Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19][C:20]1([C:25]([N:27]2[CH2:36][CH2:35][C:34]3[N:33]=[CH:32][C:31]([C:37]([F:40])([F:39])[F:38])=[CH:30][C:29]=3[CH2:28]2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:22]2[CH2:23][CH2:24][C:20]([C:25]([N:27]3[CH2:36][CH2:35][C:34]4[N:33]=[CH:32][C:31]([C:37]([F:39])([F:38])[F:40])=[CH:30][C:29]=4[CH2:28]3)=[O:26])([CH2:19][O:18][CH3:17])[CH2:21]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C2CCC(O)(c3ccc(OC)nc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to general procedures described in Scheme 2: A mixture of 4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexanone (71 mg, 0.32 mmol), (3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone VIc (100 mg, 0.29 mmol) and acetic acid (20 μL, 0.34 mmol) in dichloroethane (3 mL) was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (123 mg, 0.576 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate, then washed with NaHCO3, water and brine. The organic extract was dried, filtered and concentrated. The crude product was obtained as a mixture of isomers which were further separated by reverse phase preparative HPLC to yield isomer A (eluted at 10.092 min) and isomer B (eluted at 11.269 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(SCc3ccccc3)cccn2c1=O
Yield: 95.3 %

Procedure:
To a suspension of 0.3 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1 in 4 ml of anhydrous DMF are added 0.3 g of benzyl bromide VI-1 and 0.5 g of K2CO3, and the resultant mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water. The crystal precipitated is filtered and dissolved in CHCl3. The chloroform solution is dried over Na2SO4 and evaporated to give 0.389 g of the titled compound Ic-21.
Reaction SMILES: [O:1](F)F.[U:4].[NH3:5]>>[NH4+:5].[NH4+:5].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[U:4].[U:4]
Reactant: N
Reactant: FOF
Agent: [U]
Product: [NH4+]
Product: [O-2]

Procedure:
In greater detail, one representative method of preparing uranium dioxide from uranium hexafluoride has uranium hexafluoride reacted with water to hydrolyze the fluoride and form a water solution of uranium oxyfloride and an acid. This water solution is reacted wtih ammonia to yield a precipitate of ammonium diuranate in a slurry. The ammonium diuranate slurry is converted to a dry particulate form of uranium dioxide by heating in wet hydrogen which achieves partial defluorination and reduction of the ammonium diuranate to uranium dioxide.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14]O)=[N:3]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])=[N:3]1
Reactant: Cn1cc2c([C@H]3C[C@H]3CO)cccc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cc2c([C@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)cccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon gas atmosphere, to a solution of cis-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (130 mg, 0.643 mmol) in tetrahydrofuran (6.5 mL) were added a solution (40%, 0.351 mL, 0.771 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (219 mg, 0.835 mmol) and phthalimide (123 mg, 0.836 mmol), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added a solution (40%, 0.176 mL, 0.386 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (110 mg, 0.419 mmol) and phthalimide (61.5 mg, 0.418 mmol) were added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound as a crudely purified product.
Reaction SMILES: C[CH2:2][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].BrC/C=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].CC1CN1>C1COCC1.CCOC(C)=O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[CH:7]/[CH2:6][N:3]1[CH2:2][CH:4]1[CH3:5])[CH3:16]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCN(CC)CC
Agent: CC1CN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CN1CC1C
Reaction time: 60 h

Procedure:
Add 10 mL of NEt3 to a solution of 9.2 mL of ethyl 4-bromocrotonate and 4 mL of 2-methylaziridine in 100 mL of THF. Stir for 60 h, during which time a white precipitate forms. Dilute the reaction mixture with 300 mL of EtOAc and wash with water and then with brine. Dry the organic solution over MgSO4, filter, and concentrate in vacuo to yield 6.7 g of crude product. Purify by flash chromatography (silica gel, 1:4 hexane/EtOAc) to yield 5.2 g of E-4-(2-methyl-1-aziridinyl)-2-butenoic acid ethyl ester.
Reaction SMILES: [H-].[Na+].CO[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1)=[O:6].[C:14](#[N:16])[CH3:15].C(Cl)Cl.CO>C1(C)C=CC=CC=1>[Cl:13][C:9]1[N:8]=[C:7]([C:5](=[O:6])[CH2:15][C:14]#[N:16])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: N#CCC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of NaH (1.03 g, 26 mmol; 60% in mineral oil) in toluene (30 ml) was heated to 65° under an argon atmosphere. A solution of 6-chloro-pyridine-2-carboxylic acid methyl ester (4.4 g, 26 mmol) and acetonitrile (1.33 ml, 26 mmol) in toluene (20 ml; heating was required to dissolve the ester) was then added dropwise (exothermic), and the mixture was stirred at 65° for 24 h (compact slurry). After cooling to r.t., ice water was added while stirring. The aqueous phase was collected, washed with Et2O, neutralized with HCl, extracted with CH2Cl2, dried over MgSO4, filtered and evaporated. The product was obtained after silica gel chromatography using a CH2Cl2/MeOH gradient (2.04 g, 40%) as brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=S)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:12].[Na+].OO.[OH-]>O>[NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]c(=S)sc12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 29 (770 mg, 4.2 mmol) in water (30 mL) was added 1N NaOH (4.2 mL) and 30% H2O2 (1.0 mL) and the reaction was stirred for 1 h at room temperature. Additional peroxide (2.0 mL) and hydroxide (5.0 mL) were added and the mixture was stirred for 1 h at 70° C. The reaction mixture was filtered and the filtrate was neutralized with glacial acetic acid. The resulting precipitate was filtered off while still hot, washed with cold water and dried to yield 0.52 g (74%): mp>370° C. UV λmax (pH 1) 267 nm (ε), 289 (): UV λmax (pH 7, 11) 285 nm (ε): 1H NMR (DMSO-d6) δ 7.18 (b, 2H, NH2, exchanges with D2O), 8.12 (s, 1H, C 5 H), 12.30 (b, 1H, N3H, exchanges with D2O). Anal. Calcd. for C5H4N4OS: C, 35.71: H, 2.40: N, 33.31: S, 19.07. Found: C, 35.50: H, 2.36: N, 33.13: S, 18.79.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:24]([OH:27])[C:25]#[CH:26].Cl>O1CCCC1.CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][OH:27])=[CH:3][CH:4]=1)([F:12])[F:11]
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: OCC#Cc1ccc(SC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a degassed solution of 1-bromo-4-(trifluoromethylsulfanyl)benzene (4.8 g, 18.7 mmol) in tetrahydrofuran (40 mL) was added in the following order: copper(I) iodide (106 mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium (647 mg, 0.56 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.36 mL, 22.3 mmol). The resulting mixture was degassed one more time and a solution of propargyl alcohol (1.30 mL, 22.3 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 50° C. and then stirred at this temperature for 6 h and then left to stand at ambient temperature over night. The mixture was diluted with ether (50 mL) and acidified with 5% hydrochloric acid to pH 2. Ethereal solution was washed with water (2×15 mL), saturated solution of sodium hydrogen carbonate (15 mL) and brine (15 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 85:15) affording 3-[4-(trifluoromethylsulfanyl)phenyl]prop-2-yn-1-ol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.COC([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[NH2:22])[CH2:18][CH2:17][CH2:16]2)=O.[C:23]([O:26][CH2:27]C)(=[O:25])C>C(O)(=O)C>[NH2:22][C:21]1[CH:20]=[C:19]2[C:15](=[CH:14][CH:13]=1)[C:16]([Br:1])([C:23]([O:26][CH3:27])=[O:25])[CH2:17][CH2:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc2c(cc1N)CCC2
Solvent: CC(=O)O
Product: COC(=O)C1(Br)CCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Add N-bromosuccinimide (1.87 g, 10.5 mmol) to methyl 6-amino-indan-5-carboxylate (1.82 g, 9.53 mmol) (Example 49, Step 3) in acetic acid (9.3 mL). Stir the mixture at room temperature for 1 h. Pour the mixture into ice water and add ethyl acetate. Separate the layers and wash the organic phase with saturated NaHCO3 and brine and dry over sodium sulfate. Remove the solvent under reduced pressure. Purify with silica gel cartridge, eluting with hexanes/ethyl acetate to afford methyl 5-amino-1-bromo-indan carboxylate (2.45 g, 95%): MS (ES+): 271, 272 (M+H). Add methyl boronic acid (1.6 g, 26.7 mmol), cesium fluoride (4.6 g, 30.22 mmol) and 1-bis(diphenylphosphinoferrocene) palladium chloride (727 mg, 0.89 mmol) to methyl 5-amino-1-bromo-indan carboxylate (2.40 g, 8.89 mmol) in dioxane (60 ml), and stir at 90° C. for 12 h. Partition between water and ethyl acetate. Extract with more ethyl acetate and then combine the organic phases. Dry over sodium sulfate and remove the solvent under reduced pressure. Purify with silica gel cartridge, eluting with hexanes/ethyl acetate to afford the titled compound (1.73 g, 95%). MS (ES+): 206 (M+H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4].I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(=O)C)C.CCCCCC>CN(C)C=O.C(OC(=O)C)C>[CH:21]([O:1][NH:2][C:3]([C:5]1[C:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)c1nc(CN)ccc1C(=N)NO
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)ONC(=N)c1ccc(CN)nc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of the product of Example 54 (11-6) (0.43 g, 1.39 mmol) in dimethylformamide (5 ml) was added 2-iodopropane (210 μl, 2.1 mmol), followed by cesium carbonate (0.68 g, 2.1 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethylacetate and washed with sodium bicarbonate (saturated). The organic layer was dried over sodium sulfate, filtered and concentrated to give an orangish oil. Flash column chromatography performed in 1/1 ethylacetate/hexane followed by ethylacetate yielded 229 mg (53%) product as a crystalline solid. NMR δ (ppm) CDCl3: 8.8 (d, 1H), 7.9 (dd, 1H), 7.3 (d, 1H), 5.5 (bs, 1H), 4.7 (bs, 2H), 4.4 (d, 1H), 1.4 (s, 9H), 1.3 (d, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:16]=1)[C:8](N(OC)C)=[O:9])(=[O:3])[CH3:2].[CH3:23][Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Mg]Br.Cl>C1COCC1.C(OCC)(=O)C.O>[C:8]([C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:16]=[C:15]([S:17]([F:22])([F:18])([F:20])([F:21])[F:19])[CH:14]=1)(=[O:9])[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(NC(C)=O)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Acetylamino-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (1.2 g) was dissolved in absolute THF (30 ml) and stirred at 0° C. with lithium hexamethyldisilazide (721 μl; density: 0.8 g/l; 23% in tert-butyl methyl ether) for 30 min. At 0° C., methylmagnesium bromide (2.87 ml, 3 M in diethyl ether) was then added dropwise while stirring. After stirring at RT for 2.5 h, further methylmagnesium bromide (1 ml, 3 M in diethyl ether) was added and the mixture was stirred again for 2.5 h. For workup, 1 N hydrochloric acid was added dropwise while cooling with ice, followed by water and ethyl acetate. The organic phase was removed and the water phase was extracted twice more with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered and concentrated. The crude product (1.03 g) was combined with a crude product prepared in the same way (75 mg) and purified using silica gel with dichloromethane-methanol as the eluent. 860 mg of the desired compound were obtained.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[OH:18])[CH2:14]2.C(N(CC)CC)C>C1COCC1>[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH2:14]2
Reactant: O=C1C2CC3CC(C2)C(O)C1C3
Reactant: ClCCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C2CC3CC(C2)C(OCOCCCl)C1C3
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of 2-chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 4-oxo-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 4-oxo-2-adamantanol was converted by 98.3 and that 2.56 g (9.8 mmol, isolation yield: 97.6%) of a colorless liquid which was the intended product was obtained at a selectivity of 99.3%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccc(F)c(C2CC(=O)c3c(C)ccnc3C2)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 94.7 %

Procedure:
To a solution of 7-(2-fluoro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) were added concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(2-fluoro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 163) (1.4 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[B][B][B][B][B][B][B][B][B][B].[CH2:32]=O>CO>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])[CH3:32])=[CH:15][CH:14]=1
Reactant: C=O
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1cc(O)ccc1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc(CN(C)c2ccc(O)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To an ambient temperature solution of 4-amino-3-methyl-phenol (1.0 g, 8.12 mmol) in MeOH (77 mL) is added 4-formyl-benzoic acid methyl ester (1.47 g, 8.93 mmol) and decaborane (329 mg, 2.68 mmol). The reaction is stirred at room temperature. After 2 h, formaldehyde (1.23 mL, 16.93 mmol, 37% in water) and decaborane (329 mg, 2.68 mmol) are added to the reaction. The reaction mixture is stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is purified via chromatography to yield the title compound (2.07 g, 90%). LC-ES/MS m/e 286.2 (M+1).
Reaction SMILES: [O-]S([C:5]([F:8])(F)F)(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:53])=[C:24]([N:26]2[C:33](=[O:34])[C:32]3C=[C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])[N:29]([CH:43]([CH3:45])[CH3:44])[C:28]=3[CH:27]2[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[CH:25]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:53])=[C:24]([N:26]2[C:33](=[O:34])[C:32]3[C:5]([F:8])=[C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])[N:29]([CH:43]([CH3:45])[CH3:44])[C:28]=3[CH:27]2[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[CH:25]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccccc1-c1c(F)c2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
1-Fluoro-2,4,6-trimethyl-pyridinium triflate (0.902 mmol) was added to a solution of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.301 mmol) in 1,2-dichloroethane (4 mL) and then the mixture was heated to 80° C. in the dark. After 16 h, the reaction mixture was cooled to rt, poured into a 2% aqueous solution of sodium sulfite and extracted with EtOAc (2×). The combined organic layers were successively washed with 1M aqueous citric acid, 1M aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a beige foam. ESI-MS: tR=1.40 min, [M]+523/525 (LC-MS 1); TLC: Rf=0.25 (1:2 EtOAc/heptanes).
Reaction SMILES: C(OC([N:8]1[C:12]2[C:13]([CH:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9]1=[O:36])=O)(C)(C)C.[ClH:37].CCOCC>C(O)C>[ClH:37].[CH2:29]([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[C:12]=2[NH:8][C:9]1=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)C1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=c1[nH]c2c(C3CCNC3)cccc2n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-7-(1-tert-butoxycarbonyl-pyrrolidin-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (80 mg., 0.273 mmol) in 5 mL ethanol was heated to reflux and 2 N ethanolic hydrogen chloride was added (0.5 mL.) The reaction mixture was refluxed for 45 minutes at which point ether (2 mL) was added slowly. A solid precipitate formed on cooling and was removed by filtration to afford 40 mg of 1-benzyl-4-pyrrolidin-3-yl-1,3-dihydro-benzoimidazol-2-one hydrochloride as a tan solid. MS: 294 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)=[CH:4][N:3]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N

Procedure:
A stirred solution of 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine [prepared by the method of Taylor and Ray--JOC, 52, 3997 (1987)], 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid [commercially available or prepared by the method of Thompson and Gaudino--JOC, 49, 5237 (1984)], 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine.