Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11]C(O)=O)=[C:6]([F:15])[CH:5]=1.[Xe](F)[F:18].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][F:18])=[C:6]([F:15])[CH:5]=1
Reactant: F[Xe]F
Reactant: COC(=O)c1ccc(OCC(=O)O)c(F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCF)c(F)c1
Yield: 51.5 %

Procedure:
A solution of 4-carboxymethoxy-3-fluoro-benzoic acid methyl ester (2.73 g, 11.9 mmol) in CH2Cl2 was treated with xenon difluoride (2.23 g 13.1 mmol, 1.1 eq.) at r.t. for 16 hrs. in a teflon reactor vessel. After addition of satd. NaHCO3 solution the organic phase was dried over Na2SO4 and evaporated. The residue was chromatographed over 100 g SiO2 (Merck 230-400 mesh) with EtOAc/nHexane 1:4 affording the title compound (1.24 g, 51% yield) as a white solid. MS: m/e=202 (M+).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH:1]1([NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of 20.00 g (0.28 mol) cyclobutylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 22.00 g of diketene (0.26 mole) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 24.60 g (0.16 mol, 61% yield) of a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([OH:22])=O)[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2C=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.N1CCCCC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([N:30]4[CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]4)=[O:22])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(c1cn2c(-c3ccccc3)ncc2c2ccccc12)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from part 9 (95 mg), BOP (220 mg), piperidine (56 mg) and TEA (67 mg) in 2 ml of DMF is stirred at room temperature for 18 hours. The mixture is added to aqueous NaHCO3 solution and extracted with EtOAc. The organic layer is washed with brine and water, dried (Na2SO4), filtered and concentrated to afford a foam. Purification on a silica gel column, eluting with 5% methanol in methylene chloride, gives the title compound. 1H NMR (CDCl3) δ 1.38–1.50 and 1.60–1.80 (6H, m), 3.18–3.36 (2H, m), 3.65–3.95 (2H, m), 7.40–7.60 (6H, m), 7.75 (2H, d), 7.95 (1H, s), 8.05 (1H, s), 8.10 (1H, d). The hydrochloride salt was prepared by treating the free base in EtOAc with a solution of hydrogen chloride in ether and collecting by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[OH-].[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O1CCOCC1>[CH3:8][N:7]([CH3:9])[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-amino-N,N-dimethylbenzamide (1.3 g) in 1,4-dioxane(20 ml) was added 1N sodium hydroxide (23.4 ml) and phenyl chloroformate (1.5 ml) successively in an ice-cooled bath. The bath was removed and the reaction mixture was stirred vigorously for 3 hours during which time, phenyl chloroformate (0.7 ml) was further added. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated sodium chloride solution. After dried over anhydrous magnesium sulfate and filtered, the solvent was removed in vacuo and the residual oil was purified by flash chromatography eluting with ethyl acetate-n-hexane (2:1, V/V) to give a solid, which was recrystallized from benzene-n-hexane (5:1, V/V) to afford phenyl 3-(dimethylcarbamoyl)phenylcarbamate (1.4 g) as a colorless powder.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CO>[C@@H:6]1([NH:24][C:25]([N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCNCC
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: CCN(CC)C(=S)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine (1.102 g., 0.002 mole) was added to a solution of diethylamine (1.76 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 21 hours in the pressure bottle with the stopper well closed. The mixture was filtered and the filtrate was evaporated to a brownish syrupy material below 30° in vacuo. The residue was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky solid. The supernatant was decanted, and the residual solid was dried at room temperature in vacuo. The solid was partially dissolved in ethyl acetate to give a slurry, and chromatographed on a column of silica gel (1×20 cm) using ethyl acetate as the first solvent (60 ml.) and acetone as the second solvent (100 ml.). The 100 ml. of acetone effluent was reduced to ca. 25 ml. and was set aside at room temperature. The beige crystalls were filtered, washed with acetone, and dried at room temperature in vacuo, yielding 0.51 g. (81.5%); m.p. 106°-109°(dec.)
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29])[CH3:24]>C1COCC1.C(OCC)(=O)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28]([NH:22][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:29])[CH3:24]
Reactant: CCOC(=O)CC(=O)O
Reactant: Nc1cc(-c2ccc(F)cc2)on1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Yield: 832.3 %

Procedure:
Diisopropyl carbodiimide (0.07 mL, 0.45 mmol) and 5-(4-fluoro-phenyl)-isoxazol-3-ylamine (67 mg, 0.037 mmol) were added to a stirred solution of malonic acid monoethyl ester (50 mg, 0.37 mmol) in THF (1 mL) and stirring was continued at reflux temperature for 4 hrs. The mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate and washed with water, followed by brine solution. The organic layer collected was dried over Na2SO4 and concentrated under reduced pressure to afford 90 mg (81.8% Yield) of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)([CH3:16])[C:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8]CC)=O)=[O:4].OS(O)(=O)=O>>[OH:8][C:6]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:2]([CH3:16])([CH3:1])[C:3](=[O:4])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
Diethyl 2-(2-methyl-2-(3-(trifluoromethyl)phenyl)propanoyl)malonate (2.80 g, 7.5 mmol) was added to H2SO4 (40 mL, 237 mmol), and the mixture was stirred at room temperature for 1 hour. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as a yellow oil. The crude oil was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a yellow semi-solid (1.07 g). MS (m/e)=329.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([NH:17][C:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH2:5][C@H:6]([C:13]([O:15]C)=O)[NH:7]2.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH3:27][N:28]([CH2:29][CH2:30][NH:31][C:13]([C@H:6]1[CH2:5][C@H:4]([NH:17][C:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)=[O:15])[CH3:32]
Reactant: CN(C)CCN
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Product: CN(C)CCNC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Reaction time: 6 h

Procedure:
Trans 5,7-dichloro-2-methoxycarbonyl-4-phenylmethylcarbonylamino-1,2,3,4-tetrahydroquinoline (Example 37a) (0.3 g) was dissolved in N,N-dimethylethylenediamine (30 ml) and allowed to stand at room temperature for 6 h. After this time the reaction mixture was filtered and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml) then brine (100 ml). The organic solution was dried (MgSO4), filtered and concentrated in vacuo to give a solid which was triturated with diethyl ether and collected by filtration to give the title compound (0.19 g) as a colourless solid, m.p. 158°-159° C.; δ (360 MHz, DMSO) 1.54 (1H, ddd, J=13.0, 12.5 and 4.0 Hz, CHACHBHCCHD), 2.08 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.16 (6H, s, N(CH3)2), 2.33 (2H, t, J=6.7 Hz, CH2CH2N(CH3)2, 3.21 (2H, m, CH2CH2N(CH3)2), 3.37 (1H, d, J=14.0 Hz, CHEHFPh), 3.47 (1H, d, J=14.0 Hz, CHEHFPh), 3.74 (1H, dm, J=12.5 Hz, CHACHBHCCHD), 4.99 (1H, m, CHACHBHCCHD), 6.66 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.79 (2H, m, 6-H or 8-H and ArNH), 7.26 (5H, m, ArH), 8.01 (1H, br, s, CONHCH2CH2N(CH3)2), 8.44 (1H, d, J=7.2 Hz, CHDNHCO); m/e 488 (M+); Found C, 58.47; H, 5.84; N, 12.39 C22H26Cl2N4O2 requires C, 58.80; H, 5.83; N, 12.47%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[NH:12][C:11]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:31])=O.S1(CCCC1)(=O)=O.[OH-].[Na+]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[N:12]=[C:11]([Br:31])[N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: Fc1ccc(-c2nc(Br)n(CCCc3ccccc3)c2-c2ccncc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,3-Dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-2H-imidazol-2-one (100 g, 0.26 mol) was mixed with POBr3 (268.7 g, 0.93 mol) and sulfolane (200 g) and the reaction mixture was heated to a temperature of 120–125° C. for 1–2 h. Upon completion, the reaction mixture was cooled to 40° C. Cautiously, over about 30 min, 2N NaOH solution (53 g) was added. Additional 2N NaOH solution (53 g) was then added at faster rate. The reaction mixture was then cooled to 15–20° C. and 4N NaOH solution (802 g) was added to adjust the solution to pH 7–8. The aqueous phase was extracted with t-butylmethyl ether (3×143 g) and the organic phases combined. To the combined organic phase was added t-butylmethyl ether (107 g). The solution was washed with water (2×150 g), resulting in the precipitation of a solid, which was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:17][CH2:18]O)[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25].P(Cl)(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:17][CH2:18][Cl:28])[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25]
Reactant: CCOC(=O)c1cn(CCO)c2cc(-n3cccc3)c(F)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCCl)c2cc(-n3cccc3)c(F)cc2c1=O
Reaction time: 2 h

Procedure:
3.5 g (0.01 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate are suspended in 30 ml chloroform, 3 ml of Cl3PO are added, the mixture is kept at room temperature for 2 hours and evaporated to dryness, the residue is redissolved in chloroform, the resulting solution is washed with a sodium bicarbonate solution and then with water and evaporated, and the precipitate is recrystallized from dimethylformamide to give 3.3 g of a solid melting at 254°-256° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: N#Cc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (113 mg, 1.20 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(3-cyanophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 26; 200 mg, 0.60 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (139 mg, 0.72 mmol) and 1-Hydroxybenzotriazole (98 mg, 0.72 mmol) in DMF (20 ml) sunder nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 170 mg.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)(=[O:10])[CH3:9].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[C:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[CH2:12]1)(=[O:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2sccc2C1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2sc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
20 ml of an acetic anhydride solution containing 5.43 g (30 mmole) of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [prepared as described in step (a) above] were added dropwise at 10° to 18° C. over a period of one hour to 30 ml of an acetic acid solution containing 4.2 g (60 mmole) of 90% fuming nitric acid, and the mixture was then stirred at a temperature not greater than 18° C. for 1 hour. The reaction mixture was then poured into ice-water and extracted with methylene chloride. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and with water, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was crystallized from a mixture of hexane and toluene, to give 4.46 g of the title compound as yellow crystals.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]=[C:10]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[C:9]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=O)(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClC(Cl)C.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH3:20])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[C:8]2[C:6]1[O:3][C:1]([CH3:2])=[N:4][N:5]=1
Reactant: CC(=O)NNC(=O)c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1nnc(-c2c(-c3ccccn3)c(C(C)NC(=O)OC(C)(C)C)nc3ccc(F)cc23)o1

Procedure:
A solution of tert-butyl 1-(4-(2-acetylhydrazinecarbonyl)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.553 g, 1.183 mmol) and Burgess reagent (1.128 g, 4.73 mmol) in dichloroethane (11.83 mL) was heated in the microwave at 120° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The organic extracts were washed with brine (1×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (1H, d, J=4.3 Hz), 8.22-8.32 (1H, m), 7.80-7.92 (3H, m), 7.36-7.49 (2H, m), 7.17 (1H, d, J=7.0 Hz), 4.88 (1H, t, J=7.1 Hz), 2.34 (3H, s), 1.22-1.38 (12H, m); LC-MS (ESI) m/z 450.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14]([C:15](=O)[CH:16]([CH3:20])[CH2:17][CH:18]=O)=[C:13]([C:22]#[N:23])[C:12]([CH3:24])=[N:11]1.[CH3:25][NH2:26]>C(Cl)Cl>[CH3:25][N:26]1[CH:18]=[CH:17][C:16]([CH3:20])=[C:15]1[C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[N:11]=[C:12]([CH3:24])[C:13]=1[C:22]#[N:23]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2C(=O)C(C)CC=O)c(F)c1
Reactant: CN
Solvent: ClCCl
Product: COc1ccc(-n2nc(C)c(C#N)c2-c2c(C)ccn2C)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.5 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-methoxyphenyl)-3-methyl-5-(2-methyl-4-oxobutanoyl)-1H-pyrazole-4-carbonitrile (29 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added methylamine (2.0 M solution in methanol, 0.61 mL, 1.2 mmol) at ambient temperature in a closed microwave tube. The reaction mixture was stirred at ambient temperature for 14 h and concentrated under reduced pressure. Purification using a silica plug (heptane/CH2Cl2/Et2O-1:0:0-1:1:0-0:1:0-0:1:1) yielded 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (20 mg, 62%).
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[S:8][CH:7]=[N:6][CH:5]=1.[C:9]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])[CH3:10]>C(O)C>[C:9]([NH:12][C:13]([CH2:3][C:4]1[S:8][CH:7]=[N:6][CH:5]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1cncs1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cncs1)(NC(C)=O)C(=O)OCC
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
after dissolving 1.24 g of sodium in 20 cm3 of ethanol, 10.86 cm3 of diethyl acetamidomalonate are added, followed by heating at a temperature in the region of 75° C. After 15 minutes, a solution of 5-chloromethylthiazole in 20 cm3 of ethanol is added, followed by heating for 2 hours at a temperature in the region of 75° C. The reaction medium is evaporated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 60-200μ; diameter 6.5 cm; height 40 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume), a dichloromethane/methanol mixture (98/02 by volume) and then a dichloromethane/methanol mixture (95/5 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 3.3 g of diethyl 2-acetylamino-2-(5-thiazolylmethyl)malonate are obtained in the form of an orange-colored solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.18 (t, J=7.5 Hz: 6H); 2.00 (s: 3H); 3.75 (s: 2H); 4.17 (q, J=7.5 Hz: 4H); 7.61 (s: 1H); 8.37 (broad s: 1H); 9.00 (s: 1H)].
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]5[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:37][CH2:38]5)=[CH:29][CH:28]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1

Procedure:
2-[4-(4-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperidin-1-yl]-acetamide was prepared from 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide in an analogous manner to Example 1052a. Product isolated as an orange solid (104 mg, 54%). m.p.=170-173° C.; LCMS (m/e) 571 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=7.8 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.52-7.44 (m, 1H), 7.40 (d, 1H, J=7.5 Hz), 7.19 (d, 2H, J=8.3 Hz), 7.19-7.08 (m, 1H), 7.00 (d, 1H, J=4.7 Hz), 6.87-6.80 (m, 2H), 5.45 (bs, 1H), 4.88 (s, 2H), 3.05 (s, 2H), 3.06-2.97 (m, 2H), 2.58-2.43 (m, 1H), 2.38-2.25 (m, 2H), 1.94-1.85 (m, 2H), 1.85-1.70 (m, 2H), 0.97 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39]N>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:34]=1[NH:39][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:20]2[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:29])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Reactant: COc1ccccc1NN
Agent: Cl
Product: COc1cccc2c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 496.2 (M+H)+.