Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.C=O.CNC.CI.[Si](C#N)(C)(C)C.CC[CH2:28][CH2:29][N+:30](CCCC)(CCCC)CCCC.[F-]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:28][C:29]#[N:30]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: C=O
Agent: CNC
Agent: C[Si](C)(C)C#N
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(C)c(CC#N)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
To a solution of 5-methoxy-2-methylindole (1.0 g, 6.2 mmol, 1.0 eq.) in a mixture of acetic acid (2 mL) and water (1 mL) were added, at 0° C., formaldehyde (906 μL, 37% in H2O, 11.2 mmol, 1.8 eq) and dimethylamine (1.54 mL, 40% in H2O, 13.6 mmol, 2.2 eq). The mixture was stirred at room temperature for 2 hours and then, quenched with ice and 5 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane and then, the organic layer was dried over MgSO4 and partially evaporated. To the solution gramine in dichloromethane (20 mL) were added, under an argon atmosphere, anhydrous toluene (40 mL) and methyl iodide (772 μL, 12.4 mmol, 2.0 eq.). The mixture was stirred at room temperature for 12 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (60 mL) were added, under an argon atmosphere, TMSCN (1.17 mL, 9.3 mmol, 1.5 eq.) and TBAF (18.6 mL, 1M, 18.6 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated. The crude was taken up in ethyl acetate and the organic layer was washed with a saturated aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed and the residue purified by silica gel pad filtration (eluent: EtOAc) to afford (5-methoxy-2-methyl-1H-indol-3-yl)-acetonitrile as a yellow solid (0.55 g, 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9])([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc(N)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution tert-butyl (3-{[(3-nitrobenzyl)sulfonyl]amino}phenyl)carbamate (1.1 g, 2.7 mmol) in water (2 mL), methanol (100 mL) and acetic acid (4.1 mL) was added iron (0.60 g, 11.0 mmol) powder in one batch. The mixture was stirred at 0° C. for 2 h. The mixture was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and NaHCO3/water were added. The water layer was extracted with EtOAc once more. The organic layers were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.9 g, 90%). LCMS for C18H23N3O4S (M-tBu+H)+: m/z=322.0. 1H NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.39 (s, 1H), 7.44 (br, 1H), 7.16 (t, J=8.2 Hz, 1H), 7.12 (m, 1H), 6.94 (t, J=7.7 Hz, 1H), 7.79 (dt, J=7.2, 2.1 Hz, 1H), 6.50 (m, 1H), 6.49 (s, 1H), 6.35 (m, 1H).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CCN(CC)CC.C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][Si:18]([C:21]#[C:22][C:2]1[CH:16]=[CH:15][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CCCCN(CCCC)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCN(CCCC)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Cuprous iodide (23 mg, 1 mol %) was added to 4-iodo-N,N-dibutylaniline (4 g, 12.1 mmol), trimethylsilylacetylene (2.37 g, 24.2 mmol) and Pd(PPh3)2Cl2 (84 mg, 1 mol %) in dry Et3N (40 mL) under nitrogen. The resulting solution was stirred at room temperature for 16 h, diluted with benzene (50 mL), filtered and the solvent removed under reduced pressure. The residue was chromatographed on alumina using benzene as eluent. The solvent was removed under reduced pressure to give the title compound (3.0 g, 82%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O-:15])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.N(O[CH2:20][CH2:21]C(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)[O-]
Reactant: CC(C)CCON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a tetrahydrofuran solution (50 ml) containing ethyl 5-amino]1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate (10.5 g) was added isoamyl nitrite (14 g) and the mixture was stirred at a refluxing temperature for 2 h. The mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. n-Hexane was added to the obtained residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (7.8 g), melting point: 103–104° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)O1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Reactant: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol) Pd(Ph3P)4 (13 mg, 0.011 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (36 mg, 0.172 mmol) and toluene (0.5 mL) was stirred for 15 min. at RT. K3PO4 (73 mg, 0.345 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column DEAP, from 7% to 12% in 6 min) to afford the title compound was lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=435.1 [M+H]+.
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].[CH3:28]I>C(#N)C>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COCCCCCCCCCCCC(=O)O
Reactant: CI
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COCCCCCCCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Tetramethylammonium hydroxide pentahydrate (1.7 g, 9.4 mmol) was added to a solution of the title product of Example 1 (2.0 g, 8.7 mmol) in 45 mL of anhydrous acetonitrile. After stirring for 4 hours at room temperature, methyl iodide (0.6 mL, 9.6 mmol) was added and the resulting milky solution stirred at room temperature. The solvent was removed by rotary evaporator and partioned between diethyl ether and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.1 g) as a pale yellow liquid. The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16]C(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O>CS(C)=O>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (1.97 g) of HNSA was mixed together with one molar equivalent (1.85 g) of dicyclohexylcarbodiimide and one molar equivalent (2.0 g) of biotin in 50 ml of dimethylsulfoxide at room temperature overnight. The reaction resulted in the formation of dicyclohexyl urea as a precipitate. The precipitate was filtered off and 400 ml of dichloromethane was added to the mother liquor. After several hours a solid precipitate was formed. The yield of this crude ester was 59% of theoretical. This precipitate was analyzed spectroscopically as described in Example IA and found to contain 38% biotin-HNSA ester together with 68% of free HNSA. The solid was then purified by column chromatography on LH20 Sephadex in DMF and positively identified as described above for the preparation of mal-sac HNSA ester. The purification yielded biotin-HNSA ester of greater than 99% purity.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([S:19][C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-hydroxythiophenol (0.75 g, 6.00 mmol), cesium carbonate (3.9 g, 12 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound, (1.45 g, 92%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[N:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(=O)(=O)=O.C(N(CC)CC)C>CS(C)=O.O>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[N:14]=[C:15]([CH:19]=[O:20])[CH:16]=[CH:17][CH:18]=3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccc(Nc2ncc(-c3ccccc3)s2)n1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cccc(Nc2ncc(-c3ccccc3)s2)n1
Reaction time: 0.17 h

Procedure:
[2-(5-Phenyl-thiazol-2-ylamino)-pyridin-6-yl]-methanol (6-4), 0.60g (2.1 mmol) Sulfur trioxide-pyridine (1.01 g, 6.36 mmol) was dissolved in 10 mL anhydrous DMSO and the resulting solution was stirred for 10 min. Triethylamine (2.45 mL, 17.6 mmol) was added followed by addition of [2-(5-Phenyl-thiazol-2-ylamino)-pyridin-6-yl]-methanol (6-4), (0.60 g, 2.1 mmol). After 30 min the reaction was diluted with water and the resulting precipitate was filtered and washed with water to afford the titled compound.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH3:13])=O)(C)(C)C.C[Si](C)(C)[N:16]1[C:20](=O)[CH:19]=[CH:18][C:17]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:13][CH:12]1[CH:19]2[CH:18]([CH2:17][NH:16][CH2:20]2)[CH:9]([NH:8][CH3:6])[CH:10]=[CH:11]1
Reactant: CC=CC=CNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N1C(=O)C=CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNC1C=CC(C)C2CNCC12

Procedure:
Analogously to Example Z23, method I, 21.9 g (0.12 mol) of 1-(tert.-butyloxycarbonylamino)-1,3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide, and the product is subsequently reduced with 15.2 g (0.4 mol) of lithium aluminium hydride. The crude product is recrystallised from tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A 1,4-dioxane (6.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (610 mg, 1.46 mmol) obtained in Example 54 and t-butyl(2-aminoethyl)carbamate (700 mg, 4.38 mmol) was stirred at 120° C. for 4 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the title compound (176 mg, 22%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:39]=[CH:38][C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH2:26][CH2:25]4)[C:15](=[O:23])[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:39]=[CH:38][C:12]3[N:13]=[C:14]([N:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]4)[C:15](=[O:23])[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCOCCn1c(=O)c(N2CCN(CC(=O)OC(C)(C)C)CC2)nc2cnc(-c3ccc(OC)nc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOCCn1c(=O)c(N2CCN(CC(=O)O)CC2)nc2cnc(-c3ccc(OC)nc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of tert-butyl {4-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihydropyrido[3,4-b]pyrazin-3-yl]piperazin1-yl}acetate (174 mg, 0.32 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, concentrated and recrystallized from ethyl acetate and hexane and filtered. The {4-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihydropyrido[3,4-b]pyrazin-3-yl]piperazin1-yl}acetic acid was obtained as a white solid. (81 mg, 52% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2nccn12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cccc2ncc([N+](=O)[O-])n12
Temperature: 0 °C

Procedure:
To a solution of 19.02 g (0.10 mol) of 5-ethoxycarbonylimidazo[1,2-a]pyridine in 50 ml of conc. sulfuric acid was added dropwise, while stirring under ice-cooling, 40 ml of conc. nitric acid. The mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into ice-water, which was neutralized with a 10% aqueous solution of NaOH. The resulting precipitates were collected by filtration, washed with water and dried to afford 20.38 g of the desired compound (86.6%, a pale yellow solid).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]([NH:15][C@@H:16]([C:20]([F:23])([F:22])[F:21])[CH:17]([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:32]1([CH2:38][C:39]([NH2:41])=[O:40])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.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>O1CCOCC1.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]>[CH3:18][CH:17]([CH3:19])[C@@H:16]([NH:15][C:6]1[C:5]2[CH:24]=[CH:25][C:2]([NH:41][C:39](=[O:40])[CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:3][C:4]=2[C:13]2[C:12](=[O:14])[NH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)[C:20]([F:22])([F:21])[F:23]
Reactant: NC(=O)CN1CCOCC1
Reactant: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cc(NC(=O)CN3CCOCC3)ccc12)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one (30 mg, 0.07 mmol) in dioxane (1 mL) were added cesium carbonate (83 mg, 0.25 mmol), 2-morpholin-4-ylacetamide (10 mg, 0.07 mmol), Xantphos, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), (8.3 mg, 0.01 mmol), and Pd2(dba)3 (6.63 mg, 7.24 μmol). The solution was degassed by bubbling nitrogen gas for 5 min and heated to 100° C. for 2 hr. The solution was filtered and purified using reverse phase chromatography 100% H2O to 100% MeCN. LRMS (ESI) calc'd for (C23H27F3N5O3) [M+H]+, 478.2; found 478.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.[NH3:25]>C(O)C>[NH2:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: N
Reactant: COc1ccc(-c2nc(Cl)c3cc(OC)ccc3c2[N+](=O)[O-])cc1
Solvent: CCO
Product: COc1ccc(-c2nc(N)c3cc(OC)ccc3c2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
In a 25-mL Schlenk flask, under argon, 1-chloro-7-methoxy-3-(4-methoxyphenyl)-4-nitroisoquinoline (100 mg, 0.43 mmol) is dissolved in 20 mL of a saturated solution of ammonia in ethanol. After stirring for 4 days at 80° C., the medium is concentrated under vacuum then purified by silica gel column chromatography with dichloromethane-ethanol (95/5) as eluent in order to produce the expected amine compound 71 (79 mg, 56%) in the form of a yellow solid. 1H NMR CDCl3 δ 7.81 (d, 1H), 7.60 (d, 2H), 7.45 (d, 1H), 7.07 (s, 1H), 6.99 (d, 2H), 5.44 (s, 2H), 3.99 (s, 3H), 3.87 (s, 3H); MS 326 [M+H]+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br:7][C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:14]([CH3:20])([CH3:19])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=1.[CH2:23](Br)[CH2:24][CH3:25]>CN(C)C=O>[Br:7][C:8]1[C:17]([O:18][CH2:23][CH2:24][CH3:25])=[CH:16][C:15]2[C:14]([CH3:20])([CH3:19])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=1
Reactant: CCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
1.4 g of sodium hydride, 50% in mineral oil, were suspended in 50 ml of abs. dimethyl sulphoxide and treated dropwise while cooling with ice with 8.5 g of 2-bromo-3-hydroxy-5,5,8,8-tetra-methyl-5,6,7,8-tetrahydro-naphthalene dissolved in 60 ml of abs. dimethylformamide. The reaction mixture was stirred at 40° C. for ½ hour and subsequently a solution of 4.4 g of propyl bromide in 20 ml of dimethylformamide was added while cooling with ice. After stirring at room temperature for 20 hours the mixture was poured into ice-water, extracted with ethyl acetate and the crude product obtained after drying and evaporation of the solvent was filtered over a silica gel column (eluent hexane/ethyl acetate=9:1). 9.5 g of 2-bromo-3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene were obtained as a brownish oil. This oil was dissolved in 100 ml of abs. tetrahydrofuran and treated dropwise at −78° C. with 40 ml of tert.butyllithium, 1.4 molar in pentane. After stirring at −78° C. for ½ hour 75 ml of abs. dimethylformamide were added dropwise and the mixture was stirred at room temperature for 1 hour. The pale beige suspension was poured into ice-water and extracted with ethyl acetate. After drying and evaporation of the organic phase the crude product was filtered over a silica gel column (eluent hexane/5% ether). There were obtained 6.6 g of 2-formyl-3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene as a pale yellow oil which solidified upon cooling, melting point 51-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]/[C:23]#[N:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.C(Cl)Cl>[Pd].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][C:23]#[N:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:26][CH:27]=1
Reactant: N#C/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: N#CCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Yield: 63 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-[(E)-2-cyanoethenyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide from Example No. 133 (0.13 g) and Et3N in 50 mL 3:1 CH2Cl2 :MeOH was added 10% Pd/C (0.040 g). The reaction was placed under hydrogen balloon atmosphere for 4 hours. The reaction was filtered over Celite, the filter cake rinsed thoroughly with methanol, and the filtrate concentrated under reduced pressure to give a yellow solid. The solid was recrystallized with CH2Cl2 /MeOH/hexanes to give the desired product as an off-white solid (0.084 g, 63%).