Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:43])[CH2:15][C@@H:16]([C:22]1[CH:42]=[CH:41][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:44]O.[Li+].[OH-].Cl>C1COCC1.O>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:41]=[CH:42][C:22]([C@@H:16]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)[CH2:15][C:14]([OH:44])=[O:43])=[CH:23][CH:24]=1)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: OO
Reactant: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)c1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of the oxazolidinone 30.1 (62.0 mg, 0.107 mmol) dissolved in THF (10 mL), was added a 30% hydrogen peroxide solution (0.120 mL, 1.07 mmol) followed by a 2M LiOH solution (0.266 mL, 0.533 mmol). The resulting slurry was stirred for five hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH ˜3. The mixture was then extracted with EtOAc (1×50 mL), and the organic layer was washed with acidic sodium sulfite solution (2×30 mL) and brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 30 (29.0 mg). MS ESI (pos.) m/e: 423.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.32 (1H, d, J=1.6 Hz), 7.92 (1H, br. s.), 7.61 (1H, s), 7.42 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.12 (2H, d, J=9.0 Hz), 7.05 (1H, d, J=7.4 Hz), 6.84 (2H, d, J=9.0 Hz), 6.15 (1H, d, J=1.6 Hz), 4.95 (2H, s), 4.43 (1H, t, J=7.8 Hz), 3.08 (1H, dd, J=16.6, 8.4 Hz), 2.83 (1H, dd, J=16.4, 7.4 Hz), 1.16 (9H, s).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:25](=[O:28])[CH2:26][CH3:27])[N:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17]CC)=[O:16].O>C1COCC1>[OH:22][C:20]1[C:14]([C:15]([OH:17])=[O:16])=[N:13][N:12]([CH3:11])[C:25](=[O:28])[C:26]=1[CH3:27]
Reactant: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)c(C(=O)O)nn(C)c1=O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430 mL) at −78° C. was added a solution of diethyl 2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) prepared by the procedure described in Example 168 (step B) in THF (10 mL). The resulting mixture was slowly warmed to −40° C. over 1 hour and stirred for 1.5 hours at −40° C. To the −40° C. reaction mixture was added water (500 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the THF. The resulting aqueous mixture was quenched with 6 N aqueous HCl at 0° C. and acidified to pH 1 to 2. The resulting mixture was stirred for 16 hours at room temperature. The precipitates were filtered off and triturated with CH2Cl2 to afford 7.21 g (47%) of the desired product. The filtrate was extracted with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 3.56 g (23%) of additional desired product. The aqueous layer was extracted again with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 1.32 g (9%) of additional desired product. A total of 12.09 g (79%) of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[CH3:36][C:37]1[O:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:41][C:40]4[O:43][C:37]([CH3:36])=[CH:38][CH:39]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: Cc1ccc(C=O)o1
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A mixture of benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.0 g, 0.0063 mol), 5-methylfurfural (0.77 g, 0.007 mol), and acetic acid (1.15 g, 0.019 mol) in dichloroethane (100 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (4.1 g, 0.0195 mol) was added to the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×200 mL), and the combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel using 2%-5% methanol/dichloromethane as mobile phase to yield benzyl 4-[4-amino-3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (2.63 g, 0.0046 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.59 min. MS: MH+ 568.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:11][CH:12](O)[CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CCOCC>[Cl:3][CH2:14]/[CH:13]=[CH:12]/[CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: C=CC(O)CC1CCCCC1
Solvent: O
Solvent: CCOCC
Product: ClC/C=C/CC1CCCCC1
Reaction time: 8 h

Procedure:
Thionyl chloride (50.5 ml) was added dropwise over 1 hour to a stirred solution of 1-cyclohexyl-3-buten-2-ol (50 g) (obtained as described in European Patent Application, Publication No. 258183) in dry ether (1 litre). The solution was allowed to stand overnight and then water (750 ml) was added, and the mixture was stirred for 1 hour. The organic phase was separated, washed with water (500 ml) and saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under high vacuum to give (2E)-1-chloro-4-cyclohexylbut-2 -ene (B), as a clear liquid (42.2 g), b.p. 64-68° C. at 0.5 mm Hg; NMR: 0.8-1.8(complex m, 11H), 2.0(t, 2H), 4.0(d, 2H), 5.5-5.9(complex m, 2H); microanalysis, found: C, 69.5; H, 10.0; Cl, 20.3%; C10H17Cl requires: C, 69.5; H, 9.9; Cl, 20.5%.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])C(OCC)=O)C.C(OCC)(=O)CC(OCC)=O>Cl.O1CCOCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:5][C:4]([OH:23])=[O:3])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1COCCO1
Product: CC(=O)c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of diethyl(4-acetyl-2-nitrophenyl)malonate and diethyl malonate (54.1 g) prepared by step a) was dissolved in 4M HCl (800 mL)/dioxane (800 mL), and the solution was stirred at 100° C. for 8 hours. After cooling, dioxane was removed in vacuo, and the aqueous layer was extracted with chloroform (200 mL×1, 100 mL×2). The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the object compound (23.1 g, quantitatively) as a brown solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:2]1.C(N=[C:19]=[O:20])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O.[N-]=C=O>C1(C)C(C)=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([N:13]=[C:19]=[O:20])(=[O:12])=[O:11])=[CH:2]1
Reactant: NS(=O)(=O)c1csc2ccccc12
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1csc2ccccc12
Reaction time: 2 h

Procedure:
Ten grams of benzothiophene-3-sulfonamide, 100 ml of xylene, 3 g. of butyl isocyanate and 0.1-0.3 g. of 1,4-diazabicyclo[2,2,2]octane in admixture were heated to reflux for one half hour after which phosgene was passed into the mixture for two hours at 125°. The reaction mixture was cooled, filtered and concentrated in vacuo to yield an oil (12 g.). Infrared analysis of this oil showed an absorption peak at 2250 cm-1 consistent for the desired isocyanate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][N:25]=[CH:26]2>>[CH:26]1[C:27]2[C:22](=[C:21]([NH:20][C:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)=[O:17])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Product: O=C(Nc1cccc2cnccc12)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
Using the procedure outlined in Example 107, the title compound was prepared from 1-(5-trifluoromethylpyrid-2-yl)-piperidine-4-carboxylic acid (D101) (100 mg, 0.36 mmol) and 5-aminoisoquinoline (27 mg, 0.19 mmol) as an off white solid. MS(ES): MH+ 401, M-H+ 399.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:14][CH:13]([NH:15][C:16]([CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].C1CCN2C(=NCCC2)CC1>CC#N>[O:33]=[C:32]1[O:1][N:2]=[C:3]([CH:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:12][CH:13]([NH:15][C:16]([CH2:18][NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[O:17])[CH2:14]3)[CH2:7][CH2:6]2)[NH:4]1
Reactant: N=C(NO)C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3noc(=O)[nH]3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above intermediate from Step B (0.044 g, 0.1 mmol), 1,1′-carbonyldiimidazole (Aldrich, 0.0178 g, 0.11 mmol), DBU (Acros, 0.06 mL, 0.4 mmol) in CH3CN (1 mL) was stirred at rt overnight. The crude product was purified by HPLC to give a TFA salt as a yellowish solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22](O)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(-c2ccc(OC(=O)CCCCCC)cc2)nc1
Yield: 65.8 %

Procedure:
4-(5-Octyl-2-pyridyl)phenol (0.5 g), 0.2 g of heptanoic acid and 0.04 g 4-(dimethylamino)pyridine were dissolved in 50 ml of dichloromethane and the solution was treated portion wise with 0.4 g of N,N'-dicyclohexylcarbodiimide within 10 minutes while stirring. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate, filtered and subsequently concentrated. The crude product obtained was purified by chromatography on silica gel with toluene. Recrystallization from ethanol gave 0.4 g of 4-(5-octyl-2-pyridyl)phenyl heptanoate with a m.p. (C--S) 57° C. and cl.p. (S--I) 77° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18](C2C=CN=CC=2)[N:19]=1>>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:14]3[C:15]4[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([F:36])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[C:29]([F:36])[CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cccc(F)c5n4)cc3CC[C@@H]12
Yield: 50.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-8-fluoroquinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 78 mg (50%) of the title compound as an amorphous foam. FDMS: m/e=406. α[D]589 =+63.29 (c=0.56, chloroform).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5](C(Cl)=O)[N:6]=1.[N+](=C[Si](C)(C)C)=[N-].[BrH:17].[CH3:18][CH2:19][O:20]C(C)=O>CC#N.O>[Br:17][CH2:18][C:19]([C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1)=[O:20]
Reactant: Br
Reactant: CCOC(C)=O
Reactant: Cc1nc(C(=O)Cl)cs1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: CC#N
Product: Cc1ncc(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a solution of 2-methylthiazole-4-carbonyl chloride (0.34 g, 2.10 mmol) in dry MeCN (8 mL) cooled at 0° C., under nitrogen atmosphere, is slowly added (diazomethyl)trimethylsilane (3.14 ml, 6.29 mmol, 2.0M in hexane). The reaction is stirred at RT for 15 h (UPLC-MS monitoring: complete conversion). The reaction is cooled at 0° C. and 48% hydrobromic acid (1.23 mL, 7.34 mmol) is added dropwise. The reaction is stirred at RT for 3 hour. Then EtOAc and water are added, the organic layer is separated and the aqueous phase is neutralized with 1M NaOH and extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered and evaporated to dryness to obtain compound I228 as a dark brown gummy solid (400 mg, 87% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.C1C=CN=CC=1.F.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][OH:15])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(Br)cc1)C(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)F
Temperature: 0 °C

Procedure:
n-BuLi (2.5 M in hexanes, 1.43 mL) was added to a −70° C. THF (8.5 mL) solution of 1,4-dibromobenzene (884 mg) and the mixture was stirred for 15 minutes. A THF (8.5 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2-difluoroethylidene]pentan-2-amine (1.0 g) was then added dropwise and the mixture was stirred for 1.5 hours. The mixture was then poured slowly into an icy saturated aqueous solution of ammonium chloride under vigorous stirring and was extracted with 3 portions of ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue, which was purified on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 75:25) as eluent to yield (2S)—N-[(1S)-1-(4-bromophenyl)-2,2-difluoroethyl]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine. (2S)—N-[(1S)-1-(4-Bromophenyl)-2,2-difluoroethyl]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (200 mg) was dissolved in CH3CN (4 mL) and the solution was cooled to 0° C. HF-pyridine (40 μL) was added dropwise and the mixture was reacted for 16 hours. The mixture was poured into a saturated solution of sodium bicarbonate, ethyl acetate was added and the resultant mixture was vigorously shaken. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified on SiO2 using a gradient of hexanes and ethyl acetate (80:20 to 60:40) as eluent to yield the title compound.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([O:19]C)=[O:18])[CH:8]=1)=[O:4].[Li+].[OH-]>O.CO>[C:3]([CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)COc1cc(C(=O)OC)nc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cc(C(=O)O)nc2ccccc12
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A sample of methyl 4-methoxycarbonylmethyloxy-2-quinolinecarboxylate(0.20 g, 0.00073 mole) prepared as in Example II, was hydrolyzed by the addition of lM LiOH (2.2 ml, 0.0022 mole) in H2O/MeOH. After stirring for 18 hours, the MeOH was evaporated, the product dissolved in H2O, and acidified to pH 2.6 with lN HCl thereby precipitating a white solid. A yield of 0.15 g (83%) of 4-carboxymethyloxy-2-quinolinecarboxylic acid was obtained after filtering and drying in a vacuum dessicator. Melting point was 240° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1>C(N)(CC)C.O.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>[CH3:11][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CSc1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
To 0.52 g (2.58 mmol) N-[2-(4-ethynyl-phenyl)-1-methyl-ethyl]-acetamide (I58.3) and 0.50 g (1.98 mmol) 4-iodo-2-(methylthio)pyrimidine in 3 mL sec-butylamine and 3 mL water are added 0.14 g (0.20 mmol) bis(triphenylphosphine)dichloro-palladium and the mixture is stirred at r.t. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, DCM/MeOH 96/4). The resulting product is triturated with diethylether.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]1[CH:54]=[C:55]([CH:63]=[C:64]([F:67])[C:65]=1[F:66])[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[N:60]2[CH2:61][CH2:62][CH:57]([O:56][C:55]3[CH:54]=[C:53]([F:52])[C:65]([F:66])=[C:64]([F:67])[CH:63]=3)[CH2:58][CH2:59]2)=[CH:14][CH:15]=1
Reactant: Fc1cc(OC2CCNCC2)cc(F)c1F
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Oc2cc(F)c(F)c(F)c2)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 16 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of N-biphenyl-4-yl-malonamic acid (100 mg, 0.4 mmol) in DMF (2.0 mL) followed by HOBt (81 mg, 0.6 mmol) and EDCI.HCl (114 mg, 0.6 mmol). After 2 minutes of stirring, 4-(3,4,5-trifluoro-phenoxy)-piperidine hydrochloride (100 mg, 0.4 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine and concentrated. The remaining residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 30 mg (17% Yield) of N-biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-propionamide. LC/MS [M+H]+: 469.17, 98.06%, 1H NMR (300 MHz, DMSO-d6): δ7.6 (m, 6H), 7.4 (m, 2H), 7.3 (m, 1H), 7.1 (m, 2H), 4.6 (m, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.5 (m, 1H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]3[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(=O)[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(=O)[nH]c3)nn12
Temperature: 200 °C

Procedure:
A mixture of 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.08 g, 0.3 mmol), 5-Amino-1H-pyridin-2-one (56.1 mg, 0.510 mmol), N,N-Diisopropylethylamine (0.181 mL, 1.04 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 200° C. for 30 minutes. The reaction was concentrated and redissolved in 2 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate, extracted with DCM, dried filtered and concentrated to give 5-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1H-pyridin-2-one