Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]([OH:22])[C:16]#[C:17][Si](C)(C)C)[CH:8]=1>CO>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]([OH:22])[C:16]#[CH:17])[CH:8]=1
Reactant: C[Si](C)(C)C#CC(O)CCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Solid potassium carbonate (1.5 g) was added to a solution of (±)-5-(3-pyridyl)-1-(trimethylsilyl)pent-1-yn-3-ol (2.9 g) in methanol (50 ml) and the mixture stirred at room temperature for 24 hours. The methanol was removed under reduced pressure and water was added. The mixture was extracted with dichloromethane, the extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the sub-title compound as an oil (1.8 g) which was used immediately.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[O:28]=[C:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[C:35]([O:37][CH2:38][CH3:39])=[O:36].COC1C=CC(C=O)=CC=1>C(O)C>[OH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CCCC[C@@H]1O
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Geotrichum candidum (ATCC 34614) is cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H2O (0.5 gram), NaNO3 (2 grams), FeSO4.7H2O (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of ethyl 2-oxocyclohexanecarboxylate are dissolved in 2 ml of 95% ethanol, the resulting solution is added to the culture, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.4 grams of (1S,2S)-ethyl 2-hydroxycyclohexanecarboxylate as a yellow oil. The chiral purity of the product is greater than 99% as judged by chiral chromatography.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1>C1OCCOCCOCCOCCOCCOC1.CS(C)=O.O>[CH3:7][N:8]1[C:12]([S:1][CH2:2][CH2:3][OH:4])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: OCCS
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(Cl)c(Cl)c1SCCO
Temperature: 140 °C
Yield: 38.1 %

Procedure:
To a mixture of 26.5 g (0.34 moles) 2-mercaptoethanol, 19 g of 85% potassium hydroxide, and a few drops of 18-Crown-6 in 250 ml of DMSO, 60 g (0.32 moles) 1-methyl-3,4,5-trichloro pyrazole (product of Example 1 or 1A) were added in portions. When the addition was complete, the reaction mixture was heated to 140° C. for 1 day. The cooled reaction mixture was diluted with water and extracted with ether. The organic phase was washed four times with 200 ml water per time, dried and stripped. The crude product was chromatographed on a silica gel column. The product, 1-methyl-3,4-dichloro-5-(2-hydroxyethyl)thio pyrazole, was eluted from the column with ethyl acetate, yielding 27.7 g (37.7% yield) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:3]=1[C:4]([OH:6])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:62]1>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:3]=1[C:4]([N:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:62]1)=[O:6]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C(O)c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)c2c(F)cc(F)cc2Nc2ccc(I)cc2F)C1
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (125 mg) as a colorless oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([O-:7])=[O:6].C(=O)(O)[O-].[Na+].CCCCCCC.[CH3:26][Sn:27](Cl)(Cl)[CH3:28]>O>[SH:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([O-:7])=[O:6].[SH:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([O-:7])=[O:6].[CH3:26][Sn+2:27][CH3:28]
Reactant: C[Sn](C)(Cl)Cl
Agent: CCCCCCC(CCS)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Product: C[Sn+2]C
Reaction time: 1 h

Procedure:
Into a 2 liter flask is placed 204 gm (1.0 mole) 2-mercapto-ethylcaprylate, 200 ml water, 84 gm (1.0 mole) sodium bicarbonate and 300 ml heptane. To the above stirred mixture is added dropwise, at 30°-40° C., 110 gms (0.5 mole) dimethyltin dichloride dissolved in 200 ml water. Stir for 1 hour at 30°-40° C. and allow the layers to separate. The organic layer is washed with 200 ml water and then stripped under vacuum at about 100° C. A yield of 273 gm of dimethyltin bis(2-mercaptoethyl caprylate) is obtained. nD25 1.5060.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[CH3:12])=[N:9][CH:10]=1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>O1CCCC1>[F:14][C:15]([F:22])([F:21])[C:16](=[O:17])[CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([S:4][CH3:3])=[CH:10][N:9]=1)=[O:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CSc1ccc(C(C)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)CC(=O)C(F)(F)F)nc1
Reaction time: 17 h

Procedure:
A stirring solution of sodium hydride (0.253 g, 6.31 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled under nitrogen to 0° C. before the addition of 1-(5-methylsulfanyl-pyridin-2-yl)-ethanone (0.880 g, 5.26 mmol) in anhydrous tetrahydrofuran (20 mL). Ethyl trifluoroacetate (0.751 mL, 6.31 mmol) was added dropwise and the reaction allowed to rise in temperature to 22° C., then heated to reflux and stirred under nitrogen for 17 hours. The solvent was removed and the residue partitioned between saturated aqueous ammonium chloride (10 mL) and dichloromethane (10 mL). The aqueous layer was separated and extracted with DCM (×3). The organic layers were combined, dried and the solvent removed to yield the title compound: MS m/z 264 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:5]3=[N:6][CH:7]=2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 94.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (166 mg, 0.317 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65) (100 mg, 0.317 mmol) using sodium carbonate (101 mg, 0.952 mmol) and Pd(PPh3)2Cl2 (12 mg, 0.015 mmol) in DME/water (15/2 mL). This afforded 190 mg (94.5% yield) of the titled compound. MS: m/z=634.0 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:28]>C(Cl)Cl>[NH2:28][CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: N
Reactant: COc1nc(Cl)ccc1CCO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(Cl)ccc1CCN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.20 g (0.8 mmol) of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine in 10 ml of dry CH2Cl2 cooled to -50° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for 30 min at this temperature and an additional 10 min at -78° C. before a rapid addition of 30 ml of cold (-78° C.) NH3 (1). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford 1.0 g of crude 3-(2-aminoethyl)-6-chloro-2-methoxypyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:25]=[CH:24][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[S:11])=[C:8]([OH:26])[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[OH2:27]>O1CCCC1>[OH:4][CH:2]([CH2:3][OH:27])[CH2:1][O:5][C:6]1[CH:25]=[CH:24][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[S:11])=[C:8]([OH:26])[CH:7]=1
Reactant: O
Reactant: Oc1cc(OCC2CO2)ccc1C(=S)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCC(O)COc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
The title compound is prepared by the reaction of the compound of Example 14 with water in the presence of mineral acid in tetrahydrofuran.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])=O)=CC=1)([O-])=O.[OH-].[Na+]>C1COCC1.CCO>[N+:18]([O-:20])([O:17][CH2:16][C@H:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11][OH:10])=[O:19]
Reactant: O=C(OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of (5R)-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate (3.1 g, 8.3 mmol) in THF-EtOH (1:1, 0.5 M) at 0° C. was added sodium hydroxide 2N (10 mL, 20 mmol, 2 equiv) dropwise over 5 min. The reaction was stirred at rt for 2 h. The reaction mixture was quenched with a saturated NaHCO3 solution and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by combi-flash 120 g silica gel cartridge using gradient (0-5% in 5 min, 5-55% in 30 min, 55-70% EA/Hex in 10 min) to afford the desired product (1.51 g, Yield=81%) as a colorless oil. 1H NMR (500 MHz, acetone-d6): δ 5.52-5.48 (m, 1H), 5.01 (dd, 1H), 4.72 (dd, 1H), 3.56-3.50 (m, 3H), 1.88-1.81 (m, 2H), 1.54-1.50 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][N:27]2[CH2:26][CH2:25][C:24]3([N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][NH:22][C:23]3=[O:30])[CH2:29][CH2:28]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ClCCCn1cnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1cnc3ccccc31)CC2
Yield: 25 %

Procedure:
A mixture of 6 parts of 1-(3-chloropropyl)-1H-benzimidazole, 4.6 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2parts (25%) of 8-[3-(1H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro-[4,5]decan-4-one; mp. 191° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH2:25][CH2:26]O)([O-:22])=[O:21].C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:26][CH2:25][C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1CCBr
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
Triphenylphosphine (6.60 g, 25.2 mmol) was dissolved in dichloromethane (75 ml). Mixture was cooled to 0° C. 2-Nitrophenethyl alcohol (3.0 ml, 21.36 mmol) was added to the mixture drop-wise. A solution of carbon tetrabromide (8.50 g, 25.6 mmol) in 5 mL dichloromethane was added to the reaction mixture drop-wise. Reaction stirred at 0° C. for 45 minutes. Mixture was concentrated by roto-vap. Residue was treated with 100 mL diethyl ether. Solids were filtered off, washed with diethyl ether and discarded. Filtrate was concentrated. Silica gel chromatography on the residue eluting ethyl acetate-hexanes afforded the title compound as yellow oil in 81% yield. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 7.97 (d, J=8.05 Hz, 1 H) 7.49-7.68 (m, 1 H) 7.41 (t, J=7.68 Hz, 2 H) 3.66 (t, J=6.77 Hz, 2 H) 3.43 (t, J=7.14 Hz, 2 H).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:23]1[C:31]2[N:30]=[CH:29][NH:28][C:27]=2[C:26](=[O:32])[NH:25]/[C:24]/1=[N:33]\[NH2:34])[CH2:19][CH2:20][CH2:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[O:32]=[C:26]1[NH:25]/[C:24](=[N:33]\[NH:34][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)/[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:31]2[N:30]=[CH:29][NH:28][C:27]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)CCCc1nc(-c2ccccc2)no1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCn1/c(=N/NC(=O)CCCc2nc(-c3ccccc3)no2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid (1.44 g, 6.20 mmol), (2e)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (1.61 g, 6.82 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.02 g, 6.82 mmol) and triethylamine (1.73 ml, 12.4 mmol) in DMF (30 ml) was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (3×). The organic layer was washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the desired product (2.78 g, 99% yield) as yellowish oil. LCMS calculated for C22H27N8O3 (M+H): 451.2; found: 451.1.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][CH:9]([CH3:25])[C:10]([O:12][CH2:13][O:14][C:15](ON1C(=O)CCC1=O)=[O:16])=[O:11]>>[C:10]([O:12][CH2:13][O:14][C:15]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:16])(=[O:11])[CH:9]([CH3:25])[CH3:8]
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CC1
Product: CC(C)C(=O)OCOC(=O)NC1(C(=O)O)CC1
Yield: 43.6 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (121 mg, 1.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (259 mg, 1.0 mmol) were reacted to provide 107 mg (44% yield) of the title compound (9) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=5.99 (br s, 0.2H), 5.78 (br s, 0.4H), 5.73 (s, 1.6H), 5.59 (s, 0.8H), 2.59 (m, 1H), 1.62 (m, 2H), 1.31 (m, 2H), 1.19 (d, 6H). MS (ESI) m/z 246.10 (M+H)+; 263.11 (M+NH4)+; 268.09 (M+Na)+; 244.11 (M−H)−.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=2[Cl:51])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[Cl:51][C:42]1[CH:43]=[C:44]([C:47]([F:49])([F:50])[F:48])[CH:45]=[CH:46][C:41]=1[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(Cl)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)cc2Cl)cc1O
Yield: 11 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[2-chloro-4-(trifluoromethyl)phenyl]-ethynyl}pyridazine (Intermediate 69) in 11% yield.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH:11]([CH3:24])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:25])(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:27]([O:29][NH:30][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH:11]([CH3:24])[CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)[CH2:6][C:5]1=[O:25])[CH3:2])[CH3:28]
Reactant: CC(=O)C1C(=O)CC(C(C)CSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCONC(C)=C1C(=O)CC(C(C)CSc2ccc(C(F)(F)F)cc2)CC1=O

Procedure:
0.4 Gram of 2-acetyl-5-[1-methyl-2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione and 0.1 g of ethoxyamine hydrochloride were dissolved in 10 ml of methanol and 0.15 g of potassium carbonate was added to the resulting solution which was then refluxed for 3 hours. The reaction solution was poured into water and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.3 g of 2-(1-ethoxyaminoethylidene)-5-[1-methyl-2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.O(C)[Li].[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>>[C:10]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:7][C:6]3[CH:22]=[C:2]([C:31](=[O:32])[C:30]([F:37])([F:36])[F:29])[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]=3[O:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Li]OC
Product: O=C(O)c1cc(C(=O)C(F)(F)F)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.503 mmol, 1 eq.), LiOMe (40 mg, 1 mmol, 2 eq.) and ethyl trifluoroacetate (0.6 mL, 5.03 mmol, 10 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 77:20:3) to give the title compound as a yellowish solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]([NH2:20])=[NH:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.F[P-](F)(F)(F)(F)F.CN(C)[CH:30]=[CH:31][CH:32]=[N+](C)C.[O-]CC.[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]4[N:20]=[CH:32][CH:31]=[CH:30][N:19]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: CN(C)C=CC=[N+](C)C
Reactant: N=C(N)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Product: c1cnc(-c2cccc(-c3cnn(-c4cccnc4)c3)n2)nc1

Procedure:
Under argon, 0.73 g (2.7 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carboxamidine and 0.8 g (2.9 mmol) of (3-dimethylaminoallylidene)dimethylammonium hexafluorophosphate in 30 ml of ethanol were heated under reflux with 3 ml of sodium ethoxide as a solution in ethanol (21%, corresponds to 8.1 mmol) for 6 h. The mixture was concentrated, Na citrate buffer, dil. aqueous sodium hydroxide solution to pH=9, aq. NaCl and ethyl acetate/THF were added, the aqueous phase was extracted three more times with dichloromethane/2-propanol and the combined organic phases were dried with MgSO4 and concentrated by evaporation. The residue was recrystallized from ethanol, during this operation, the mixture was briefly boiled with activated carbon and filtered whilst still hot, the filtrate was concentrated slightly and the precipitate formed was washed with MTBE and dried on a rotary evaporator. The residue was purified further by filtration through silica gel using acetone.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=O)[CH3:11]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNc1ccc(I)cc1
Product: CC(=NNc1ccc(I)cc1)c1ccncc1

Procedure:
Analogously to the process described in Example 1A, 5.0 g (21.36 mmol) of 4-iodophenylhydrazine and 4-acetylpyridine give 6.67 g (92% of theory) of the title compound.