Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO>[O:13]=[C:9]([CH3:8])[CH2:10][C:11]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:12]
Reactant: CCCNCCC
Reactant: C=C1CC(=O)O1
Solvent: CO
Product: CCCN(CCC)C(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A solution of 27.80 g (0.28 mol) N,N-di-n-propylamine was added dropwise to a solution of 20.00 g (0.24) diketene in 100 ml MeOH at 0° C. After stirring for 3 hours at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 38.05 g of product was obtained as a slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]([NH2:19])=[O:18])=[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([NH:24][C:25]([N:13]1[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:11]2[CH2:12]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: NC(=O)c1c(-c2cccc(F)c2)nn2c1CNCC2
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N1CCn2nc(-c3cccc(F)c3)c(C(N)=O)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 1K (30 mg, 0.115 mmol) in DMF (1 mL) was added tert-butylisocyanate (28.6 mg, 0.288 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with water (2×5 mL), brine, dried over Na2SO4 and concentrated to afford the crude product as brown semi-solid. The residue was dissolved in a mixture of acetonitrile and methanol and was purified via preparative HPLC. Fractions containing the desired product (0.01 g, 24%) were combined and dried under vacuum. MS(ES): m/z=360 [M+H]+; HPLC Ret. Time 6.66 min. and 6.14 min. (HPLC Methods A and B); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (m, 2H), 7.25 (m, 2H), 7.25 (bs, 1H), 6.98 (bs, 1H), 6.26 (s, 1H), 4.69 (s, 2H), 4.11 (t, J=5.7 Hz, 2H), 3.80 (t, J=5.7 Hz, 2H), 1.29 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([N+:19]([O-])=O)=[C:17]([OH:22])[C:16]([Cl:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25].O>C(O)(=O)C.[Fe]>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:22])[C:16]([Cl:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2[N+](=O)[O-])c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Yield: 70.7 %

Procedure:
This compound was prepared in the manner of Step B of Example 1, using 1.5 grams (0.004 mole) 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 3.0 grams (0.054 mole) of iron dust, and 5 mL of water in 50 mL of glacial acetic acid, yielding 1.0 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH2:27])[N:21]=[CH:20]3)O1.[C:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[C:43](I)[C:42]3=[O:49])[CH:39]=2)[C:34]([CH3:51])([CH3:50])[CH2:33]1)(=[O:31])[CH3:30].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C>[C:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([NH2:27])[N:21]=[CH:20]5)[C:42]3=[O:49])[CH:39]=2)[C:34]([CH3:51])([CH3:50])[CH2:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CC(C)(C)c2ccc(-n3ccc(C)c(I)c3=O)cc21
Reactant: CC1(C)OB(c2ccc3nc(N)ncc3c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(C)(C)c2ccc(-n3ccc(C)c(-c4ccc5nc(N)ncc5c4)c3=O)cc21
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a resealable tube charged with potassium phosphate (0.588 g, 2.77 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.275 g, 1.02 mmol), 1-(1-acetyl-3,3-dimethylindolin-6-yl)-3-iodo-4-methylpyridin-2(1H)-one (0.390 g, 0.924 mmol), S-Phos (0.0227 g, 0.0554 mmol), and palladium acetate (0.0104 g, 0.0462 mmol) was added isopropyl alcohol (6.0 mL) and water (2 mL). The mixture was heated at 75° C. After 5 hrs, the mixture was diluted with EtOAc and water. The organic fraction was washed with brine and dried with sodium sulfate. After concentration in vacuo, the resulting solid was adsorbed onto silica gel and purified by silica gel chromatography using 2-10% MeOH in CH2Cl2 to afford 1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-(2-amino-6-quinazolinyl)-4-methyl-2(1H)-pyridinone as a white solid. M+H+=440.2.
Reaction SMILES: [C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:28])([CH2:26][NH2:27])[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[N:25][CH2:24][C:23]([CH3:28])([CH3:22])[CH2:26][N:27]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Reactant: CC(C)(CN)CN
Solvent: Cc1ccccc1
Product: CC(C)(CN=Cc1ccccc1P(c1ccccc1)c1ccccc1)CN=Cc1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
Under argon, a solution of 2-(diphenylphosphino)benzaldehyde (522.7 mg, 1.8 mmol) and 2,2-dimethyl-1,3-propanediamine (93.3 mg, 0.9 mmol) in toluene (15 mL) was stirred at room temperature for 15 h. Then the reaction mixture was heated at 80° C. (oil bath) for 2 h 30 min. Next, the solvent was removed in vacuo, and an orange solid was recovered (476.8 mg, 0.74 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:16](#N)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]1
Reactant: CC#N
Reactant: COC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN1CCC(OC)(c2cccc(F)c2F)C1
Temperature: 110 °C
Yield: 27 %

Procedure:
A mixture of 3-(2,3-difluorophenyl)-3-methoxypyrrolidine (0.4 g, 1.87 mmol), acetonitrile (5 ml), sodium carbonate (0.52 g, 3.74 mmol) and iodoethane (0.28 g, 1.87 mmol) was heated at 110° C. in a sealed tube under microwave irradiation for 10 minutes. Water (30 ml) was added and the aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic phases was dried (MgsO4) and evaporated to give the crude product (0.45 g). Purification by flash chromatography (ethyl acetate/methanol 1:1) and by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.12 g, 27%). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 94-98° C. MS m/z (rel. intensity, 70 eV) 241 (M+, 5), 226 (54), 211 (27), 141 (50), 71 (bp).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([N+:23]([O-])=O)=[CH:21][CH:22]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])=[O:8])=[CH:5][C:4]([CH3:27])=[N:3]1>CO.[C].[Pd]>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([CH3:26])=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[CH:5]=3)=[O:8])[CH:15]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2C)n(C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 1,3-dimethyl-N-{2-methyl-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (3.38 g, 9.20 mmol) in methanol (20 mL) was added palladium carbon (50% water-containing product, 300 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (2.94 g, 95%) as a white solid.
Reaction SMILES: CO[C:3](=[O:23])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)=[N:5]/[O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-]>CO>[Cl:22][C:14]1[CH:13]=[C:12](/[C:4](=[N:5]\[O:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)/[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: COC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Yield: 36.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid methyl ester (prepared as in Example 1, 98 mg, 0.27 mmol), methylurea (44 mg, 0.60 mmol) and a 6-10 wt. % solution of magnesium methoxide in methanol (1.33 mL, 0.10 mmol) were combined and warmed in a 70° C. oil bath for 16 h. After cooling, the reaction mixture was diluted with methanol (2 mL) and filtered through celite. The celite was washed with ethyl acetate (100 mL) and the combined filtrates were washed with water (40 mL), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-1-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetyl]-3-methyl-urea (40 mg, 36%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C16H20ClN3O5S [M+] 401.08, found 402 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.65 (m, 4 H, 2×CH2), 1.87 (m, 4 H, 2×CH2), 2.94 (d, J=4.9 Hz, 3 H, NCH3), 3.32 (s, 3 H, SO2CH3), 4.92 (m, 1 H, OCH), 7.50 (brd, Jo=8.2, 1 H, Ar), 7.60 (brs, 1 H, Ar), 8.02 (brm, 1 H, NH), 8.21 (d, Jo=8.2 Hz, 1 H, Ar), 8.82 (s, 1 H, NH).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]2[N:31]=[CH:32][C:33]([C:34]3[CH:35]=[N:36][C:37]4[C:42]([CH:43]=3)=[CH:41][C:40]([F:44])=[CH:39][CH:38]=4)=[C:10]2[N:9]=1)[CH3:7])(=O)=O.C(N(CC)C(C)C)(C)C.[N-:54]=[N+:55]=[N-:56].[Na+]>CS(C)=O>[N:54]([CH:6]([C:8]1[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[N:11]2[N:31]=[CH:32][C:33]([C:34]3[CH:35]=[N:36][C:37]4[C:42]([CH:43]=3)=[CH:41][C:40]([F:44])=[CH:39][CH:38]=4)=[C:10]2[N:9]=1)[CH3:7])=[N+:55]=[N-:56]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(N=[N+]=[N-])c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl methanesulfonate (6.8 g, 10.3 mmol) in DMSO (100 mL) and N,N-diisopropyl-ethylamine (8.95 mL, 51.4 mmol) was added sodium azide (2.0 g, 30.8 mmol). After 4 hours the reaction was complete by HPLC. The contents of the flask were transferred to a separatory funnel, washed twice with water and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-(1-azidoethyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (6.2 g; 99% yield) as a dark yellow oil. HPLC: 6.67 min (Method D). LCMS: No ion detected.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:3]1=2.[CH2:19](O)[CH3:20]>>[O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:3]1=2
Reactant: O=C(O)c1ccc2oc3ncccc3c(=O)c2c1
Reactant: CCO
Product: CCOC(=O)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 10.5 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid and 150 ml of ethanol is allowed to absorb 10 g of hydrogen chloride gas, and then refluxed for 16 hours. The ethanol is distilled off, and water is added to the crystalline residue. The mixture is extracted with chloroform, and the chloroform layer is washed with aqueous potassium carbonate solution and dried. The chloroform is distilled off, and the residue is recrystallized from ethanol to give ethyl 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylate melting at 131°-132°C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.ClCCl.[NH2:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([O:34][CH3:35])[O:32][CH3:33])=[C:27]([F:36])[CH:26]=2)[CH2:20]1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[C:1]([NH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([O:32][CH3:33])[O:34][CH3:35])=[C:27]([F:36])[CH:26]=2)[CH2:20]1)(=[O:3])[CH3:2]
Reactant: COC(OC)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(OC)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F

Procedure:
Acetic anhydride-pyridine-dichloromethane solution (1 to 1.5 to 3, 4 mL) was added to BAL resin immobilized 5-(S)-aminomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one, and the mixture was agitated for ca. 2 h (until negative ninhydrine test indicated completion of the acylation). The resin was filtered, washed liberally with methanol and dichloromethane and dried under vacuum.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:12]([C:16]1[CH:40]=[CH:39][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH3:38])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CCC>[NH2:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=[C:2]([C:25]2[C:24]([CH3:38])=[C:23]([NH:22][C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:40][CH:39]=3)[CH:28]=[CH:27][CH:26]=2)[CH:3]=1
Reactant: Nc1cc(Cl)nn2ccnc12
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCCCO
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 22.4 %

Procedure:
A mixture of 6-chloro-imidazo[1,2-b]pyridazin-8-ylamine (0.048 g, 0.29 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.169 g, 0.444 mmol), potassium phosphate (0.120 g, 0.567 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.024 g, 0.058 mmol), palladium acetate (0.007 g, 0.03 mmol), 0.5 mL of n-butanol and 0.2 mL of water in a sealed tube was stirred at 100° C. for 2 d. The resulting cloudy orange mixture was partitioned between 5 mL of ethyl acetate and 5 mL of water, and the aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to an orange oil. Column chromatography (60->100% EtOAc/hexanes) afforded 0.026 g (23%) of N-[3-(8-amino-imidazo[1,2-b]pyridazin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=4)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)cc2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 1, step 2) was reacted with (3-methylsulfonylphenyl)boronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(3′-methanesulfonyl-biphenyl-4-yl)-3-phenyl-imidazolidin-2-one as an off-white solid. MS: 533.2 ([M+H]+)
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH:12]2[CH2:17]OC(C)(C)[O:14][CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S(OC[C@@H]2COC(C)(C)O2)(=O)=O)=CC=1.[F:40][C:41]1([F:85])[CH2:46][CH2:45][CH:44]([C:47]2[C:56]3[CH:55]([OH:57])[CH2:54][C:53]([CH3:59])([CH3:58])[CH2:52][C:51]=3[N:50]=[C:49]([CH:60]3[CH2:65][CH2:64][N:63]([C:66]4[N:71]=[CH:70][C:69]([OH:72])=[CH:68][N:67]=4)[CH2:62][CH2:61]3)[C:48]=2[CH:73]([F:84])[C:74]2[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][CH:75]=2)[CH2:43][CH2:42]1>>[F:85][C:41]1([F:40])[CH2:42][CH2:43][CH:44]([C:47]2[C:56]3[CH:55]([OH:57])[CH2:54][C:53]([CH3:58])([CH3:59])[CH2:52][C:51]=3[N:50]=[C:49]([CH:60]3[CH2:61][CH2:62][N:63]([C:66]4[N:71]=[CH:70][C:69]([O:72][CH2:17][CH:12]([CH2:13][OH:14])[CH2:11][OH:10])=[CH:68][N:67]=4)[CH2:64][CH2:65]3)[C:48]=2[CH:73]([F:84])[C:74]2[CH:75]=[CH:76][C:77]([C:80]([F:82])([F:81])[F:83])=[CH:78][CH:79]=2)[CH2:45][CH2:46]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(CO)CO)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Example 39 were performed except for using (2,2-dimethyl-1,3-dioxan-5-yl)methyl p-toluenesulfonate, which was synthesized with the method described in J. Dubois et al., Tetrahedron, 1991, Vol. 47, pp. 1001-1012, instead of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate, and from 4.04 g (6.23 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 2.73 g of the title compound was obtained as a white solid (yield: 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:48])([F:47])([F:46])([F:45])[F:44])[CH:42]=1)[C:37](O)=[O:38])#[N:33]>>[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:47])([F:48])([F:44])([F:45])[F:46])[CH:42]=1)[C:37]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]2[C:15]3[N:16]([N:17]=[C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=5)[CH:12]=4)[CH:14]=3)[C:18]([CH3:29])=[CH:19]2)[CH:22]=1)=[O:38])#[N:33]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(C#N)cc(S(F)(F)(F)(F)F)c6)ccc5C)cc(C)n4n3)cn2)cc1

Procedure:
100 mg (0.24 mmol) of the compound of Example 9A and 66 mg (0.24 mmol) of the compound of Example 23A were reacted and worked up analogously to the procedure of Example 48A. This gave 153 mg (77% pure, 73% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH2:25]([NH:27][CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:26]>C(#N)C>[CH2:25]([NH:27][CH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:3][C:2]=2[F:1])[CH2:30]1)[CH3:26]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1
Yield: 87.6 %

Procedure:
To 0.62 g (1.8 mmol) of 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.23 g (1.0 equivalent) of N-ethyl-3-pyrrolidinemethanamine and 0.28 g (1.0 equivalent) of 1,8-diazobicyclo [5.4.0]undec-7-ene in 5 ml of acetonitrile. The reaction was refluxed for one hour and then checked by thin layer chromatography. Excess (10%) N-ethyl-3-pyrrolidine methanamine was added as necessary and the mixture heated to reflux for an additional two hours. The solids were then filtered and washed with ether to give 0.70 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 249°-251° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:36][CH:37]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)cc2)CC1
Yield: 35.3 %

Procedure:
A mixture of 0.05 g (0.17 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.05 g (0.20 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 0.05 g (0.25 mmole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was diluted with dichloromethane and saturated aqueous sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give 0.030 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-134).