Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[CH:12]=[C:11]([Si](C)(C)C)[O:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)c1cc(-c2cccnc2Br)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1ncccc1-c1ccon1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.8 %

Procedure:
To a solution of [3-(2-bromo-3-pyridyl)isoxazol-5-yl]-trimethyl-silane (620 mg, 2.09 mmol) in methanol (18 mL), potassium carbonate (29.12 mg, 208.59 μmoles) is added in one portion. The mixture is stirred at room temperature for 24 h. The solvent is removed in vacuum. The crude is partitioned between ethyl acetate and saturated solution of ammonium chloride. The organics are washed with water and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude is purified by normal phase Isco chromatography using as eluent hexane/ethyl acetate from 66/33 to 50/50 as to give 140 mg of title compound as white solid. MS (m/z): 225/227 (M+1/M+3)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:7][CH:8]=1>[Pd].CO.CC(=O)OCC>[CH3:1][O:2][C:3]1[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Yield: 82.9 %

Procedure:
4-[5-methoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine (0.2 g, 1 eq) was stirred under hydrogen balloon with palladium on carbon (10 percent, 0.1 g, 0.15 eq) in a mixture of MeOH and EA (1:1, 8 mL) at room temperature overnight. The reaction mixture was then filtered through Celite, volatiles were removed in vacuo, and the residue was purified by flash chromatography to give a white solid (0.15 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12]OCC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])=[CH:12][NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[C:27]([F:26])([F:35])[F:36])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCOC=C(S(=O)(=O)c1ccc(Cl)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 50.1 %

Procedure:
A solution of 1,1-bis(4-chlorophenylsulphonyl)-2-ethoxyethene (1.26 g) and 2-(trifluoromethyl)aniline (0.48 g) in dimethylacetamide (20 ml) was heated at reflux for 2 hours, and then it was cooled and poured onto ice (50 g). The resulting white precipitate was filtered off, washed with water and recrystallised from ethanol, to give 1,1-bis(4-chlorophenylsulphonyl)-2-[2-(trifluoromethyl)anilino]ethene (0.8 g), m.p. 169°-171° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:3][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 28.8 g (0.25 mol) trans-4-aminocyclohexanol in 200 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) 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 200 ml of ethyl acetate. This gave 33.6 g (0.17 mol, 71% yield) of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10](I)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:11]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2-c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 50 %

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.95 g, 0.00256 mol) in dimethoxyethane (30 mL) and water (60 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (1.14 g, 0.00281 mol), sodium carbonate (0.68 g, 0.00640 mol) and tetrakis (triphenylphosphine)palladium (0) (0.30 g, 0.00026 mol) at 80° C. for 3 days. The solid was filtered and washed with water. The solid was triturated with ethyl acetate (75 mL) for 6 hours and filtered, washing with ethyl acetate (20 mL). The solid was then triturated with methanol (75 mL) for 6 hours and filtered, washing with methanol (20 mL). The solid was dried in vacuo to give crude N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.672 g, 0.00128 mol) as a tan solid:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:11][CH2:12][C:13](OC)=[O:14])[C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: COC(=O)CCn1c(=O)c2cc(Br)cnc2n(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2cc(Br)cnc21
Temperature: -60 °C
Reaction time: 3 h
Yield: 131.9 %

Procedure:
To a solution of methyl 3-(6-bromo-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propanoate (5.1 g, 14.96 mmol) in THF (500 mL) at −60° C., was added diisobutylaluminium hydride (1.5 M in toluene, 40 mL, 60 mmol) dropwise. The reaction was stirred at −60° C. for 3 h, warmed to 0° C., quenched with aq. NH4Cl (150 mL) then extracted with EA (200 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to give 6-bromo-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (6.2 g, >100% yield) as a yellow oil. LCMS: MH+ 314 and TR=0.882 min. Used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]#[N:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37]>C(O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13](/[C:15](=[N:36]/[OH:37])/[NH2:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:32])([F:33])[F:31])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(C#N)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(/C(N)=N/O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 80 °C

Procedure:
A mixture of the product of Step A of Example 2 (0.12 g, 0.25 mmol), hydroxylamine hydrochloride (43.48 mg, 0.626 mmol) and TEA (0.087 mL, 0.626 mmol) in ethanol (1.2 mL) in a sealed tube in Ar was heated at 80° C. overnight. After removal of solvent, the residue was partitioned between EtOAc and brine, separated, dried over Na2SO4. Purification by CombiFlash (eluent: 8% methanol in DCM) gave the product as a white solid. 1H-NMR (400 MHz, CDCl3): δ 1.30-1.45 (m, 9H), 1.70-1.99 (m, 3H), 2.38 (br. s., 1H), 3.09 (d, J=9.3 Hz, 3H), 3.28-3.54 (m, 3H), 3.65-3.89 (m, 3H), 4.23 (d, J=5.1 Hz, 1H), 4.44-4.93 (m, 5H), 7.72 (br. s., 1H), 8.69 (s, 1H); LC/MS: C23H31F3N6O4: m/z 513 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:28]O)[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[S:40][CH2:28][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[N:11]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(N[C@@H](CO)C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CSC(c2ccccc2OCc2ccccc2)=N1

Procedure:
N-[2-(Benzyloxy)benzoyl]-L-serine benzyl ester (20 mg, 0.05 mmol) and Lawesson's reagent [2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide] (20 mg, 0.05 mmol, 1 equiv.) were dissolved in toluene (15 mL). After being refluxed overnight under nitrogen, the reaction mixture was diluted with EtOAc (20 mL), washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel eluting with hexanes/EtOAc (6/1) to yield thiazoline (7) as a clear oil. Rf=0.3 (hexanes/EtOAc, 6:1); 1H NMR (300 MHz, CDCl3) δ8.00 (dd, 1H, ArH), 7.51-7.49 (m, 2H, ArH), 7.42-7.25 (m, 9H, ArH), 7.02-6.95 (m, 2H, ArH), 5.28 (d, 1H, PhCHH), 5.20 (d, 1H, PhCHH), 5.18 (s, 2H, CH2Ph), 5.12 (dd, 1H, CHCH2), 3.60-3.47 (m, 2H, CHCH2); MS (FAB) m/z 404 MH+, measured exact mass: 404.1313, calculated exact mass: 404.1320.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1cccc(I)c1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Yield: 47.9 %

Procedure:
Under the conditions of example 5A, 6.2 g of N-(3-iodophenyl)-1,1,1-trifluoromethanesulfonamide is reacted with 2.07 g of trimethylsilylacetylene, worked up, and the crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 2.72 g of N-[3-(2-trimethylsilylethinyl)-phenyl]-1,1,1-trifluoromethanesulfonamide is obtained as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])[C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To (2R,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (4.812 g, 20.81 mmol) in DMF (30 mL) at 0° C. was added tert-butylchlorodimethylsilane (9.409 g, 62.43 mmol) and triethylamine (10.53 g, 104.0 mmol). The cold bath was removed and the reaction mixture was stirred for 16 hours. The mixture was diluted with EtOAc (50 mL) and 10% NaOH (30 mL), and the phases were separated. The organic phase was washed with 10% NaOH. The combined aqueous phases were acidified with concentrated HCl until pH=2. The aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product 6.86 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][N:6]2[CH:11]=1>CO.[Pd]>[F:12][C:2]([F:1])([F:13])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1
Reactant: FC(F)(F)c1cn2ccncc2n1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1cn2c(n1)CNCC2
Reaction time: 12 h
Yield: 95.9 %

Procedure:
2-(Trifluoromethyl)imidazo[1,2-a]pyrazine 12b (2.40 g, 12.55 mmol) was dissolved in 100 mL of methanol, followed by addition of Pd—C (10%, 480 mg), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to obtain 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 12c (2.30 g, yield 95.8%) as a yellow oil.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]#[N:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[NH:25][N:24]=[N:23][N:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(C#N)cc1COc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2nnn[nH]2)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A mixture of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile (148) (100 mg, 0.35 mmoles), sodium azide (27 mg, 0.415 mmoles) and potassium carbonate (62 mg, 0.45 mmoles) in dimethylformamide (5 ml) was heated at 90° C. for 96 hours then at 120° C. for 24 hours. The mixture was evaporated and the residue purified by HPLC to afford compound 149 as a white solid (64 mg). LC/MS System D; Rt=9.53 mins, m/2 (ES+)=333 (M+H for C19H16N4O2).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[O:28]1[CH2:27][CH2:26][N:25]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:39]3[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=3)[N:3]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-Boc-piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine (200 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine 7 following General Procedure A followed by Boc removal with 1N HCl in dioxane to generate 159 after reversed phase HPLC purification. MS (Q1) 413 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O)(=O)C.[H][H]>[Pd].C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CCCCN1

Procedure:
50 ml of ethyl 2-(2-pyridyl)acetate, 18.7 ml of acetic acid, 5 g of Pd—C (water-containing product) and 200 ml of ethanol were charged in an auto clave, and the mixture was stirred at 70° C. for 9 hours at a hydrogen pressure of 56 kg/cm2. The Pd—C was filtered off and ethanol was evaporated, to give 72.3 g of white crystals.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[C:15]([F:19])([F:18])[CH:16]=[CH2:17]>>[F:18][C:15]([F:19])=[CH:16][CH2:17][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C=CC(F)(F)Br
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC=C(F)F

Procedure:
The title compound was prepared as a pale yellow oil in 70.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-3,3-difluoro-1-propene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)CN
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CNc1nc(Cl)ncc1[N+](=O)[O-]

Procedure:
To a solution of 5 g of 2,4-dichloro-5-nitro-pyrimidine in 150 ml of dichloromethan 3.1 g of neopentylamine and 10.5 ml of diisopropylethylamine were added in succession at 0° C. After 2 hours the mixture was washed with saturated NaHCO3 solution, dried over sodium sulfate and evaporated to dryness yielding (2-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as yellow cristals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17](=[O:42])[NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[N:28]=[CH:27][C:26]3[N:32]=[C:33]([CH2:38][O:39][CH2:40][CH3:41])[N:34]([CH2:35][CH2:36][CH3:37])[C:25]=3[C:24]=2[CH:23]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:40]([O:39][CH2:38][C:33]1[N:34]([CH2:35][CH2:36][CH3:37])[C:25]2[C:24]3[CH:23]=[C:22]([O:21][CH2:20][CH2:19][NH:18][C:17](=[O:42])[O:16][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:31]=[CH:30][C:29]=3[N+:28]([O-:9])=[CH:27][C:26]=2[N:32]=1)[CH3:41]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
mCPBA (60% pure, 12.76 g, 44.36 mmol) was added in one portion to a solution of tert-butyl[2-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate (14.4 g, 33.6 mmol) and chloroform (150 mL); the reaction mixture was stirred for 30 minutes. The reaction mixture was then poured into saturated aqueous sodium carbonate (100 mL) and stirred for 30 minutes. Chloroform (250 mL) was added, and the organic fraction was washed sequentially with 5% aqueous sodium carbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting red oil was triturated with ethyl acetate to provide 9.7 g of tert-butyl 2-[(2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate as a peach-colored powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][N:15]([CH2:39][CH2:38][CH2:37][CH:36]=[CH2:35])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a mixture of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitrophenylsulfonamido)propanoate iii (150 mg, 0.37 mmol) in 3 mL of DMF was added potassium carbonate (102 mg, 0.74 mmol.). This mixture was stirred at rt for 20 min followed by the addition of 5-bromo-1-pentene (65 □L, 0.55 mmol.). The reaction mixture was stirred at rt for 2 days. It was then filtered, concentrated and purified by silica gel chromatography (eluting with 25% ethyl acetate in hexane) to give 75 mg (43%) of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoate iv as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 1.42 (s, 9H), 1.54-1.64 (m, 2H), 1.97 (q, J=7.20 Hz, 2H), 3.37 (m, 2H), 3.57-3.80 (m, 2H), 3.72 (s, 3H), 4.42 (dd, J=8.60, 5.31 Hz, 1H), 4.91-5.01 (m, 2H), 5.69-5.79 (m, 1H), 7.75-7.85 (m, 3H), 8.04 (m, 1H); MS m/z 372 (M++1-Boc).
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:6]([C:7]1[C:2]([C:3]([OH:5])=[O:4])=[N:1][CH:10]=[CH:9][CH:8]=1)(=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10 g (67 mmol) quinolinic acid anhydride was suspended in 50 ml benzene and 17.9 g (134 mmol) AlCl3 was added in portions while cooling on ice. After completion of the addition, it was stirred for a further 3 hours at room temperature, carefully admixed with ice and aspirated from the precipitate which was present. The crude product was purified by column chromatography on silica gel 60 using ethyl acetate/dichloromethane 1/1 as the eluent.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[O:5][C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][C:11]1[CH:10]=[C:9]([C:4]2[O:5][C:6]([CH2:7][O:8][S:24]([CH3:23])(=[O:26])=[O:25])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nc(C)c(CO)o2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C)c(COS(C)(=O)=O)o2)c1
Reaction time: 0.08 h
Yield: 66 %

Procedure:
Cool (0° C.) a solution of [2-(3-methyl-phenyl)-4-methyl oxazol-5-yl]-methanol (Example 3, 756 mg, 4 mmol) in dichloromethane (16 mL) and add, sequentially, DMAP (51 mg, 0.4 mmol), triethylamine (552 μL, 4 mmol) and methanesulfonyl chloride (323 μL, 4.2 mmol). Stir the resulting solution for 5 min., remove the cooling bath and stir for 25 min. Dilute this solution with ether, wash with hydrochloric acid (5 mL, 2M), brine, dry over MgSO4 and concentrate to give the title compound (743 mg).
Reaction SMILES: C(N)CCC.Br[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu](I)I>[CH:7](=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: C#CCCCC
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: CCCCC#CC=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.7 %

Procedure:
A mixture of palladium tetrakis(triphenylphosphine) (21 mg, 0.018 mmol), butylamine (2.5 mL) and Compound 49a (200 mg, 0.724 mmol) were stirred at room temperature for 45 minutes. Copper iodide (10.3 mg, 0.05 mmol) was then added, followed by hex-1-yne (41.6 μL, 0.362 mmol). The solution was heated for 3-5 hours at 70° C. till change in colour to depth blue. The reaction was quenched with ammonium chloride, extracted with diethyl ether, washed with brine, dried over magnesium sulphate, filtered, concentrated to dryness and purified by preparative HPLC-MS e affording the title product (78 mg).