Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:19]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])C>C1COCC1.CO>[Cl:31][C:28]1[S:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:19]3[C:9]4=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]4[CH:7]=[C:6]3[C:4]([OH:5])=[O:3])[CH:25]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc2cc(C(=O)O)n(Cc3cc(-c4ccc(Cl)s4)on3)c2cn1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 1.3 g (2.814 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 30 mL THF and 15 mL MeOH 11.26 mL 1M LiOH solution were added and the mixture was stirred at 50° C. for 3 h. The organic solvents were removed in vacuo, 50 mL of water were added and the pH was adjusted to pH 2 with 1N HCl solution. The desired product precipitated and was filtered, washed with water and dried over P2O5. Yield 1.11 g.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:17])[C:9]=1[NH:10]2.[C:18]([Si](C)(C)C)([F:21])([F:20])[F:19].[F-].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8]([C:18]([F:21])([F:20])[F:19])([OH:17])[C:9]=1[NH:10]2
Reactant: O=C1CCCc2c1[nH]c1c(Cl)cc(Cl)c(Cl)c21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 5,6,8-trichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.3 mmol) in anhydrous THF (5 mL), cooled to 0° C., CF3TMS (0.5 mL) followed by CsF (0.026 g, 0.17 mmol) were added. The reaction mixture was stirred at 0° C. for 1 h, cooled to room temperature and stirred for an additional 16 h, quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to afford the title compound as a yellow solid (0.042 g, 32%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.42 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 3.02 (m, 2H), 2.21 (m, 1H), 1.96 (m, 3H).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=O>C1C=CC=CC=1>[CH3:1][NH:2][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: O=Cc1ccccn1
Reactant: CN
Solvent: c1ccccc1
Product: CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Methylamine gas was bubbled through the benzene solution(60 ml) of 10.7 g(100 mmol) of 2-pyridinecarboxaldehyde for 2 hours. Benzene was distilled off under a reduced pressure and the residue was taken up in 40 ml of ethanol. To the resulting solution was added 5.7 g of NaBH4 in three portions and the resulting mixture was stirred at room temperature for 8 hours. To the reaction mixture was added 0.5N hydrochloric acid with care not to allow the pH below 6. 300 ml of dichloromethane was added thereto and the resulting solution was washed three times with 1M NaHCO3 solution of pH 10. The organic layer was concentrated under a reduced pressure to give 10.4 g of the title compound(yield: 85%).
Reaction SMILES: O.[NH2:2][C:3]1[NH:4][C:5](=[O:22])[C:6]2[S:11][C:10](=[O:12])[N:9]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:7]=2[N:8]=1.S1C2C(=O)N=CNC=2NC1=O>>[CH2:20]([OH:21])[C@H:18]1[O:19][C@@H:13]([N:9]2[C:10](=[O:12])[S:11][C:6]3[C:5]([N:4]=[C:3]([NH2:2])[NH:8][C:7]2=3)=[O:22])[C@H:14]([OH:15])[C@@H:16]1[OH:17]
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=c1[nH]c2[nH]cnc(=O)c2s1
Solvent: O
Product: Nc1nc(=O)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1

Procedure:
5-Amino-3-beta-D-ribofuranosylthiazolo(4,5-d)pyrimidine-2,7(3H,6H)-dione monohydrate; Thiazolo(4,5-d)pyrimidine-2,7(3H,4H)-dione, 5-amino-3-beta-D-ribofuranosyl-, monohydrate) is administered in association with a compound of the invention (e.g., represented by a formula selected from I-XXIII).
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]=[C:10]=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH3:27]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH3:27])[N:15]([CH2:14][CH2:13][NH:12][C:10]([NH:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Reactant: CCOP(=O)(N=C=O)OCC
Product: CCOP(=O)(NC(=O)NCCn1c(C)nc2c(N)nc(C)c(C)c21)OCC

Procedure:
Using the method of Examples 118-133, diethoxyphosphinyl isocyanate was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 399.1926.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K+].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH-:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].O.C(OCC)C>CN(C=O)C.C(O)(=O)C>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:3]=2)(=[O:36])=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 6.1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (Example 1, Section a) to d)) in 100 ml of dry DMF 8.8 g of 4-tert.-butyl benzene sulfonamide potassium salt was added at room temperature. The solution was stirred over night at room temperature. The solution was added to a mixture of 150 ml of water and 100 ml of diethyl ether. The pH was adjusted to 5 by adding acetic acid. The precipitate that formed was collected, washed with water and diethyl ether. The resulting powder was suspended in boiling ethyl acetate. The mixture was allowed to cool in an icebath. Eventually, the solid material was collected and dried to yield 6.6 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)4-pyrimidinyl]-benzene sulfonamide as beige crystals. LC-MS: tR=5.80 min, [M+1]+=525.31, [M−1]−=523.48.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[CH3:15].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:15]
Reactant: COC(=O)c1ccc(OCCO)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OCCO
Temperature: 70 °C
Reaction time: 22 h
Yield: 44.1 %

Procedure:
To a solution of methyl 4-(2-hydroxyethoxy)-3-methyl-benzoate (1.87 g, 8.9 mmol) in dioxane (16 mL) was added 1N NaOH (5 mL) and the reaction mixture was heated at 70° C. for 18 hours. 5M NaOH (0.5 ml) was added and the reaction was stirred at 70° C. for 22 hours. The reaction mixture was cooled and solvent was concentrated in vacuo and the crude residue was dissolved in water (20 mL) and extracted with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1 M HCl solution and extracted with ethyl acetate (2×20 mL). The organics were separated, dried with Na2SO4 and concentrated in vacuo to give 4-(2-hydroxyethoxy)-3-methyl-benzoic acid (0.77 g, 44%) as a white solid. ESI-MS m/z calc. 196.1. Found 197.0 (M+1)+; Retention time: 0.72 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.96-7.49 (m, 2H), 7.00 (d, J=8.6 Hz, 1H), 4.87 (t, J=5.4 Hz, 1H), 4.06 (t, J=5.0 Hz, 2H), 3.75 (q, J=5.1 Hz, 2H), 2.17 (d, J=20.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4](C)[N:3]=1.[CH3:12]C1C2OC=CC=2C(=O)NC=1.CC1NC(=O)C2C=COC=2C=1>>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH3:12])=[CH:4][N:3]=1
Reactant: Cc1c[nH]c(=O)c2ccoc12
Reactant: Cc1cc2occc2c(Cl)n1
Agent: Cc1cc2occc2c(=O)[nH]1
Product: Cc1cnc(Cl)c2ccoc12

Procedure:
The title compound was prepared according to the procedure described for 4-chloro-6-methylfuro[3,2-c]pyridine (Example 12, Step B) except 7-methylfuro[3,2-c]pyridin-4-(5H)-one was substituted for 6-methylfuro[3,2-c]pyridin-4-(5H)-one. Title compound was obtained in 98% crude yield and used as is. A portion was crystallized from cold diethyl ether for microanalysis, mp. 51.5°-53° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[N+:14]([CH:17]([CH:20]=O)[CH:18]=O)([O-:16])=[O:15].[Na]>C(O)(=O)C>[N+:14]([C:17]1[CH:20]=[N:12][C:9]2=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=[C:10]2[CH:18]=1)([O-:16])=[O:15]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1ccn(-c2ccccc2)n1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2nn(-c3ccccc3)cc2c1
Temperature: 25 °C

Procedure:
Compound 3A (3.0 g, 18.868 mmol) and sodium nitromalonaldehyde monohydrate (2.623 g, 18.868 mmol, prepared according to the procedures reported in Org. Synth. IV. 844, (1963)) in acetic acid (100 mL) was refluxed for 24 hours. After cooling to RT, the reaction was concentrated under reduced pressure to remove most of the acetic acid. The resulting residue was dissolved in CH2Cl2 (200 mL), then washed with IN aqueous NaOH (2×200 mL), water (100 mL), saturated NaCl (100 mL). The organic layer was dried (MgSO4), and concentrated to give a dark brown residue. The residue was purified by silica gel column chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (1:99 ratio) to give the title compound, 5-nitro-2-phenyl-2H-pyrazole[3,4-b ]pyridine as a beige colored solid (300 mg). LC/MS (method A): retention time=2.62 min; (M+H)+=241.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=[O:7]>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:1]
Reactant: [Li]C
Reactant: Cc1ccc([N+](=O)[O-])cc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])cc1C(C)O
Yield: 100.8 %

Procedure:
Following the General Procedure of Description 8, MeTiCl3 was freshly prepared prior to use from commercial titanium tetrachloride (TiCl4) (10.0 mL, 17.3 g, 91.0 mmol) and methyl lithium (MeLi) (1.6 M in Et2O, 57.0 mL, 91.0 mmol) in anhydrous diethyl ether (Et2O) (400 mL). A solution of 2-methyl-4-nitro-benzaldehyde (5j) (12.4 g, 75.01 mmol) in anhydrous Et2O (200 mL) was added. Aqueous work-up afforded 13.7 g (99% yield) of the target compound (5k) as a yellow solid. The material was of sufficient purity to be used directly in the next step without further isolation and purification procedures. Rf: ˜0.47 (EtOAc/Hxn=1:2 v/v). 1H NMR (300 MHz, CDCl3): δ 8.41 (d, J=2.4 Hz, 1H), 8.00 (dd, J=8.4, 2.4 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 5.16 (q, J=6.3 Hz, 1H), 2.43 (s, 3H), 1.96 (br. s, 1H), 1.50 (d, J=6.3 Hz, 3H) ppm. The analytical data correspond to the data of compound (5b) of Method A.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@H:16]([OH:33])[C@H:17](OS(C1C=CC(C)=CC=1)(=O)=O)[C:18]([O:20][CH3:21])=[O:19].C(OCC)(=O)C>CN(C)C=O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@H:16]1[O:33][C@H:17]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1O[C@@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
0.26 ml of water and 1.20 g of potassium carbonate were added to a solution of 1.12 g of methyl (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-(p-toluenesulfonyloxy)propionate dissolved in 15 ml of dimethylformamide, and the mixture was stirred at room temperature overnight. Ethyl acetate and ice water were added to the reaction mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1) to obtain 502 mg of methyl (2R,3R)-3-(2,4-difluorophenyl)-2-epoxypropionate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.Cl.[CH3:12][O:13][NH2:14].C([O-])(=O)C.[Na+]>CO>[CH3:12][O:13][N:14]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: CON
Reactant: O=C1COc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C1COc2ccccc21
Yield: 89.1 %

Procedure:
6.7 g (0.05 mol) of benzofuran-3-one are boiled under reflux with 4.2 g (0.05 mol) of O-methylhydroxylamine hydrochloride and 4.1 g (0.05 mol) of sodium acetate in 50 ml of methanol for 3 hours. The solvent is distilled off in vacuo and the reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. 7.27 g (89.2% of theory) of crude benzofuran-3-one O-methyl oxime are obtained. For analysis, it is distilled under 2 torr at 70° C. in a bulb tube. An oil is obtained which, both according to the NMR analysis and according to the HPLC analysis, comprises two stereoisomers (79% of isomer B and 21% of isomer A).
Reaction SMILES: O.[CH3:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1.[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[I:14][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[CH3:2]
Reactant: Cc1csc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 24.7 %

Procedure:
7-Methylthieno[2,3-b)pyrazine-2,3(1H,4H)-dione hydrate (1.0 g, 5.0 mmol) was suspended in 60 ml of acetic acid and benzyltrimethylammonium dichloroiodate 95% (2.1 g, 5.75 mmol) and zinc chloride (1.64 g, 12.0 mmol) was added. The mixture was stirred for 4.5 h at room temperature, the precipitate was filtered off, washed with acetic acid, water and dried. The crude compound (1.13 g) was recrystallized from acetic acid/water and twice from ethanol to give 0.38 g (24%) of the title compound. Decomp. above 240° C. 1H-NMR (DMSO-D6, δ): 2.12 (s, 3H), 11.98 (s, 1H), 12.22 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[CH:19]=1>[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([CH:32]([C:31]1[C:26]2[N:27]([C:23]([C:21]3[S:22][C:18]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=4)=[CH:19][C:20]=3[CH3:39])=[C:24]([CH3:38])[N:25]=2)[N:28]=[C:29]([CH3:37])[CH:30]=1)[CH2:35][CH3:36])[CH3:34]
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C(F)(F)F)n4)cc3C)c(C)nc12
Yield: 43.1 %

Procedure:
Using a procedure similar to Example 25, 2-chloro-6-trifluoromethyl-pyridine (0.29 mL, 1.22 mmol), 1.34 M n-Bu-Li (0.80 mL, 1.07 mmol), ZnCl2 (2.14 mL, 1.07 mmol), 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.20 g, 0.44 mmol, 43%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.18 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.30-3.40 (m, 1H), 6.69 (s, 1H), 7.50 (dd, J=7.5, 0.9 Hz, 1H), 7.65 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.84 (dd, J=7.9, 7.5 Hz, 1H). LC/MS (m/z): calcd. for C24H25F3N4S (M+H)+: 459.3. found: 459.2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-5-nitrobenzimidazole in concentrated sulfuric acid was added fuming nitric acid at −5° C. Upon addition of the fuming nitric acid, the reaction mixture was warmed to 0° C. held for 1 h and poured into crushed ice. The precipitate which formed was filtered, washed with water, and dried overnight at 40° C. to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([F:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:17])=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1OS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([F:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:20]1[CH:21]=[CH:22][C:23]([Si:25]([CH3:27])([CH3:26])[CH3:28])=[CH:24][C:19]=1[F:18])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CCOC(=O)c1c(N)c2cncc(F)c2n1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cncc(F)c2n1C
Temperature: 25 °C
Yield: 138.3 %

Procedure:
A degassed solution of 3-amino-7-fluoro-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (900 mg, 3.8 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (1.44 mg, 4.56 mmol), Pd2dba3 (174 mg, 0.19 mmol), Xantphos (220 mg, 0.38 mmol) and Cs2CO3 (2.48 g, 7.6 mmol) in toluene (10 ml) was heated at 150° C. for 20 minutes using microwave irradiation. The reaction mixture was cooled to ambient temperature then filtered through a pad of Celite® washing with ethyl acetate. The filtrate was concentrated in vacuo and the resultant residue subjected to flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in cyclohexane) to provide the title compound as a yellow/orange solid (2.12 g, 69%). LCMS (method B): RT=4.15 min, M+H+ 404.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][NH:9][O:10][CH3:11].C1(C)C=CC=CC=1.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>O>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CNOC
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)N(C)OC

Procedure:
Potassium carbonate (62.4 g) was added in portions at 0° C. over 10 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (250 g) in water (250 ml), then toluene (250 ml) was added and the mixture was stirred until the internal temperature reached 2° C. Butyryl chloride (26 ml) was added dropwise over 10 minutes, then the mixture was stirred at 0° C. for 5 minutes and at ambient temperature for 1 hour. The aqueous phase was separated and shaken with toluene (2×100 ml), then the combined toluene solutions were dried (Na2SO4) and the solvent was removed in vacuo to give N-methoxy-N-methylbutyramide (21.0 g) as a pale-yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH:31]([NH:34][C@@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)([CH3:33])[CH3:32].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]([CH:31]([CH3:33])[CH3:32])[C@@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)N[C@@H](C)COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3ccc([N+](=O)[O-])cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Over a period of about 5 min, a solution of 0.42 g of 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridin-6-yl)benzoyl chloride in 10 ml of acetonitrile is added dropwise to a mixture, cooled with ice/water, of 0.31 g of 4-nitro-benzoic acid (S)-2-isopropylamino-propyl ester hydrochloride and 0.5 g of triethylamine in 10 ml of acetonitrile. The reaction mixture is stirred at RT for about 15 h and then substantially concentrated under reduced pressure, and the highly viscous residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The resin-like residue is purified by silica gel chromatography, and the product fraction is separated off and concentrated. This gives 0.34 g of the title compound as a solid foam.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH:10]([CH3:26])[CH2:11][CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1COCC1>[CH3:9][CH:10]([CH3:26])[CH2:11][C:12]1([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25]
Reactant: CC(C)CC1CCN(CCc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.7 %

Procedure:
LDA (2.0M, 11.5 mL, 23.0 mmol) is added to a solution of 3-(2-methylpropyl)-1-(2-phenylethyl)-2-pyrrolidinone (4.70 g, 19.2 mmol) and THF (80 mL) at -78° C. The solution is stirred at -78° C. for 45 minutes, and tert-butyl bromoacetate (3.4 mL, 23 mmol) is added. The solution is allowed to warm to 0° C. over 2 hours and is allowed to stir overnight at room temperature. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgSO4) and purification by column chromatography (10% EtOAc/5% CH2Cl2 /hexane) to give 4.67 g (68%) of the title compound as a colorless oil. An analytical sample is crystallized from hexane (mp 50° C.).