Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=O)[NH2:6].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H:45]([NH:50][C:51]([NH2:53])=N)[C@@H:44](O)[C@@H:43]2[NH:55][C:56]([NH2:58])=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O>>[CH:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:45]2[N:50]=[CH:51][N:53]=[C:43]3[N:55]=[CH:56][NH:58][C:44]=23)[O:10][CH:8]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: c1coc(CNc2ncnc3nc[nH]c23)c1

Procedure:
Cell Culture and Treatment. FD lymphoblast lines were grown in RPMI-1640 and primary fibroblast lines in Dulbecco's modified Eagle's media (DMEM) with Earle's balanced salts. Both media were supplemented with 2 mM L-glutamine and 1% penicillin/streptomycin and either 10% (lymphoblast) or 20% (fibroblast) fetal bovine serum (Invitrogen). Kinetin was obtained from both MicroSource Discovery Systems and Sigma and dissolved at 10 mM in either DMSO or water. FD cells were cultured in the presence of kinetin for 72 hours except where noted. Benzyladenine, zeatin, and 2iP were obtained from Sigma and dissolved in DMSO at 10 mM. These compounds were tested at concentrations of 1 μM, 10 μM, 50 μM, and 100 μM. Cycloheximide was obtained from Sigma and dissolved at 10 mg/ml in DMSO. Cells were treated with 100 μM kinetin for eight hours, then 50 μg/ml cycloheximide was added to the cultures for four hours16.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14].FC(F)(F)[C:20](O)=[O:21].C1N2CN3CN(C2)CN1C3>>[F:1][C:2]1[C:3]([CH:20]=[O:21])=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][C:7]2([CH3:14])[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(F)c2c(c1)C(C)(C)CC(=O)N2C
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(c(F)c1C=O)N(C)C(=O)CC2(C)C
Temperature: 25 °C
Yield: 52 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 74 mg (0.312 mmol) 8-fluoro-6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one, 3 ml of trifluoroacetic acid and 53 mg (0.38 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 16 hours and then cooled to ambient temperature. The reaction mixture was quenched first with water and then 30 ml of saturated aqueous bicarbonate solution and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude product was purified on silica gel eluting with ethyl acetate to afford 43 mg (52%) of the desired product. Mass spectrum APCI m/e 266 (p+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1.O>O1CCOCC1>[Cl:8][C:5]1[N:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
Under an argon atmosphere a solution of 1.08 g (7.05 mmol) 3,6-dichloro-pyridazin, 10 mL 2 M Na2CO3 solution and 80 mg (0.14 mmol) chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II) in 150 mL 1,4-dioxane is heated to 110° C. At this temperature a solution of 1.13 g (7.05 mmol) 4-chlorophenyl-boric acid in 50 mL 1,4-dioxane is added dropwise within 2 h and the reaction mixture is heated for another hour. After cooling it is combined with 100 mL water, extracted with 100 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 8:2).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:27])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([F:19])[CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C>O.C1COCC1.CO>[C:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][C:8]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)([F:19])[C:7]([OH:27])=[O:6])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(F)(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(F)(C(=O)O)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 74.9 %

Procedure:
Lithium hydroxide monohydrate (0.27 g, 6.45 mmol) in H2O (5 mL) was added to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid ethyl ester (580 mg, 1.61 mmol) in THF (5 mL) and MeOH (5 mL). After being stirred for 12 hours, the mixture was concentrated in vacuo, diluted with H2O, and extracted with DCM (3 times, discarded). The aqueous phase was then acidified to pH 1 and extracted with DCM (2 times). The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid (400 mg). The material was used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH:27][CH:28]([CH3:32])[C:29]([NH2:31])=[S:30])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:31]=[C:29]([CH:28]([NH:27][C:24](=[O:26])[CH3:25])[CH3:32])[S:30][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Reactant: CC(=O)NC(C)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(C(C)NC(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-(acetylamino)thiopropionamide in ethanol gave 7-[2-[1-(N-acetylamino)ethyl]-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 236°-238° C., which was hydrolyzed with refluxing 6N hydrochloric acid to afford the title compound, mp 246°-250° C. (dec).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 36 h
Yield: 93.4 %

Procedure:
To a 250 mL round bottom flask was added N-Boc-4-chloro-L-phenylalanine (0.971 g, 3.24 mmol), potassium carbonate (0.448 g, 3.24 mmol), a stir bar and 30 ml of acetone. To this was added dimethyl sulfate (0.613 ml, 6.48 mmol) and the reaction was allowed to proceed at ambient temperature for 36 h. The reaction was quenched with water (15 ml), and the product was extracted with ethyl acetate (4×100 ml). The organics were pooled, washed with brine, and dried over sodium sulfate. The organics were filtered and concentrated in vacuo to provide a pale yellow residue. The residue was purified by column chromatography on a Biotage SP1, 40M Biotage silica cartridge, eluting with a linear gradient of hexanes-ethyl acetate to provide the title compound as a pale yellow foam (950 mg). Mass spectrum (ESI) 214.1 (M-Boc). 1H NMR (600 MHz, CDCl3): δ 7.24 (d, J=8.3 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 4.96 (d, J=7 Hz, 1H), 4.56 (d, J=6 Hz, 1H), 3.71 (s, 3H), 3.08 (dd, J=5.7, 5.7 Hz, 2H), 3.01 (dd, J=5.9, 6.0 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1)#[CH:16]>O1CCOCC1.O.C(Cl)Cl.CCCCCCC.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:15]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=3)[CH:16]=2)=[N:18]1
Reactant: [N-]=[N+]=Nc1ccc(CCC(=O)O)cc1
Reactant: C#Cc1n[nH]c2ccccc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCCC
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
3-(4-Azidophenyl)propanoic acid (Bachem, 672 mg; 3.5 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (500 mg; 3.5 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (7.5 mL). D-(−)-isoascorbic acid sodium salt (139 mg; 0.70 mmol; 0.2 eq.) followed by a solution of copper sulfate pentahydrate (35 mg; 0.14 mmol; 0.04 eq.) in water (0.75 mL) were added. The reaction mixture was stirred at 90° C. for 48 h. Dioxane was partially removed under reduced pressure, water was added and the mixture was extracted with EtOAc (three times). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was sonicated in DCM (5 mL) and heptane (10 mL). The resulting solid was filtered and dried under high vacuum to afford the title compound as a brown solid (875 mg, 75%). 1H NMR (300 Mz, DMSO-d6) δ: 13.37 (brs, 1H), 9.27 (s, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.46-7.41 (m, 1H), 7.27-7.22 (m, 1H), 2.92 (t, J=7.5 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H). HPLC (Condition A): Rt 3.14 min (purity 93.5%). MS (ESI+): 334.2, MS (ESI−): 332.2.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19].O>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1Cl
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(F)cc1
Yield: 75.8 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.0441 mole) of ethyl 2-chloro-(p-fluoro)benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C. To 4.0 g (0.015 mole) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate was added 30 ml. of concentrated hydrochloric acid and 30 ml. of glacial acetic acid. The carboxylate did not dissolve completely. To this mixture was added 30 ml. of chloroform. The carboxylate dissolved gradually into the chloroform solution. the reaction mixture was cooled to 0°-5° C. with an ice bath. To the above mixture was added with vigorous stirring 4.0 g (0.058 mole) of sodium nitrite. The reaction mixture was stirred at 5°-10° C. for 30 minutes and poured into a solution of 1.48 g (0.0150 mole) of cuprous chloride in 20 ml. of concentrated hydrochloric acid. After the gas evolution subsided, the reaction mixture was diluted with water. The chloroform layer was separated and the aqueous layer was extracted with chloroform. The combined chloroform solution was washed with water followed by saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residual solid was recrystallized from ethanol to give 3.3 g (77%) of ethyl 2-chloro-4-(p-fluorophenyl)-5-thiazolecarboxylate as orange needles, m.p. 113°-114° C.
Reaction SMILES: [CH2:1]([C:7]1[C:16](N)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N([O-])=O.[Na+].[Br:22]Br.[OH-].[NH4+]>Br>[Br:22][C:16]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCCCCCc1nc2ccccc2cc1N
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [NH4+]
Product: CCCCCCc1nc2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of 2-hexyl-quinolin-3-ylamine in hydrobromic acid at -10° C. was added aqueous solution of sodium nitrite followed by bromine and was allowed to warm up to RT. The reaction was continued for 1 day. Next day the reaction mixture was neutralized using aqueous ammonium hydroxide solution and was extracted with ether. The organic layer was washed with aqueous sodium thiosulfate. The product was purified by column chromatography.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH2:8])[CH3:2].[K+].[CH2:31]([S:33]([NH-])(=[O:35])=[O:34])[CH3:32]>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH:8][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Reactant: CCS([NH-])(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNS(=O)(=O)CC
Yield: 19.4 %

Procedure:
A solution of the methanesulfonic acid ester intermediate of Example 48 (25 mg, 53 μmol) and ethanesulfonamide potassium salt (16 mg, 106 μmol) in DMF (2 mL) is stirred at 60° C. for 18 h. The mixture is concentrated and separated by prep. HPLC to give the title compound (5 mg) as a colourless oil; LC-MS: tR=1.14 min, [M+H]+=487.14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:74][C:75]([F:79])([F:78])[CH2:76][NH2:77]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:77][CH2:76][C:75]([F:79])([F:78])[F:74])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: NCC(F)(F)F
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC(F)(F)F)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2,2,2-trifluoroethanamine (6.56 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (24.6 mg, 68%). LC-MS m/z 655 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][CH2:14][CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.[Zn]>[NH2:9][C@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C@H:12]([CH2:11][OH:10])[CH2:13][CH2:14][O:15][CH2:16]1
Reactant: Fc1ccccc1[C@]12COCC[C@H]1CON2
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccccc2F)COCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Zinc (11.6 g) was added to a solution of (±)-(3aR*,7aS*)-7a-(2-fluorophenyl)hexahydropyrano[3,4-c]isoxazole (3.95 g) in acetic acid (78.4 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. An ice-cooled 0.5 N sodium hydroxide solution was added to the residue. The aqueous layer was extracted with ethyl acetate and a mixed solution of ethyl acetate and tetrahydrofuran. The organic layers were combined and washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (3.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a mixture of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (15.5 g, 77 mmol), 2-Chloro-5-hydroxy-pyridine (9.9 g, 77 mmol) and triphenylphosphine (24.24 g, 92.4 mmol) in THF, diisopropylazodicarboxylate (18.6 g, 92.4 mmol) was added at 0° C. and stirred for 18 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo, resulting residue was purified by flash column chromatography to give tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (11 g, 45%); MS: 335.2 (M+23).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:18]([OH:20])=O)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)=[C:5]([F:21])[CH:4]=1)[CH3:2].FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.N1C=CC=CC=1.[NH2:46][CH2:47][CH2:48][OH:49]>CN(C=O)C>[OH:49][CH2:48][CH2:47][NH:46][C:18]([C:11]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])=[CH:15][C:14](=[O:16])[N:13]([CH3:17])[CH:12]=1)=[O:20]
Reactant: NCCO
Reactant: CCc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCc1ccc(Nc2cc(=O)n(C)cc2C(=O)NCCO)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.50 g, 1.72 mmol) was reacted with pentafluorophenyl trifluoroacetate (0.92 mL, 5.20 mmol) in the presence of pyridine (0.45 mL) in DMF (15 mL). The solution was allowed to stir at room temperature for 15 hours and then treated with 2-Amino-ethanol (0.50 mL, 8.60 mmol) as in example 75 to afford the 4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethyl)-amide (0.47 g, 82%). 1H NMR [400 MHz, (CD3)2SO] δ 9.82 (s, 1H), 8.35 (t, J=5.4 Hz, 1H), 8.20 (s, 1H), 7.27 (t, J=8.4 Hz, 1H), 7.12 (d, J=11.8 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 5.38 (s, 1H), 4.72 (t, J=5.1 Hz, 1 H, OH), 3.44 (t, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.22 (t, J=12.8, 6.8 Hz, 2H), 2.58 (q, J=7.1 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H). (APCI+) calcd for C17H20FN3O3 333.36 (M+1), found 334.1.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)[CH3:25]>>[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH3:25]
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CCc1ccccc1-c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with 2-ethylphenylboronic acid to give 477. MS (ESI+) 400.2. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.38-7.31 (m, 2H), 7.30-7.23 (m, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.12 (dd, J=8.2, 1.7 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 5.93 (hept, J=6.2 Hz, 1H), 4.65-4.41 (m, 4H), 2.61 (q, J=7.6 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H), 1.07 (t, J=7.5 Hz, 3H)
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[Br-].[C:23]1([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.10 g, 3.42 mmol) in N,N-dimethylformamide (20 mL) were added diphenylmethane bromide (0.93 g, 3.76 mmol) and potassium carbonate (0.52 g, 3.76 mmol), and the mixture was stirred at 60° C. for 3 hours. This reaction mixture was diluted with ethyl acetate and water and, after phase separation, the aqueous layer was extracted with ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in acetic acid (20 mL). To this solution was added concentrated sulfuric acid (10 ml), and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from hexane-ethyl acetate to provide 0.58 g of the title compound. Yield 37%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:16].[Na+]>Cl>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: [OH-]
Reactant: CSc1nccc(-c2ccnc(F)c2)n1
Agent: Cl
Agent: [Na+]
Product: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Temperature: 25 °C
Yield: 49 %

Procedure:
A suspension of 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 30.9 mmol) in 2N HCl (100 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and placed in an ice bath. The pH was adjusted to about 7 with 2N NaOH (about 100 mL). The resulting solids were collected by filtration, washed with water and dried to give 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (5.07 g) as a solid. This material was placed in the thimble of a Soxhlet apparatus and was attached to a 1 L flask charged with ethyl acetate (500 mL). The material was continuously extracted for 3 days. The resulting white precipitate from the ethyl acetate layer was collected by filtration (3.3 grams, 49% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (br, s, 1H), 8.75 (d, J=5.0 Hz, 1H), 7.79 (d, J=5.0 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.13 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 2.58 (s, 3H); m/z (APCI-pos) M+1=220.0.