Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:16][CH:17]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19][NH:18]1.[Cl-].[NH4+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH2:23][CH:17]2[CH3:16])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1CCNC(C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC1CCC(C)N(c2cc(Cl)ncn2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
Into 3 ml of acetonitrile were added 0.2 g of 4,6-dichloropyrimidine, 0.56 g of potassium carbonate and 0.26 g of 2,5-dimethylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 3 hours at 80° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.3 g of 1-(6-chloropyrimidin-4-yl)-2,5-dimethylhexahydro-1H-azepine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]=[C:6]=[S:7].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[S:7])[NH:15][NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCN=C=S
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Product: COCCNC(=S)NNc1ccccc1
Yield: 66.7 %

Procedure:
In benzene was dissolved 11.7 g of 2-methoxyethyl isothiocyanate with stirring, and 11.9 g of phenylhydrazine was added thereto at room temperature. The resulting mixture was heat refluxed for 6 hours, followed by cooling. The thus precipitated crystals were removed by filtration to obtain 4-(2-methoxyethyl)-1-phenylthiosemicarbazide (yield: 66.7%). This product can be used in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl.[OH-].[K+]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([NH2:11])[N:17]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(Nc2cc(C)nc(N)n2)cc1
Yield: 94.2 %

Procedure:
Compound No. 17 (CNI-1794): A suspension of p-aminoacetophenone (1.35 g) and 2-amino-4-chloro-6-methylpyrimidine (1.435 g) in 20 mL water was treated with 0.85 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out and dried to give 2.28 g 4-(4-acetylphenyl)amino-2-amino-6-methylpyrimidine, mp 194-196° C. Of this, 1.21 g was treated with methyl iodide (3 mL) in dimethylformamide (15 mL) at room temperature for 42 hr. Dilution with ethyl acetate and filtration gave 1.11 g 4-(4-acetylphenyl)amino-2-amino-1,6-dimethylpyrimidinium iodide as a white powder, mp 302-3° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>>[N:1]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)c1ccc(CBr)cc1
Product: CC(=O)c1ccc(Cn2ccc3ccccc32)cc1

Procedure:
The title compound was prepared from 1H-indole (0.55 g, 4.69 mmol) and 1-(4-(bromomethyl)phenyl)ethanone (1.00 g, 4.69 mmol) following a procedure similar to General Procedure A. The title compound was purified using automated column chromatography method 1 (0.410 g, 35%). 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J=8.2 Hz, 2H), 7.69 (d, J=7.5 Hz, 1H), 7.21 (m, 6H), 6.61 (d, J=3.1 Hz, 1H), 5.41 (s, 2H), 2.58 (s, 3H). 13C NMR (100 MHz, MeOD): δ 198.58, 143.95, 136.22, 136.04, 128.94, 128.39, 128.17, 126.51, 121.19, 120.37, 119.06, 109.29, 101.24, 48.95, 25.23. ESI-HRMS: calc. for C17H15NO: [M+H]+=250.1226 m/z, found: [M+H]+=250.1232 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17](OC(C)C)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 0 °C

Procedure:
A stirred suspension of 26 from Example 5 (18 g, 50.18 mmol) in 300 ml dry diethyl ether is kept under a stream of nitrogen at room temperature. LiAIH4 (1.9 g, 50 mmol) is added in portions and the mixture is stirred over night. The mixture is poured into a mixture of ice-water and ethyl acetate. The resulting emulgation is filtered through celite and the phases are separated. The aqueous phase is extracted once with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographied on silica gel using successively ethyl acetate and a mixture of ethyl acetate and methanol (9:1) as eluents. Yield of 27: 7.69 g (51%). Mp 107-109° C.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([CH:46]([CH:48]2[CH2:50][CH2:49]2)O)[CH:43]=[N:44][CH:45]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1.N1(C2OC(N3CCCCC3)=NN=2)CCCCC1>C1(C)C=CC=CC=1>[CH2:32]([O:39][C:40]1[CH:45]=[N:44][CH:43]=[C:42]([C@H:46]2[CH2:48][C@@H:50]2[CH2:49][O:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH:41]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: OC(c1cncc(OCc2ccccc2)c1)C1CC1
Reactant: Oc1cccnc1
Agent: C1CCN(c2nnc(N3CCCCC3)o2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(COc2cncc([C@H]3C[C@@H]3COc3cccnc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (237 mg, 0.94 mmol, 1.6 equiv.) was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in a 10 mL round-bottom flask with a side neck. The flask was equipped with rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar (3 times), and the flask was cooled with an ice bath. Tri-n-butylphosphine (232 μL, 0.94 mmol, 1.6 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 10 min. The resulting colorless solution was then added dropwise (via syringe) with ice cooling to a solution of (1S,2S)-2-[(5-(benzyloxy)-3-pyridyl]cyclopropylmethanol (50 mg, 0.59 mmol) and 3-hydroxypyridine (89 mg, 0.94 mmol, 1.6 equiv.) in a 25 mL round-bottom flask (equipped with a magnetic stirrer and an Ar balloon). The resulting mixture was warmed to room temperature and stirred for 6 h. Air was bubbled through the mixture with stirring for 1 h. Toluene was evaporated, and the residue was purified by CC on SiO2 (15×1.0 cm, EtOAc) to give the crude product, which was contaminated with a by-product, 2,5-di-(1-piperidinyl)-1,3,4-oxadiazole. This material was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 22.7-24.0 min) to give a yellowish oil (125 mg, 64%). MS (EI) m/z 332 (M+, 67%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])=[O:5])#[N:2]>[OH-].[Na+]>[NH2:2][C:1]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)NC(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(=O)[nH]c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
1-(2-Cyano-acetyl)-3-phenyl-urea (12.6 g, 62.1 mmol) was taken in 50 ml 2M sodium hydroxide (aq.) and stirred at room temperature for 2 h under LC-MS control. After cooling down by immersing in ice bath and neutralization with acetic acid and thus formed solids were separated by filtration, washed well with ice cold water and dried under high vacuum yielding white solids (11.9 g, 58.6 mmol, 94.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])=[CH:18][NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:27]=1.[C:28]([Cu])#[N:29]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[C:15]([C:13]2[S:12][C:11]3[C:5]4[CH:4]=[CH:3][C:2]([C:28]#[N:29])=[CH:27][C:6]=4[O:7][CH2:8][CH2:9][C:10]=3[CH:14]=2)=[N:16][NH:17][CH:18]=1
Reactant: N#C[Cu]
Reactant: Clc1ccccc1-c1c[nH]nc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Product: N#Cc1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedure of Example 53, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-1H-pyrazole and CuCN gave 275. MS: (ESI+) 404.1
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)(C)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:31][C:28]([CH:29]=[C:6]3[CH2:5][CH2:4][CH2:3][N:2]=[C:7]3[C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Agent: [Cl-]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (95 mg, 0.38 mmol) and 5-(4-nitrophenyl)furfural (99 mg, 0.46 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature, concentrated under reduced pressure and treated with saturated NaHCO3(aq). This mixture was then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 10.5:7:7:1:0.1 hexane:MtBE:CH2Cl2:MeOH:NH4OH (1 liter). One sample was recovered that appeared to be highly crystalline. This material was re-crystallized from hot methanol. The crystals were recovered by vacuum filtration, washed with isopropanol then dried under vacuum giving 50 mg (36%) of an orange crystalline solid. LC-MS: RT=5.16 min, [M+H]+=360.0.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: N[C@@H]1CCC[C@H]1OCc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@@H]1CCC[C@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of (1R,2R)-2-benzyloxycyclopentylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×15 mL). The product was suspended in EtOH and the solvent was evaporated (to remove THF residue). The solid was dried in vacuo, affording the title compound (717 mg, 46%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.53 (d, 1H, J=11.2 Hz), 4.42 (d, 1H, J=11.2 Hz), 4.02 (m, 1H), 3.36 (m, 1H), 3.01 (t, 2H, J=7.8 Hz), 2.81 (t, 2H, J=7.8 Hz), 2.01 (m, 4H), 1.65 (m, 3H), 1.49 (m, 1H). 13C NMR (D2O, 125 MHz) δ ppm 137.00, 129.07, 129.01, 128.77, 81.78, 71.81, 63.89, 48.02, 45.34, 29.93, 27.43, 21.61, 20.94. [α]D=−38.8° (c=0.00122 in water). ES-MS 314 (M+1).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[CH2:21]([NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:40]=[C:36]([C:37]([NH2:39])=[O:38])[C:35]([OH:41])=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([N:28]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:41])=[C:36]([C:37](=[O:38])[NH2:39])[CH:40]=1)[CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reactant: FC(F)(F)c1csc(-c2ccc(OCC3CO3)cc2)n1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nc(C(F)(F)F)cs3)cc2)ccc1O

Procedure:
A solution of 7.0 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-4-(trifluoromethyl)-thiazole and 6.01 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 150 ml of isopropanol is heated under reflux for 18 hours and the solvent is subsequently removed in a rotary evaporator. The 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-thiazol-2-yl]-phenoxy]-2-propanol, obtained in the form of an oil, is further processed in that form.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[O:18])[CH:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)[CH3:2].[CH3:26][N:27]1CCN(C)C1=O>>[CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[O:18])[CH:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:26]#[N:27])[CH:20]=1)[CH3:2]
Reactant: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1cccc(Br)c1
Reactant: CN1CCN(C)C1=O
Product: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1cccc(C#N)c1

Procedure:
To 10 ml of 1,3-dimethyl-2-imidazolidinone, 0.7 g of 4-ethyl-3-(3-bromophenyl)-1-(3-trifluoromethylphenyl)-2-pyrrolidinone (Compound No. 25) and 1.2 g of cuprous cyanide were added. After the resultant mixture was stirred at 160° C. for 4 hours, the insoluble matter was filtered off from the reaction mixture and the filtrate was poured into water, followed by extraction with toluene. The extract was dried over anhydrous sodium sulfate, concentrated in an evaporator, and then purified by chromatography on a silica gel column, whereby 0.35 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.F[C:12]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=1[NH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:14][C:13]2[CH:12]=[CH:18][C:17]([O:19][CH3:20])=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(N)c(F)c1
Reactant: ClCc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,4-dichloro-5-chloromethyl-pyrimidine (3.70 g, 18.7 mmol) (from Example 1b supra), 2-fluoro-4-methoxy-phenylamine (2.40 g, 17.0 mmol) (from Example 14a supra) and potassium carbonate (4.70 g, 34.0 mmol) in acetone (100 mL) was stirred at room temperature for 18 hours. The precipitate was filtered off and the solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This residue was purified by flash chromatography eluting with ethyl acetate-hexanes (1:4) to give [(2,4-dichloropyrimidin-5-yl)methyl]-(4-methoxyphenyl)-amine. (Yield 3.99 g, 78%).
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>O>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([O:7][P:1]([OH:4])([OH:3])=[O:2])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 3 h

Procedure:
The resting cells mentioned above were dried at a room temperature and dried further in a phosphorus pentoxide desiccator under a vacuum overnight. Fifty mg of the dried cells were put into 2 ml of a reaction mixture containing 10 μmoles ADP, 200 μmoles glucose 250 μmoles phosphate buffer, 5 μmoles MgCl2.6H2O and the amount of the inhibitor shown in Table 5 or 6. The reaction mixture was held at 30° C. for 3 hours, and then heated in boiling water for 3 minutes. ATP formed in the reaction mixture was determined colorimetrically.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](=[O:46])([O-])[O-].[K+].[K+]>C(#N)C>[CH3:9][O:8][CH2:1][CH:2]([N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:22][CH2:21]1)[CH2:3][O:46][CH3:43]
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Solvent: CC#N
Product: COCC(COC)N1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Yield: 400 %

Procedure:
39 g (154.6 mmol) of the title compound of Example 5a and 44.43 g (77.3 mmol) of 1,4,7-tris-(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane (produced according to Chem. Soc., Perkin Trans. 1, 12:3329, 1991) and 85.14 g (616 mmol) of potassium carbonate in 800 ml acetonitrile are refluxed for 24 hours. Solid is filtered out, and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in 700 ml of methylene chloride and extracted twice with 300 ml of water. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent =methylene chloride/methanol 20:1).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.FC(F)(F)C(O)=O.N>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(N)COC1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of tert-butyl {[3-(dibenzylamino)oxetan-3-yl]methyl}carbamate (13.0 g, crude), 20% palladium hydroxide on carbon (2.0 g) and trifluoroacetic acid (0.5 mL) in methanol (20 mL) was stirred overnight under hydrogen atmosphere (1 bar). After being basified with ammonia solution in methanol, the resulting mixture was filtered and concentrated in vacuo to afford 5.8 g of the crude product, which was used for the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].C1COCC1.[CH:14]1([CH2:20][Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]([OH:8])[CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]CC1CCCCC1
Reactant: Cc1ncsc1C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ncsc1C(O)CC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A 3-neck, 100 mL round-bottom flask was charged with the product from Example 22D (412.6 mg, 3.5 mmol) and anhydrous THF (15 mL) under N2 atmosphere. The reaction was cooled to −10° C. Cyclohexylmethylmagnesium bromide (7 mL, of a 1.0M solution in ether, 7 mmol) was added dropwise. The reaction was stirred for 1 hour, warmed to room temperature, and stirred for an additional 3 hours. The reaction was quenched with 10 mL THF/1M HCl (1:1). The aqueous and organic layers were separated. The pH ofthe aqueous layer was adjusted to 3 with 1M HCl. The aqueous layer was extracted with EtOAc (3×10 mL). All organic layers were combined and washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by silica gel column (1:1 EtOAc/hexanes) to provide 425.2 mg (58%) of the title compound as an orange oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:7]=12.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[C:12]3[CH:13]=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:17]=3[C:18](=[O:19])[C:7]=12
Reactant: Cc1ccnc2c1C(=O)c1ccccc1-2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccnc2c1C(=O)c1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
A mixture of 35.2 ml of 98.9% strength sulfuric acid with 35.2 ml of 99% strength nitric acid was added dropwise at from +5° to 10° C. to a solution of 15.6 g (0.08 mol) of 4-methyl-5H-indeno[3,2-b]-pyridin-5-one in 35.2 ml of conc. sulfuric acid in the course of 1 hour. After stirring at 25° C. for 14 hours and additionally stirring at 70° C. for 4 hours, the mixture was cooled to 20° C., stirred into 500 g of ice and brought to pH 10 with a 50% strength aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, the combined extracts were concentrated under reduced pressure and the residue was crystallized at +10° C. using 30 ml of ether. 13 g (67% of theory) of 4-methyl-7-nitro-5H- indeno[3,2-b]pyridin-5-one were obtained as yellow crystals of m.p. 225°-227° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH2:9](Cl)[C:10](=[CH2:12])[CH3:11]>>[CH2:9]([CH:3]([C:4](=[O:8])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:1])[C:10](=[CH2:12])[CH3:11]
Reactant: C=C(C)CCl
Reactant: CCCC(=O)CCC
Product: C=C(C)CC(CC)C(=O)CCC

Procedure:
3-Methallyl-4-heptanone was prepared starting from 4-heptanone and methallyl chloride, analogously as described in example 1 in the allylation section.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:20]([N:27]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCC.CCOCC>[CH2:20]([N:27]1[CH2:31][CH2:30][C:29]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:8])=[O:7])([OH:32])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N-(tert-butyl)benzenesulfonamide (536 mg, 0.00251 mol) in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium in pentane (4.4 mL) under nitrogen at −78° C. The mixture was stirred at −78 Celsius for 15 min, then at 0 Celsius for 1 hour, and then cooled down to −78 Celsius again. A solution of 1-benzylpyrrolidin-3-one (400.0 mg, 0.002283 mol) in ether (3 mL) was added to the above solution. The reaction solution was stirred at −78 Celsius for 2 hours, then quenched with saturated NH4Cl aqueous solution, and then extracted with EtOAc. The organic phase was washed with brine, then dried over MgSO4. The residue was purified by flash chromatography on silica gel column with 30% AeOEt in hexanes to give the desired compound (350 mg, 39% yield). MS (ESI): 389.1 (M+H+).