Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=O)[CH:23]=[C:13]2[C:12]1=[O:26])[CH3:10].O>C(O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=[N:2][OH:3])[CH:23]=[C:13]2[C:12]1=[O:26])[CH3:10]
Reactant: CCn1c(=O)c2cc(C=O)cn2c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c2cc(C=NO)cn2c2ccccc21
Yield: 80.6 %

Procedure:
A mixture of 1.5 g (21.6 mmole) of hydroxylamine hydrochloride, 2 g (24.4 mmole) of sodium acetate, 3.4 g (14.1 mmole) of the product of Example 25, 20 ml of water and 40 ml of ethanol was warmed on a water bath for one hour and the mixture was evaporated to a volume of 20 ml. The mixture was filtered and the recovered product was rinsed with water and dried over P2O5 under vacuum to obtain 2.9 g of 4,5-dihydro-5-ethyl-4-oxopyrrolo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime in the form of colorless needles melting at 262°-264° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>>[CH2:18]([N:13]1[C:12]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1cccs1
Product: CCn1nc2c(c1-c1cccs1)CCNCC2
Yield: 114.1 %

Procedure:
The title compound (101 mg) was prepared as in Example 177, Steps C and D, using 148 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 306 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C13H17N3S, 247.11; found, m/z 248.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.62-7.57 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.05 (m, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.33-3.27 (m, 2H), 3.24-3.18 (m, 2H), 3.07-3.01 (m, 2H), 2.80-2.73 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: CO.[OH-:3].[K+].[Cl:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=[N:23]\[O:24][CH3:25])/[C:21]#N)=[CH:10][CH:9]=[CH:8][N:7]=1.[OH2:26]>>[Cl:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=[N:23]\[O:24][CH3:25])/[C:21]([OH:26])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: [OH-]
Reactant: CO/N=C(/C#N)c1ccccc1COc1cccnc1Cl
Reactant: O
Agent: [K+]
Solvent: CO
Product: CO/N=C(/C(=O)O)c1ccccc1COc1cccnc1Cl
Yield: 42.8 %

Procedure:
Methanol (2 ml) and a 50% aqueous solution of potassium hydroxide (0.07 g, 0.66 mmol) were added to (E)-2-(2-chloro-3-pyridyloxymethyl)-a-methoxyiminophenylacetonitrile (0.11 g, 0.33 mmol). The mixture was stirred under reflux for 6 hours. After completion of the reaction, water (100 ml) was added, and the resulting 10 mixture was washed with methylene chloride (50 ml). Hydrochloric acid (1N, 1 ml) was added, and the mixture was extracted with methylene chloride (50 ml) twice. The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to dryness to give (E)-2-(2-chloro-3-pyridyloxymethyl)-α-methoxyiminophenylacetic acid (0.05 g, 42.8 %) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[CH3:22][O-:23].[Na+].O.Cl>CO>[CH3:22][O:23][C:17]1[N:18]=[CH:19][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)=[N:15][CH:16]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)cn1
Temperature: 140 °C
Yield: 74.7 %

Procedure:
To a reaction vial containing (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (120 mg, 0.344 mmol) in methanol was added sodium methoxide (74 mg, 1.375 mmol). The reaction mixture was heated at 140° C. for 1 h under microwave irradiation, poured into water, acidified with HCl solution and extracted with solution of DCM:IPA (4:1). The combined organics were dried and concentrated to give the title compound (70 mg). LCMS m/z=273.3 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[S:10][C:9]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[C:2]([C:6]1[S:10][C:9]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:31]([O:33][CH3:34])=[O:32])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)C1CCNC(c2ccc(C(C)(C)C)s2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)s2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Methyl 2-(5-tert-butylthiophen-2-yl)piperidine-4-carboxylate hydrochloride (2.36 g, 7.42 mmol) and DIPEA (3.24 mL, 18.56 mmol) were dissolved in DCM (30 mL). Methyl chloroformate (0.690 mL, 8.91 mmol) was added and the reaction mixture stirred at room temperature for 1 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding dimethyl 2-(5-tert-butylthiophen-2-yl)piperidine-1,4-dicarboxylate (2.490 g, 99%) as a dark oil. MS m/z 340 (M+H)+
Reaction SMILES: [SH:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH2:10]([C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:11]O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:30][C:13]([F:31])([C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][O:4][C:3](=[O:5])[CH:2]([SH:1])[CH2:6][C:7]([O:9][CH2:11][CH2:10][C:13]([F:30])([F:31])[C:14]([F:28])([F:29])[C:15]([F:26])([F:27])[C:16]([F:24])([F:25])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[O:8]
Reactant: O=C(O)CC(S)C(=O)O
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CC(S)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 94.7 %

Procedure:
Mercaptosuccinic acid (Aldrich) (12.5 g, 0.083 mole) and 1H,1H,2H,2H-perfluorooctan-1-ol (Fluorochem Ltd.) (60.6 g, 0.166 mole) were suspended in toluene (400 ml). p-Toluene sulfonic acid hydrate (Aldrich) (0.36 g) was added and the mixture refluxed under argon atmosphere for 72 hours in a flask equipped with a Dean & Stark reflux condenser. The solution was allowed to cool and the toluene was removed by evaporation under reduced pressure. The resulting oil was redissolved in ethyl acetate (1000 ml) and washed with saturated aqueous sodium hydrogen carbonate (800 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2-mercaptosuccinic acid bis-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) ester as a pale yellow oil (66.2 g, 100% yield).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N[C@@H]1C(=[O:39])N2[C@H](C(OC(C)(C)C)=O)CCCN2CCC1>>[O:39]=[C:6]1[CH2:5][CH2:4][C@H:3]([NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2](=[O:1])[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](NC(=O)CCc3ccccc3)C(=O)N12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](N)C(=O)N12
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)CCc3ccccc3)C(=O)N12

Procedure:
(1S,9S)t-Butyl octahydro-10-oxo-9-(3-phenylpropionylamino)-6H-pyridazino-[1,2-a] [1,2]diazepine-1-carboxylate (44b), was prepared from (1S, 9S)-t-butyl 9-amino-octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (Attwood et al., J. Chem. Soc. Perkin 1, pp. 1011-19 (1986)) as for 44a, to afford 810 mg (81%) of a colorless oil: [α]D23 -33.5° (c 0.545, CH2Cl2); IR (film) 3334, 2935, 1737, 1728, 1659, 1642; 1H NMR (CDCl3) δ 7.24 (5H, m), 6.75 (1H, d, J=6.7), 5.27 (1H, m), 4.92 (1H, m), 3.39 (1H, m), 3.03 (4H, m), 2.55 (3H, m), 2.33 (1H, m), 2.17 (1H, m), 1.80 (5H, m), 1.47 (9H, s), 1.39 (1H, m). MS(FAB, m/z): 416 (M+ +1), 360, 211, 143, 97.
Reaction SMILES: C1C=C([O:7]O)C(C(O)=O)=C(C(O)=O)C=1.[CH2:15]([C:17]1[N:22]=[C:21]2[CH2:23][CH2:24][S:25][CH2:26][C:20]2=[C:19]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[N:42]=[N:43][N:44]([C:46]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:45]=3)=[CH:31][CH:30]=2)[CH:18]=1)[CH3:16].[OH2:65]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH2:15]([C:17]1[N:22]=[C:21]2[CH2:23][CH2:24][S:25](=[O:7])(=[O:65])[CH2:26][C:20]2=[C:19]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[N:42]=[N:43][N:44]([C:46]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[N:45]=3)=[CH:33][CH:34]=2)[CH:18]=1)[CH3:16]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCSC2
Reactant: O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCS(=O)(=O)C2
Reaction time: 4 h

Procedure:
Monoperoxyphthalic acid, magnesium salt hexahydrate (1.38 g) was added to a mixture of 7,8-dihydro-2-ethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5H-thiopyrano[4,3-b]pyridine (1.5 g) and benzyltriethylammonium chloride (0.3 g) in dichloromethane (50 ml) and water (20 ml). The mixture was stirred for 4 hours and then a further quantity of monoperoxyphthalic acid, magnesium salt hexahydrate (138 mg) was added. Stirring was continued for 1 hour and then the mixture was diluted with dichloromethane (100 ml) and water (100 ml). The organic layer was separated and dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromtography, eluting with methanol/dichlormethane (1.49 v/v) to give 7,8-dihydro-2-ethyl-4-[(2'-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4yl)methoxy]-5H-thiopyrano[4,3b]pyridine S,S-dioxide (A) (320 mg), as a foam; NMR (CDCl3); 1.3(t, 3H), 2,75(q, 2H), 3.35(t, 2H), 3.55(t, 2H), 4.15(s, 2H), 5.0(s, 2H), 6.65(s, 1H), 6.9-7.0(m, 6H), 7.1-7.5(m, 16H), 7.95-8.0(m, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:21]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)no1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2noc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 394.03 g/mol.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[H][H].[C:24](Cl)(=[O:26])[CH3:25]>O1CCOCC1>[C:24]([O:14][CH:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[CH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Reactant: CC(=O)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)OC(C(=CC1CCCCC1)n1cncn1)C(C)(C)C
Yield: 36.7 %

Procedure:
A solution of 13.15 g (0.05 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (prepared as described in Example II-2) in 50 ml of dioxane was added dropwise to a suspension of 1.5 g of 80% strength sodium hydride in 50 ml of dioxane. After the evolution of hydrogen had ceased, 3.9 g (0.05 mol) of acetyl chloride were added dropwise to the mixture. The mixture was heated under reflux for 4 hours. After the mixture had cooled, the solvent was distilled off in vacuo, and the residue was taken up in methylene chloride and the solution was extracted with water. The organic phase was dried over sodium sulphate and filtered, and the solution was concentrated. The residue was purified over a column (silica gel; methanol: chloroform=1:3). 5.6 g (35.4% of theory) of 3-acetoxy-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene were obtained as a slightly yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[CH2:9][OH:10].I[CH3:12]>O1CCCC1>[CH3:12][O:10][CH2:9][C:5]1[O:6][CH:7]=[CH:8][C:4]=1[CH3:3]
Reactant: Cc1ccoc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1occc1C
Reaction time: 1 h
Yield: 113.2 %

Procedure:
Under an inert atmosphere sodium hydride (0.25 g ˜60%, 6.2 mmol, 1.1 equiv.) was suspended in dry tetrahydrofuran. At 5° C. a solution of (3-methyl-furan-2-yl)-methanol (0.63 g, 5.6 mmol) in dry tetrahydrofuran was added dropwise. The mixture was stirred at room temp. for one hour, then iodomethane (0.9 g, 6.2 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred overnight at room temp., quenched with diluted acid and extracted with diethyl ether. The combined, organic extracts were washed with brine, dried over magnesium sulfate dihydrate, filtered and concentrated under reduced pressure to give 0.8 g of the title compound as a light yellow oil. GC-MS (EI): M=126.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>CCO>[Cl:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:2][OH:3])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(CCl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccc(CCl)cc1
Temperature: 50 °C

Procedure:
Hydroxylamine hydrochloride (10.11 g, 145.5 mmol) was added to a solution of 4-(chloromethyl)benzaldehyde 4 (7.5 g, 48.51 mmol) in EtOH. The mixture was heated at 50° C. for 3 h then concentrated in vacuo. The residue was partitioned between DCM and water. The combined organic extract was dried (MgSO4) and concentrated in vacuo yielding a white solid that was used without further purification (8.1 g, 98%). 1H NMR (400 MHz, DMSO) δ 4.77 (2H, s), 7.46 (2H, d, J=8.0 Hz), 7.60 (2H, d, J=8.0 Hz), 8.15 (1H, s), 11.32 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:1][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of benzyl N-(2-hydroxyethyl)carbamate (5.9 g, 30 mmol), N-hydroxyphthalimide (4.9 g, 30 mmol), and triphenylphosphine (7.9 g, 30 mmol) in tetrahydrofuran (100 mL) was added diethyl azodicarboxylate (5.2 g, 30 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), dried over Na2SO4, and filtered. After evaporating the filtrate, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (9.3 g, 91%). 1H-NMR (300 MHz, CDCl3) δ 7.84 (m, 2H), 7.78 (m, 2H), 7.37 (m, 5H), 5.97 (br s, 1H), 5.14 (s, 2H), 4.27 (t, J=4.9 Hz, 2H), 3.51 (q, J=5.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:20]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Product: CCOC(=O)C(=O)c1csc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1

Procedure:
The title compound was prepared from ethyl (2-amino-4-thiazolyl)glyoxylate and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (28.2 mg) with purity >80%. LCMS (pos) m/z 417.0.
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[N:10]=1.ClC1N(C)C(=O)C2N=CN(C3CCCC3)C=2N=1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[OH:41].C(N(CC)CC)C>CC#N>[OH:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[NH:35][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[N:10]=1
Reactant: Cn1c(Br)nc2c(ncn2C2CCCC2)c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cn1c(Cl)nc2c(ncn2C2CCCC2)c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2c(ncn2C2CCCC2)c1=O

Procedure:
A mixture of 2-bromo-1-methyl-9-cyclopentylpurin-6-one and 2-chloro-1-methyl-9-cyclopentylpurin-6-one (1.4 g) is mixed with (±) trans-2-aminocyclopentanol (1.2 g, 11 mmol) and triethylamine (1.2 ml) in CH3CN (20 ml) and heated to reflux for 12 hr. The resultant mixture is cooled, concentrated in vacuo, and partitioned between EtOAc/THF 1:1 and brine. The organic layers are concentrated in vacuo and the residue is purified by flash chromatography using 6% EtOH in CH2Cl2 to give 2-(trans-2-hydroxycyclopentylamino)-1-methyl-9-cyclopentylpurin-6-one, a solid (1.4 gm, MS FAB: M+H=318). The 2-(trans-2-hydroxy cyclopentylamino )-1-methyl-9-cyclopentylpurin-6-one (1.3 g, 4.1 mm), triphenylphosphine dibromide (prepared from triphenylphosphine (1.2 g) and bromine (0.2 ml)) in DMF (20 ml) is stirred at room temperature for 18 hr and heated to 70° C. for 12 hr. Dilute NaOH is added to the cooled reaction mixture to adjust the pH to 10, and the resultant solution is extracted with EtOAc/THF 1:1. The organic layer is concentrated in vacuo and purified by flash chromatography using 15% EtOH in CH2Cl2 and recrystallized from CH2Cl2 /hexane, to give the title compound, a solid, mp 194°-195° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 42 %

Procedure:
24.42 g (200 mmol) of 4-hydroxybenzaldehyde are dissolved in 250 ml of N,N-dimethylformamide and treated with 27.64 g (200 mmol) of potassium carbonate. At 100° C., 53.55 g (240 mmol) of tert-butyl α-bromoisobutyrate are added dropwise. The mixture is stirred for another hour, a further 200 mmol of potassium carbonate and 240 mmol of tert-butyl α-bromoisobutyrate are added and, after 4 hours at 100° C., 1 l of water is added. Following extraction with diethyl ether, washing with 1 N aqeuous sodium hydroxide solution and saturated sodium chloride solution and drying over magnesium sulphate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) and dried under reduced pressure. The target compound is obtained in the form of colourless crystals in a yield of 42%.
Reaction SMILES: CO[CH:3]([O:7]C)[N:4]([CH3:6])C.[Cl:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[N:26][O:27][CH3:28])C(N)=O)=[CH:12][CH:11]=1.[NH2:31][OH:32].C(O)(=O)C>C(OCC)(=O)C>[Cl:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[N:26][O:27][CH3:28])[C:3]([N:4]=[CH:6][NH:31][OH:32])=[O:7])=[CH:12][CH:11]=1
Reactant: NO
Reactant: CON=C(C(N)=O)c1ccccc1COc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CON=C(C(=O)N=CNO)c1ccccc1COc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
N,N-Dimethylformamide dimethylacetal (0.53 g, 4.5 mmol) was added to 2-(4-chlorophenoxymethyl)-α-methoxyiminophenylacetamide (0.48 g, 1.5 mmol), and the mixture was stirred under reduced pressure (ca. 40 mmHg) at 60° C. for 0.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and a mixture of aqueous 50% hydroxylamine solution (0.20 g, 2 mmol) and acetic acid (3 ml) was added to the residue under ice-cooling. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)-N-hydroxyaminomethylene-α-methoxyiminophenylacetamide (0.41 g, 75.6%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N.[NH2:45][C:46](=[N:58]O)[C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[C:49]([F:57])[CH:48]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:57][C:49]1[CH:48]=[C:47]([C:46]2[N:45]=[C:13]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:19])[F:18])=[CH:17][CH:16]=3)[O:15][N:58]=2)[CH:56]=[CH:55][C:50]=1[C:51]([O:53][CH3:54])=[O:52]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: N#CC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C(F)(F)F)cc3)n2)cc1F
Temperature: 100 °C
Yield: 70 %

Procedure:
In a microwave vial were added 4-(2-trifluoromethylphenyl)benzoic acid (Fluorochem, 53.2 mg; 0.20 mmol; 1 eq.), triphenylphosphine polymer bound (375 mg; 0.60 mmol; 3 eq.) and trichloroacetonitrile (30 μl; 0.30 mmol; 1.50 eq.). Anhydrous THF (2 mL) was added and the reaction vessel was sealed and heated to 100° C. for 5 min in the microwave. After cooling, the reaction vessel was uncapped and without filtering, Intermediate 1 (46.7 mg; 0.22 mmol; 1.10 eq.) in anhydrous THF (2 mL) was added to the solution along with DIEA (69 μl; 0.40 mmol; 2 eq.). The reaction was capped and heated at 150° C. for 15 min. After cooling, the reaction vessel was uncapped again and the resin was filtered, the filtrate passed through an NH2 SPE column (2 g) and washed by additional THF (2×2 mL). Solvents were evaporated, affording the title compound as a brown solid (61.9 mg; 70%). It was used in the next step without further purification. LC/MS (Method A): 443.3 (M+H)+. HPLC (Method A), Rt 5.98 min (Purity: 87.9%).