Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH:13](O)[CH3:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C1C=CC=CC=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.C(=O)([O-])[OH:33].[Na+]>N1C=CC=CC=1.O>[C:23]([O:30][CH2:14][CH2:13][S:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)(=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1
Reactant: CC(O)SCCc1ccc2c(c1)OCO2
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCCSCCc1ccc2c(c1)OCO2)c1cccnc1
Temperature: 0 °C

Procedure:
4 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]ethanol prepared in the same manner as that of Example 2 was dissolved in 20 ml of pyridine. 50 ml of benzene was added to the solution. 4.7 g of nicotinic chloride hydrochloride was added thereto under stirring and the mixture was heated on a boiling water bath for 2 h. The reaction mixture was poured into ice/water. 100 ml of water and sodium hydrogen-carbonate were added thereto to make it weakly alkaline. After extraction with ethyl acetate, the ethyl acetate layer was washed with water four times and dried over sodium sulfate. The solvent was distilled off and the residue was purified according to silica gel column chromatography (benzene:ethyl acetate=3:1) to obtain 2 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10](CO)=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:5])=[O:4].Cl[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.CN(C=[O:37])C>O>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:9]([CH:15]([CH3:16])[CH3:17])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1CO
Reactant: CN(C)C=O
Agent: c1c[nH]cn1
Solvent: O
Product: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O[Si](C)(C)C(C)(C)C
Yield: 92 %

Procedure:
A solution of 4-hydroxymethyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 149, 760.0 mg, 2.55 mmols), chloro-tert-butyl-dimethylsilane (470.0 mg, 3.18 mmols), and imidazole (225.0 mg, 3.25 mmols) in 6 mL DMF was stirred at 25° C. for 17 hours. The solution was diluted with H2O and extracted with Et2O and the combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO3, H2O, and saturated aqueous NaCl, and dried (MgSO4) before being concentrated under reduced pressure. Column chromatography (2-5% EtOAc-hexanes) afforded 970.0 mg (92%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:28]2[C:29]([C:30]#[N:31])=[C:32]([F:35])[CH:33]=[CH:34][C:27]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.12 g, 6.0 mmol) in DCM (7 mL) was added triethyloxonium tetrafluoroborate (969 mg, 5.1 mmol) and the reaction mixture stirred at RT for 3 h, during which time the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (7 mL). 3-Amino-6-fluoro-2-phenylaminobenzonitrile (400 mg, 1.8 mmol) was added and the reaction was heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (411 mg, 61%). LCMS (Method C): RT=3.55 min, [M+H]+=381.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 1-(3-chloro-phenyl)-2-nitro-ethanol (26 g, 0.14 mol) in DMF (50 mL) were added imidazole (28.6 g, 0.42 mol) and chlorotriethylsilane (25.3 g, 0.17 mol). The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude product was purified by flash chromatography (2% EtOAc/hexane) to yield the title compound (37 g, 91%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (1H, s), 7.27-7.32 (3H, m), 5.40 (1H, dd, J=3.2, 9.5 Hz), 4.51 (1H, dd, J=9.5, 12.1 Hz), 4.36 (1H, dd, J=3.3, 12.1 Hz), 0.85 (9H, t, J=7.5 Hz), 0.54 (6H, q, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:15][C:16]=2[CH3:17])=[O:10])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(O)(C(F)(F)F)=O.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:15][C:16]=2[CH3:17])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCNCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 209 mg of 1-Boc-piperizine in 1 mL of BuOH. The reaction mixture was evaporated to afford tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate. 150 mg of tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate was treated with TFA (1 mL) containing trace amounts of H2O for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 0.1N sodium hydroxide and brine, dried (MgSO4) and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide. MS (Q1) 408.3 (M)+.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12](O)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][CH3:5])=[O:2].C(O)=[O:20].C([O-])=O.[Na+].C1(C=CC(O)=CC=1)O>O1CCOCC1.O>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:13]([OH:17])[CH:14]=[CH:15][C:16]1=[O:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC(O)c1ccco1
Reactant: O=CO
Agent: O=C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCC1C(=O)C=CC1O

Procedure:
A stirred mixture of 2.0g (7.87 mmol) of α-(6-carbethoxyhexyl)furfuryl alcohol (Example 4), 5.93 ml of 97% formic acid, 268 mg of sodium formate, 10 mg of hydroquinone, and 40 ml of 3:2 dioxane-water is stirred at reflux for 18 hr. The solution is cooled, saturated with salt, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give an amber oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1(CN)CCCC1>>[CH:5]1([CH2:1][NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:4][CH2:3][CH2:2][CH2:23]1
Reactant: NCC1CCCC1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NCC2CCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (cyclopentylmethyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.09 (m, 2H), 1.30-1.38 (m, 2H), 1.38-1.49 (m, 4H), 1.80-1.94 (m, 4H), 2.26 (s, 3H), 3.14 (bs, 2H), 4.70 (bs, 2H), 7.37-7.42 (m, 2H), 7.91 (t, J=7.52, 1H), 8.09-8.13 (m, 1H), 8.43 (s, 1H), 8.55-8.62 (m, 1H), 12.65 (bs, 1H); MS (ESI) m/z 312.8 (M+1)+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:26][NH2:27].[NH2:28][NH2:29].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][NH:27][C:6]1[C:3]2[C:4]([NH2:5])=[N:28][NH:29][C:2]=2[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Reactant: CN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2cc(NC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a 20-mL vial was added 2,6-difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (100 mg, 0.290 mmol), DMF (1 mL), and methylamine (2 M in THF, 0.174 mL, 0.347 mmol). The reaction was stirred overnight at room temperature. An additional 0.6 equiv of methylamine solution (2 M in THF) was added and the reaction stirred at room temperature for 3 days over the weekend. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethanol (1.5 mL), and hydrazine (0.101 mL, 1.737 mmol) and Hunig's base (0.152 mL, 0.869 mmol) were added. The reaction was heated at 150° C. for 60 minutes in a microwave reactor. The reaction mixture was concentrated, and the residue dissolved in DMSO and purified by RPHPLC. The product fractions were combined, basified with NaHCO3 and extracted with EtOAc. The organics were combined, dried and concentrated to afford the title compound (40.5 mg) as a brown solid. LC-MS (ES) m/z=369 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 2.73-2.91 (m, 6H), 3.03-3.15 (m, 1H), 3.39-3.52 (m, 1H), 3.62 (d, J=2.5 Hz, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.01-4.15 (m, 1H), 4.41-4.55 (m, 1H), 5.07 (s, 2H), 5.59-5.74 (m, 1H), 6.26-6.62 (m, 3H), 7.14 (br. s., 1H), 11.35 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])([CH3:5])[C:3]#[CH:4].CO.O.Cl>O1CCCC1>[CH3:5][C:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)Oc1cccc(C(=O)OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#CC(C)(C)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.7 %

Procedure:
To a solution of methyl 3-[(1,1-dimethylprop-2-yn-1-yl)oxy]benzoate (4.0 g, 18.3 mmol) in tetrahydrofuran (10 mL) were added lithium hydroxide•monohydrate (865 mg, 20.6 mmol), methanol (10 mL) and water (5 mL), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid, and extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.8 g, 99%) as a colorless oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH:19]([O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OC(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.3 %

Procedure:
To 220 mg of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with acetonitrile. Filtration of the precipitate gave 210 mg of 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: I[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.O.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>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][N:10]=[CH:11][C:2]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:27]
Reactant: Cc1ccccc1B(O)O
Reactant: CNC(=O)c1ccncc1I
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccncc1-c1ccccc1C
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a suspension of 450 mg (1.7 mmol) 3-iodo-N-methyl-isonicotinamide in 10 ml toluene were added successively 60 mg (0.05 mmol) tetrakis(triphenylphosphine)palladium(0), 2.5 ml 2 M sodium carbonate solution in water and 342 mg (2.5 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 20 h. The aqueous layer was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 341 mg (87%) of the title compound as a light yellow solid. M.p. 90-92° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10](=[O:27])[CH:11]=[CH:12][N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:4]([F:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC>C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[C:34]([C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10](=[O:27])[CH:11]=[CH:12][N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:4]([F:28])[CH:3]=1)(=[O:36])[CH3:35]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)cccc2c1-c1c(F)cc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(4-bromo-2,6-difluorophenyl)-6-(2,4-difluorophenyl)-2H-quinolizin-2-one (30 mg, 0.067 mmol) in toluene (1.4 mL) was added tributyl(1-ethoxyvinyl)stannane and tetrakis(triphenylphosphine)palladium (7.74 mg, 0.007 mmol) and heated to 90° C. for 1½ h. The reaction was cooled, filtered through celite, and diluted with THF. The mixture was added 2N HCl and stirred for 20 min to complete the reaction. The crude mixture was diluted with H2O and EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, and condensed. The crude residue was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (7.9 mg).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[F:20][C:21]([F:34])([C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[CH:22]=[CH2:23]>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:21]([F:34])([C:24]([F:32])([F:33])[C:25]([F:30])([F:31])[C:26]([F:27])([F:29])[F:28])/[CH:22]=[CH:23]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)/C=C/c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Palladium(II) acetate (0.5 mg, 0.002 mmol) was added to a solution of 1 (15.0 mg, 0.0472 mmol) and 3,3,4,4,5,5,6,6,6-nonafluorohex-1-ene (8.9 mg, 0.089 mmol) in 0.44 g of 95% aqueous ethanol. The reaction mixture was stirred at room temperature for 1 d and filtered through a pad of Celite 545. Removal of the solvent gave a pale yellow oil which was purified by SiO2 column chromatography with hexane to give 7a as colorless oil (17.1 mg; 81%): IR (ATR): {tilde over (v)}=2918, 2849, 1663, 1234, 1134, 844 cm−1. MS (GC, EI): m/z=448 [M+], 429 [M+-F], 302 [M+-SF6], 279 [M+-C3F7], 152 [M+-C3F12S]. 1H NMR (500 MHz, CDCl3): δ=7.80 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.20 (d, J=16.2 Hz, 1H), 6.30 (dt, J=16.2, 12.0 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.7 (C), 137.7 (CH), 136.5 (C), 127.8 (2CH), 126.7 (2CH), 117.7 (CH) ppm. 19F NMR (470 MHz, CDCl3): δ=83.4 (quint, J=150 Hz, 1 F), 62.6 (d, J=150 Hz, 4 F), −81.0 (s, 3 F), −112.0 (s, 2 F), −124.0 (s, 2 F), −125.7 (s, 2 F) ppm.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=[O:12])([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(=O)(O)O.[NH2:18][NH:19][C:20]([NH2:22])=[NH:21].C(=O)=O>O>[N:1]([CH2:2][C:3]([O-:5])=[O:4])([CH2:6][C:7]([O-:9])=[O:8])[CH2:10][C:11]([O-:13])=[O:12].[NH2:18][NH:19][C:20]([NH2:22])=[NH2+:21].[NH2:18][NH:19][C:20]([NH2:22])=[NH2+:21].[NH2:18][NH:19][C:20]([NH2:22])=[NH2+:21]
Reactant: N=C(N)NN
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NNC(N)=[NH2+]
Product: O=C([O-])CN(CC(=O)[O-])CC(=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Nitrilotriacetic acid (1.0 g, 5.23 mmol) was dissolved in 10 ml of distilled water. Aminoguanidine bicarbonate (2.14 g, 15.69 mmol) was added in portions at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for three days. The water was removed in vacuo with heating to approximately 90° C. The product was isolated as a white solid.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH:7]=[CH:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11]
Reactant: [H][H]
Reactant: C[C@]12C=C[C@H](O1)C(=O)CC2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H](O1)C(=O)CC2=O
Yield: 56.7 %

Procedure:
To a solution of (1R*,5S*)-1-methyl-8-oxabicyclo[3.2.1]oct-6-ene-2,4-dione (12.0 g, 0.079 mol) in ethyl acetate (100 ml) is added 10% palladium on carbon (2.4 g), followed by stirring under a 1 bar hydrogen atmosphere for 24 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford (1R*,5S*)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6.90 g) as pale yellow solid.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)C.C1(P([Pd-4](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)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:21]1[CH:22]=[CH:23][S:19][CH:20]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: OB(O)c1ccsc1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COCOc1c(-c2ccsc2)c(C)cc2cc(OC)ccc12
Temperature: 160 °C

Procedure:
2-bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.35 g, 1.12 mmol), thiophene 3-boronic acid (0.359 g, 2.81 mmol), tetrakis(triphenylphosphino)palladium (0) (0.031 g, 0.027 mmol), 2 M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) were added in a sealed tube and heated at 160° C. for 20 min. Reaction mixture was cooled to room temperature then diluted with diethyl ether. The mixture was washed with water followed by brine, dried over Na2SO4, filtered and concentrated. The crude material purified with a gradient of 1% EtOAc to 4% EtOAc in hexanes over 45 min to afford the title compound (199) as oil, 0.347 g, (98%). 1H NMR (400 MHz, d-CDCl3): δ 2.29 (s, 3H), 3.23 (s, 3H), 3.93 (s, 3H), 4.76 (s, 2H), 7.06-7.07 (m, 1H), 7.10-7.15 (m, 2H), 7.25-7.26 (m, 1H), 7.40-7.42 (m, 2H), 8.04 (d, J=9.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([OH:51])=[O:50])[CH2:45][CH2:46][CH2:47][NH2:48])=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:48][CH2:47][CH2:46][CH2:45][C@@H:44]([C:49]([OH:51])=[O:50])[NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
6.00 g (12.33 mmol) of the compound from example 1A was dissolved in 120 ml dichloromethane. 2.57 g (12.33 mmol) N2-(tert-Butoxycarbonyl)-L-ornithine was added. The reaction mixture was split into 6 portions. The portions were heated for 90 min in a sealed tube at 75° C. in a microwave synthesizer. The combined reaction mixture was extracted with approx. 100 ml saturated ammonium chloride solution. The aqueous phase was twice back extracted with approx. 30 ml dichloromethane each. The combined organic phases were extracted with approx. 50 ml brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 40/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.63 g (4.06 mmol, 33% of theory, 89% purity) of the desired product.