Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:22])[N:7]2[CH3:21].[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](Br)[CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:23][C:24]1[CH:29]=[C:28]([C:11]2[C:3]([O:2][CH3:1])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:21])[C:6](=[O:22])[CH2:5]3)[CH:27]=[N:26][CH:25]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Reactant: Brc1cncc(Br)c1
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1c(-c2cncc(Br)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (80 mg, 0.264 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 188 mg, 0.792 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.320 mL, 0.63 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (144 mg, 0.016 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) tilt 333.0246 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.24 (s, 3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCCNCC(=O)O
Yield: 77 %

Procedure:
To a solution of 13.0 g. (5.46 × 10-2 moles) of N-(o-nitrobenzyl)ethyl glycine in 200 ml. of absolute ethyl alcohol was added slowly 0.76 g. (5% by weight) of 10% Pd/C catalyst and the mixture placed on a Paar hydrogenator. The mixture was shaken until theoretical hydrogen (16.4 × 10-2 moles) had been absorbed, removed from the Paar and the mixture filtered under suction. The catalyst was washed with ethyl alcohol and the solvent removed in vacuo affording a yellow oil. Purification of the oil was effected by distillation yielding 8.8 g. (77% yield) of a colorless oil; b.p. 124°-126° C. (0.03 mm).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)=[O:16]
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CN1CCC(N)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(NC(=O)c2cc(Cl)ccc2F)CC1

Procedure:
A mixture of 23.9 g 4-amino-1-methyl-piperidine, 48.5 g 5-chloro-2-fluoro-benzoyl chloride, 44 ml triethylamine and 550 ml benzene is refluxed for 2 hours. Thereafter the solvent is evaporated off in vacuo and the residue is added dropwise under stirring to water. The solution is made alkaline and extracted with toluene. The toluene phase is dried and evaporated. The residue is recrystallised from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 143°-145°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH:25]([CH:27]([OH:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][C:23]2=[O:35])=[CH:18][C:17]=1[F:36].[H-].[Na+].[CH3:39]I>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH:25]([CH:27]([O:34][CH3:39])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][C:23]2=[O:35])=[CH:18][C:17]=1[F:36]
Reactant: COc1cc2nccc(Oc3ccc(N4CC(C(O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N4CC(C(OC)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-4-(hydroxy(phenyl)methyl)pyrrolidin-2-one (Example 48, 0.1 g, 0.2 mmol) in THF/DMF (1 mL:1 mL) was added NaH (0.1 g, 2.5 mmol) solid. The reaction was stirred at RT for 1 h. MeI (0.1 mL, 1.6 mmol) was added via a syringe and the reaction was stirred for 1 h. The reaction was quenched with 10 mL of satd. NH4Cl solution and 10 mL of water. The solution was diluted with 50 mL of EtOAc. The organic phase was separated and was washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by chromatography (10% EtOAc/hexanes to EtOAc) to give colorless film. MS (ESI pos. ion) m/z: 503.5 (M+H). Calc'd Exact Mass for C29H27FN2O5: 502.53.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)=[C:4]([F:16])[CH:3]=1.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH2:14][CH3:15])[C:9]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:18]#[N:17])=[CH:20][CH:21]=2)=[O:11])=[C:4]([F:16])[CH:3]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCCOC(C(=O)O)c1ccc(Br)cc1F
Product: CCCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F

Procedure:
(RS)-(4-Bromo-2-fluoro-phenyl)-propoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-propoxy-acetamide. Colorless oil. MS 405.3 ([M+H]+)
Reaction SMILES: C([Mg]Cl)=C.CO[CH:7]([Si:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH:13]=[CH2:14])[CH:11]=[CH2:12])OC.O>C1COCC1>[CH3:7][Si:10]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH:11]=[CH2:12])[CH:13]=[CH2:14]
Reactant: C=C[Si](C=C)(c1ccccc1)C(OC)OC
Agent: C=C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C[Si](C)(C=C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
158 ml of a solution of vinylmagnesium chloride in THF is added dropwise using a dropping funnel in 1 h at room temperature under nitrogen to 13.1 ml of a solution of dimethoxymethylphenyldivinylsilane in 36 ml of anhydrous THF. The temperature is controlled with a water bath. After addition, the mixture is stirred at room temperature for 16 h and then refluxed for 2 h. 40 ml of H2O is then added and the mixture is stirred for 30 min. The white precipitate that forms is filtered and is then rinsed with ethyl acetate. The filtrate is extracted with ethyl acetate twice. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. 12.56 g of methyl-phenyl-divinyl-silane is obtained in the form of a clear yellow oil, which is then used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Nc1ccc(F)c(F)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(N)ccc(F)c1F
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 2-amino-5,6-difluoro benzoic acid (3.78 g, 21.8 mmol) in tetrahydrofuran (500 mL) was added EDCl.HCl (8.5 g, 44.0 mmol, 2.0 equiv.), HOBT (5.9 g, 44 mmol, 2.0 equiv.) and ammonia as a 0.5M solution in dioxanes (218 mL, 109 mmol, 5 equiv.). The resultant slurry was stirred for 24 hours, and then solids removed by filtration through celite. The filtrate was taken to a residue under reduced pressure and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (Ethyl acetate/Hexanes) to afford analytically pure 2-amino-5,6-difluorobenzamide as a white crystalline solid (2.73 g, 15.8 mmol, 72% Yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.78 (s, 2 H), 6.45 (ddd, J=9.16, 4.03, 1.83 Hz, 1 H), 7.10-7.18 (m, 1 H), 7.69 (d, J=11.00 Hz, 2 H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:34]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5](=[O:62])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH:57]([CH3:59])[CH3:58])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:61])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[I-].[Na+].Br.[OH:66][C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][C:75]=1[OH:76])[CH2:72][NH:71][CH2:70]2.C(N(CC)CC)C>CC(C)=O>[OH:66][C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][C:75]=1[OH:76])[CH2:72][N:71]([CH2:2][C:3]1[CH2:4][S:5](=[O:62])[C@@H:6]3[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH:57]([CH3:59])[CH3:58])/[C:30]4[N:31]=[C:32]([NH:35][C:36]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[S:33][CH:34]=4)[C:25](=[O:61])[N:7]3[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:70]2
Reactant: Oc1cc2c(cc1O)CNC2
Reactant: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CN3Cc4cc(O)c(O)cc4C3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2.0 g (2.26 mmol) of Benzhydryl 3-chloromethyl-7-[(Z)-2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate 1-oxide was dissolved in 40 ml of acetone, and 750 mg (5 mmol) of sodium iodide was added thereto under cooling with ice. The mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and water were added. The organic layer was washed with a sodium metabisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was dissolved in 10 ml of N,N-dimethylformamide, and 790 mg (3.4 mmol) of 5,6-dihydroxyisoindoline hydrobromide was added thereto, then 0.47 ml (3.38 mmol) of triethylamine was dropwise added at room temperature. The reaction solution was stirred at the same temperature for 2 hours, and then N,N-dimethylformamide was distilled off under reduced pressure. To the residue, chloroform and water were added. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flush column chromatography (5% methanol-chloroform) to obtain 1.74 g (yield: 78%) of the above-identified compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][C:9]2=[O:14])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)CCc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), 4-methoxybenzyl chloride (388 μL, 2.86 mmol) and potassium carbonate (1.08 g, 7.80 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow solid which was subjected to flash chromatography on silica gel using 1% MeOH/CH2Cl2 to give an off-white solid (605 mg, 74.5%). 1H-NMR (DMSO-d6) δ: 8.15 (d, J=2.7 Hz, 1H), 8.02 (dd, J=2.7, 9.0 Hz, 1H), 7.15 (dd, J=3.0, 9.0 Hz, 1H), 6.88-6.85 (m, 4H), 5.14 (s, 2H), 3.70 (s, 3H), 3.11-3.06 (m, 2H), 2.80-2.75 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([NH:18]C(OC(C)(C)C)=O)=NS(C(F)(F)F)(=O)=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C[OH:36]>>[C:6]([NH:8][C:9]([NH2:18])=[O:36])([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(N)=O
Reaction time: 7 h
Yield: 62 %

Procedure:
To a solution of amine 90 (300 mg, 0.62 mmol) and Goodman's reagent (392 mg, 1.00 mmol) in MeOH (60 mL) was added DIPEA (0.45 mL, 2.5 mmol) at room temperature. The reaction mixture was stirred for 7 h and then concentrated. The residue was dissolved in CHCl3 (200 mL) and washed with saturated NaHCO3 (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 90:9:1 CHCl3/CH3OH/NH4OH) to afford Boc-urea 92 (280 mg, 62%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (t, J=7.8 Hz, 2H), 7.57 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.19 (s, 2H), 4.18 (t, J=5.4 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.82 (t, J=6.3 Hz, 2H), 2.12 (t, J=5.7 Hz, 2H), 1.85-1.70 (m, 4H), 1.54 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Temperature: 150 °C

Procedure:
To a 2 mL heavy-walled tube was added (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (127 mg, 0.471 mmol), 4-(4-chlorophenyl)-4-oxobutanoic acid (91 mg, 0.428 mmol), Na2CO3 (136 mg, 1.284 mmol), dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (3.03 mg, 4.28 μmol), dioxane (1 mL), and water (0.15 mL). The tube was sealed and heated to 150° C. for 10 min under microwave irradiation. The mixture was purified by preparative HPLC to give the title compound as a white solid. LCMS m/z=366.1 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.3 Hz, 0.4H), 1.37 (d, J=6.3 Hz, 2.6H), 1.54-1.65 (m, 1H), 1.90-2.05 (m, 2H), 2.18-2.26 (m, 1H), 2.62 (t, J=7.8 Hz, 2H), 2.95-3.10 (m, 2H), 3.16-3.30 (m, 3H), 3.38-3.68 (m, 4H), 7.46 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 8.06 (d, J=8.2 Hz, 2H), 9.34 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[H-].[Na+].[CH3:33][CH2:34][OH:35]>>[CH2:34]([O:35][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)[CH3:33]
Reactant: CCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3ccccc3F)c2n1

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) was placed in EtOH (10 mL) and the mixture stirred under Ar. Approximately 2 mL of the ethanol was distilled off to dry the mixture. When the mixture was cooled to 23°, some of the starting material sulfone crystallized out. NaH (11.5 mg, 0.46 mmol) was added. The reaction did not go to completion, so additional NaH (4 mg, 0.16 mmol) was added. The solvent was removed in vacuo, and the residue was flash chromatographed on silica gel eluted with 60-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 137-139°, LC MS m/z=394(MH+) Retention time=2.32 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([NH:12][CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CI
Reactant: Nc1cc2ccccc2cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cc2ccccc2cc1N
Temperature: 2.5 °C
Reaction time: 0.12 h
Yield: 30.9 %

Procedure:
A solution of 2,3-diaminonaphthalene (500 mg, 3.16 mmol) in anhydrous dimethylformamide (3 mL) was cooled in an ice bath and treated with sodium hydride (130 mg of a 61% dispersion in mineral oil, 3.31 mmol). The mixture was stirred at 0-5° C. for 7 minutes, then treated with methyl iodide (0.206 mL, 3.31 mmol) and stirred in the cold for an additional 15 minutes. After warming to room temperature, the mixture was diluted with ethyl acetate (30 mL), washed with water (5×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark solid (0.5 g). The crude product was purified by silica gel chromatography (2.75×24 cm column) using 5% ethyl acetate in dichloromethane as eluting solvent. The product fractions were combined and evaporated to afford 2-amino-3-methylamino-naphthalene (168 mg) as a solid.
Reaction SMILES: C[OH:2].[C:3]([NH:16][C@@H:17]1[C:23](=[O:24])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1)(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(Cl)Cl.N1C=CC=CC=1>[C:3]([NH:16][C@H:17]([C:23]([OH:22])=[O:24])[CH2:18][CH2:19][C:20]([OH:2])=[O:21])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CO
Reactant: CCCCCCCCCCCC(=O)N[C@H]1CCC(=O)OC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 8 h
Yield: 84.4 %

Procedure:
10.00 g (0.00892 mol) of mono-terminal carbinol-modified silicone was dissolved in 10.00 g of methylene chloride and 1.00 g of pyridine. 4.67 g (0.0150 mol) of lauroylglutamic acid anhydride was added to the reaction mixture, and then the mixture was stirred overnight. The reaction liquid was concentrated and separated after adding hexane and a 90% methanol aqueous solution. The hexane layer was concentrated to obtain 10.64 g (0.00753 mol) of lauroylglutamic acid-modified silicone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:25])([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[CH:13]([F:15])[F:14].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:12]([F:11])([F:25])[CH:13]([F:14])[F:15])[CH:18]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
EX-528A) 3-nitroaniline (1.87 g, 13.51 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.9 mmol), then solid NaBH(OAc)3 (3.73 g, 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 3.25 g (70%) of the desired N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy) benzenemethan-amine product as a brown oil. HRMS calcd. for C15H13F4N2O3: 345.0862 [M+H]+, found: 345.0864. 1H NMR (CDCl3) δ4.4 (s, 2H), 4.5 (s, 1H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 2H), 7.5 (d, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH:22]([CH2:24][CH3:25])[CH3:23]>CN(C)C=O>[CH:22]([N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20])([CH2:24][CH3:25])[CH3:23]
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Reactant: CCC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)n1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 50 °C
Yield: 11.6 %

Procedure:
To a suspension of NaH (47 mg of a 60% suspension of NaH in mineral oil) in 6 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (202 mg, 0.85 mmol). The reaction mixture was heated to 50° C. to 60° C. resulting in a yellow solution. The solution was cooled slightly, and 2-iodobutane (140 μL, 1.22 mmol) was added. The reaction was heated at 50° C. for 20 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography eluting with 2:1 ethyl acetate:hexane gave 29 mg (12%) of 8-sec-butyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 155-156° C.