2-one (1.91 g, 7.23 mmol), iron powder (2.02 g, 36.2 mmol), ammonium chloride (0.19 g, 3.55 mmol) were suspended in ethanol (30 ml) and water (15 ml) and heated to reflux for one hour. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and 3-(2-aminobenzyl)-6-methyl-[1,3]-oxazepan-2-one (1.02 g) was obtained by evaporating the solvent under reduced pressure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=[C:13]([Cl:16])[C:14]=1F>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=[C:13]([Cl:16])[C:14]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(-n2cccn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyrazole (1.43 g, 21,0 mmol) in 3 ml of DMF is added dropwise at RT to a suspension of sodium hydride (50%; 1.0 g, 21.0 mmol) in 10 ml of DMF. The mixture is stirred at RT for 30 min., after which it is added dropwise at 5° over a period of 30 min. to a solution of 3,5-dichloro-4-fluoronitrobenzene (3.0 g, 15.0 mmol) in 20 ml of DMF. After reaction is complete, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with water and with brine and dried to give a yellow solid, 1-(2,6-dichloro-4-nitrophenyl)-pyrazole.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([O:8]C(C)=O)[C@@H:3]1[O:12]C(C)=O.[OH2:16].[Br-].[Li+].O>C(#N)C>[OH:16][CH:6]1[O:7][C@@H:2]([CH3:1])[C@@H:3]([OH:12])[C@@H:4]([OH:8])[CH2:5]1
Reactant: O
Reactant: CC(=O)O[C@@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: C[C@@H]1OC(O)C[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.7 %

Procedure:
To a solution of 3,4-di-O-acetyl-L-fucal (5.0 g) and lithium bromide hydrate (5.0 g) in acetonitrile (150 ml), activated resin prepared as in Example 1 (3.0 g) and water (6 ml) were added and stirred at room temperature for 15 min. The product was isolated as described for Example 1. Purification by chromatography on a column of Silica Gel using ethyl acetate-hexane (3:8) as eluant gave the title compound (4.0 g). α:β=9:4. [α]D20 =-57.6°±2°(c 1.03, CHCl3). 1H NMR δ: 5.45 (d, H-1α), 5.35 (m H-3α), 5.19 (H-4α), 5.10 (d, H-4β), 4.98 (m, H-3β), 4.87 (dd, H-1β), 4.33 (H-5α), 3.73 (m, H-5β), 2.04 & 1.86 (m, H-2). MS (calc. mass=232). Obs. m/e 231.13, 215.12, 155.09 (100%).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: Fc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Cl)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-chloropropionyl chloride (49 ml) in dichloromethane (50 ml) was added to a mixture of anhydrous aluminium trichloride (55.5 g) in dichloromethane (120 ml). The mixture was stirred for 10 minutes at room temperature and then a solution of fluorobenzene (39.5 ml) in dichloromethane (30 ml) was added dropwise. The resulting mixture was stirred for one hour, allowed to stand for 16 hours and then poured on to an ice-hydrochloric acid mixture. The two phase mixture was vigorously stirred at room temperature for 11/2 hours, separated and the aqueous layer washed with dichloromethane (2×50 ml). The combined organic extracts were then washed with aqueous sodium hydroxide (3N, 2×100 ml), water (1×100 ml) and brine (1×100 ml), dried (MgSO4) and evaporated under reduced pressure to afford 2-chloro-1-(4-fluorophenyl)-1-propanone, 71.3 g.