Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:39])[C:28]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:29])=[CH:22][C:21]=3[F:40])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:41][CH3:42])C1C=CC=CC=1>CO.CN(C=O)C.ClCCl.C(OCC)(=O)C.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:40][C:21]1[CH:22]=[C:23]([NH:26][C:27](=[O:39])[C:28]([NH:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:29])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:41][CH3:42])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1O
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of N-{4-[(7-benzyloxy-6-methoxyquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(2-phenylethyl)ethanediamide (32 g, 56 mmol) in methanol (200 mL), DMF (100 mL), dichloromethane (100 mL), ethyl acetate (100 mL) and acetic acid (5 mL) was added palladium hydroxide (4.2 g) and the mixture was shaken on a Parr hydrogenator under a hydrogen pressure of 45 psi for 4 h. The resulting suspension was filtered through celite and the solid residue was washed with boiling dichloromethane (2 L) and acetone (2 L). The combined filtrates were evaporated to yield N-{3-fluoro-4-[(7-hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide as an off-white solid (25.6 g, 95%). 1H NMR (400 MHz, d6-DMSO): δ 11.06 (s, 1H), 10.25 (br s, 1H), 9.12 (t, 1H), 8.40 (d, 1H), 8.01 (dd, 1H), 7.50-7.44 (m, 2H), 7.31-7.23 (m, 6H), 6.39 (d, 1H), 3.95 (s, 3H), 2.85 (t, 2H), 2.50 (m, 2H); IR (cm−1): 1666, 1624, 1585, 1520, 1481, 1427, 1377, 1256, 1211, 1194, 1022, 880, 850, 839, 802, 750, 700; LC/MS (M+H=476).
Reaction SMILES: CC1(C(Cl)=O)CC(C)C1.C1(C(Cl)=O)CCCCC1.[C:19]([NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH:36]([CH3:41])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])=[C:29]([O:42][C:43]([CH:45]([CH3:50])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:44])[CH:28]=1)=[O:26])([CH3:22])([CH3:21])[CH3:20]>>[CH3:50][C:45]1([C:43]([O:42][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=2[O:33][C:34]([C:36]2([CH3:41])[CH2:40][CH:38]([CH3:39])[CH2:37]2)=[O:35])[CH:25]([OH:26])[CH2:24][NH:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:44])[CH2:48][CH:47]([CH3:49])[CH2:46]1
Reactant: CC(C)CC(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C(C)CC(C)C
Agent: CC1CC(C)(C(=O)Cl)C1
Agent: O=C(Cl)C1CCCCC1
Product: CC1CC(C)(C(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2OC(=O)C2(C)CC(C)C2)C1

Procedure:
When 1,3-dimethylcyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(1,3-dimethylbutanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(1,3-dimethylcyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([S-:31])[CH3:30].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][S:31][CH2:29][CH3:30])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[S-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSCC[C@H]1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of the mesylate from Step F (3.6 g, 8.3 mmol) in 100 mL of DMF at 0° C. was added sodium ethanethiolate (1.4 g, 16.6 mmol). After 2 hours, the reaction was poured into EtOAc, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1NC2CCC1C2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (664 mg, 3.92 mmol) in chloroform (8 ml) were added triethylamine (0.55 ml, 3.92 mmol) and 4-methoxybenzene sulfonyl chloride (892 mg, 4.32 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl 2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (927 mg, 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[O:20][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:23]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.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>[CH3:18][C:19]1[O:20][C:21]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:22][N:23]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)o1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
A mixture of Example A1 (600 mg, 2.38 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (648 mg, 3.10 mmol), K2CO3 (989 mg, 7.15 mmol) and Pd(PPh3)4 (138 mg, 0.119 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. overnight. Additional 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (100 mg) and Pd(PPh3)4 (50 mg) were added, the mixture heated at 80° C. for 5 h, then cooled to RT and treated with water and EtOAc. The solids were removed via filtration through diatomaceous earth, the layers of the filtrate separated and the organic layer was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (323 mg, 45%). MS (ESI) m/z: 299.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.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>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([CH2:15][CH:14]=[CH2:13])[CH:3]=1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1cc(C(=O)OC)ccc1C
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 101.8 %

Procedure:
Argon was bubbled into a solution of methyl 3-bromo-4-methylbenzoate (11.45 g, 50 mmol), allyltributyl-stannane (16.72 g, 50.5 mmol) and lithium chloride (5.30 g, 125 mmol) in DMF (100 mL) with magnetic stirring for 20 minutes. Dichlorobis(triphenyl-phosphine)palladium (0.81 g, 1.16 mmol) was then added and mixture heated at 95° C. for 1.5 hours. After cooling to room temperature, the mixture was partitioned between ether-hexanes (1:1 V/V) and water. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Isco RediSep 330 g silica gel, 5% then 35% dichloromethane in hexanes) to give 3-allyl-4-methyl-benzoic acid methyl ester (9.68 g, 100%) as a colorless oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([Li])CCC.C1(C)C=CC(S(O[CH2:29][CH2:30][F:31])(=O)=O)=CC=1>C1COCC1>[F:31][CH2:30][CH2:29][C:2]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CCF)SCCCS1
Reaction time: 1.33 h
Yield: 108.1 %

Procedure:
A solution of commercially available reagent of tert-butyl [1,3]dithiane-2-carboxylate (2.0 g, 9.69 mmol) in THF (20 mL) was cooled to −78° C., and n-butyl lithium (1.67 M solution in n-hexane, 8.62 mL, 13.6 mmol) was then added over 10 minutes. The mixture was stirred for 80 minutes, and 2-fluoro-ethyl toluene-4-sulfonate (2.95 g, 13.5 mmol, known compound, ref. Tetrahedron (2005), 61 (35), 8410-8418) was then added. The mixture was stirred at −78° C. for 30 minutes, and the cooling bath was then removed. The mixture was stirred while allowing the temperature to gradually return to room temperature, and stirred at room temperature for 20 hours. After confirming the consumption of the starting materials by LCMS, the mixture was quenched with water (100 mL), and then extracted with dichloromethane (100 mL). The aqueous layer was further extracted with dichloromethane (50 mL). The combined dichloromethane layer was washed with a saturated aqueous solution (100 mL) of ammonium chloride and a saturated aqueous solution (100 mL) of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure. The resulting residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain tert-butyl 2-(2-fluoro-ethyl)-[1,3]dithiane-2-carboxylate (2.79 g, quant.).
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1
Reactant: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)c1ccccc1

Procedure:
A solution of 5-[2-benzyloxy-4-(2-methyl-3-oxo-3-phenylpropyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (15 mg) in 4 mL of EtOH/water (1:1) is hydrogenated over Degussa Pd/C (5 mg) at 1 atm for 15 min. The catalyst is filtered and the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC followed by lyophilization to give the title compound. (M−1)−=373. HPLC retention time=1.13 min (Method A).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CO[Na].[CH3:33][O:34][CH:35]([O:39][CH3:40])N(C)C>CO>[CH3:33][O:34][CH:35]([O:39][CH3:40])[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][C:16]2[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:15]=2)[CH2:29][CH2:28]1
Reactant: COC(OC)N(C)C
Reactant: C1CCNC(CCC2CCNCC2)=NC1
Agent: CO[Na]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCC(CCC2=NCCCCN2)CC1
Temperature: 90 °C

Procedure:
The dihydrochloride salt of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (1.6 g, 5.8 mM) in methanol (12 ml) which contained MeONa (12 mM) and dimethylformamide dimethyl acetal (20 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give the 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl] 1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.1 g, 5 mM) and diisopropylethylamine (0.96 ml) in 20 ml dry CHCl3 was added the solution (CHCl3 8 ml:MeOH 1 ml) of above piperidine-carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and then at room temperature for 3 hrs. The solvent was then removed, and water added (30 ml). The aqueous solution, washed with ethylacetate, was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to yield [2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.85 g, 38% yield)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].FC1C=CC(C=O)=CC=1.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc(F)cc1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(F)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-2-(4-fluoro-phenyl)-5-methyl-oxazole (prepared from 4-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 2 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[C:16]([N:20]1[C:25](=[O:26])[C:24]([Cl:27])=[C:23]([SH:28])[CH:22]=[N:21]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([N:20]1[C:25](=[O:26])[C:24]([Cl:27])=[C:23]([S:28][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:3]=[C:2]([Cl:1])[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:6]=2)[CH:22]=[N:21]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(F)(F)C(Cl)=Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(C=C(Cl)C(F)(F)F)cc2)c(Cl)c1=O

Procedure:
1.2 g of 4-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzyl bromide and 0.8 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.7 g of potassium carbonate in 10 cc of dimethylformamide.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:43]=[C:44]([NH2:57])[C:45]4[C:49]([CH:50]=3)=[N:48][N:47](C3CCCCO3)[CH:46]=4)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.CC1C=CC(S(O)(=O)=O)=CC=1.N>C1COCC1>[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:50]=[C:49]4[C:45]([CH:46]=[N:47][NH:48]4)=[C:44]([NH:57][C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:2]5[CH2:3][CH2:4][CH2:5][CH2:6]5)[CH:12]=4)=[O:15])[CH:43]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1ccnc(N2CCCC2)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccnc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
A solution of 2-(1-pyrrolidinyl)-4-pyridinecarboxylic acid hydrochloride (38 mg, 0.16 mmol, available from Maybridge) in anhydrous THF (2 ml), was treated with 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.026 ml, 0.2 mmol, available from Acros) and stirred at room temperature under nitrogen for 2 h. The mixture was then treated with anhydrous DIPEA (0.131 ml, 0.75 mmol) followed by a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg, 0.15 mmol) in THF (2 ml). The mixture was stirred under nitrogen for a further 6 h. Solvents were removed by blow down under a stream of nitrogen and the residue was then dissolved in methanol (3 ml) and evaporated further in a vacuum centrifuge. The residue was then dissolved in methanol (5 ml) then treated with macroporous tosic acid (102 mg, 0.452 mmol) and stirred for 17 h at room temperature. Addition of 0.88 ammonia solution (0.5 ml) was followed by stirring at room temperature for a further 30 mins and then the mixture was separated using a hydrophobic frit. The organic layer was concentrated in vacuo and the residue purified by HPLC (Method E) to afford the title compound (8 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>C(Cl)Cl.O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCN(C)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of N-methyl piperazine (5.7 g; 57 mmol; 2 eq) in dry DCM (150 mL) are added Et3N (5.75 g; 57 mmol; 2 eq) and 1-(bromomethyl)-4-methoxy-2-nitrobenzene (7 g; 28.5 mmol; 1 eq). The mixture is stirred at room temperature for 8 h then diluted with water (150 mL). The organic phase is washed with brine and dried. The solvent is removed under vacuum to afford 6.5 g (86%) of the title compound as a viscous liquid. 1H NMR (CDCl3, 400 MHz) δ 7.46-7.44 (m, 1H), 7.34 (s, 1H), 7.08-7.05 (m, 1H), 3.86 (s, 3H), 3.73 (s, 2H), 2.54-2.46 (very br s, 8H), 2.29 (s, 3H). LC/MS (ES+): 266.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][C:45]=1[CH3:46].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][C:45]=5[CH3:46])=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-4-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (380 mg, 71%) as a brown solid.
Reaction SMILES: Br[CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[SH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)CCCCCS
Reactant: CCCCCCCCCCCCC#CC(Br)CCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC#CC(CCCCC(=O)OC)SCCCCCC(=O)OC

Procedure:
A mixture of methyl 6-bromo-7-eicosynoate, methyl 6-mercaptohexanoate (1.21 g) in 70 ml DMF was treated with Cs2CO3 (2.44 g) as in Example 45 to give 1.02 g of methyl-6-[(6-methoxy-6-oxohexyl)thio]-7-eicosynoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([O:27]CC)=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([OH:27])=[O:26])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Yield: 100.1 %

Procedure:
A mixture of 2.8 g of ethyl 1-(4-fluorophenyl)1,4 -dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylate, 20 ml of 10% potassium hydroxide solution and 10 ml ethanol was heated on a steam bath for 3 hrs. The reaction mixture was cooled and acidified with acetic acid. The solid product was collected and washed with acetone to give 2.6 g 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid. A sample of the compound was converted to its monomethanesulfonate salt, m.p. 280-281° C. when recrystallized from acetonitrile.