Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(OC)(OC)OC.CN1CCCC1=O.F[C:16]([F:36])(F)/[C:17](=[N:24]\[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][N:34]=1)[C:28]([O:30][CH3:31])=[O:29])/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:36][C:16]1[N:34]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]2=[N:24][C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Agent: COP(OC)OC
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccn2c(F)c(-c3ccccc3)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Trimethyl phosphite (1.9 ml) was added to an N-methylpyrrolidone (10 ml) solution of the (Z)-methyl 2-((2,2,2-trifluoro-1-phenylethylidene)amino)isonicotinate (2.5 g) obtained in (Example 2.19) <Step 1>, and the obtained mixture was then stirred in microwave at 150° C. for 60 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=90:10-50:50), so as to obtain the title compound (1.9 g) in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH:13]=[O:14])[CH:4]=1.[CH3:15][Mg]Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH:13]([OH:14])[CH3:15])[CH:4]=1
Reactant: COc1cc(C=O)cc2c1OCCO2
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc2c1OCCO2
Temperature: 0 °C

Procedure:
In a 250 mL round-bottomed flask, 0.60 g (3.1 mmol) of 10 was dissolved in 15 mL of anhydrous tetrahydrofuran. The solution was cooled to 0° C. and treated with 1.1 mL (3.3 mmol) of 3M methyl magnesium chloride in THF. The reaction was stirred for a few minutes then quenched with a 1N HCl solution. The mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to afford the alcohol 11.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[C:38]([O:41][CH2:42][C:43](Cl)=[O:44])(=[O:40])[CH3:39]>O1CCCC1>[C:38]([O:41][CH2:42][C:43](=[O:44])[NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:12]=3)=[N:6][N:5]2[CH:30]=1)(=[O:40])[CH3:39]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 80.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.725 mmol), triethylamine (152 μL, 1.08 mmol), 2-chloro-2-oxoethyl acetate (94 μL, 0.870 mmol) and tetrahydrofuran (7 mL) as starting materials and in the same manner as in Example 388, the title compound (299 mg, 80%) was obtained as a white powder.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[C:29](O)(=[O:32])[CH2:30][OH:31].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:30](=[O:31])[CH2:29][OH:32])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CO)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (110 mg) in dimethylformamide (6 ml) were added, under argon, glycolic acid (19 mg), diisopropylethylamine (32 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 159 mg). Then diisopropylethylamine (64 mg) was added once again to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-{3-[2-(1-glycoloylpiperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl methanesulphonate (15 mg, 12%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][CH:39]([OH:41])[CH3:40]>>[CH:39]([O:41][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1)([CH3:40])[CH3:38]
Reactant: CC(C)O
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OC(C)C)c5ccccc45)cc3)ccnc2c1

Procedure:
In a 5 mL sealed tube, was dissolved 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (0.100 g, 0.224 mmol) in iPrOH (0.500 mL). To this was added cesium carbonate (0.110 g, 0.336 mmol) and the mixture was irradiated for 30 min at 140° C. in the microwave. When the reaction was determined to be complete by LC/MS, it was concentrated. The mixture concentrate was purified using Isco silica gel chromatography, using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2, followed by reverse phase chromatography (Gilson, 10-90% TFA/acetonitrile in water over 15 min). The product-containing fractions were extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through fritted funnel, and concentrated to yield 4-isopropoxy-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS [M+H]+=470.0; Calc'd=469.6 for C26H23N5O2S
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH2:27][NH:28]C(OC(C)(C)C)=O)=[C:15]2[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42]>O1CCCC1.C(OCC)(=O)C>[ClH:42].[NH2:28][CH2:27][C:16]1[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:18](=[O:22])[C:19]2[C:14]([C:15]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[CH:13][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:21][CH:20]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ccc2c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of 6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (0.07 g, 0.13 mmol) in tetrahydrofuran (2 mL) was added a solution, of 4N hydrogen chloride in ethyl acetate (10 mL). The obtained solution was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from diethyl ether to give 3-aminomethyl-6-benzyloxycarbonylamino-2-isobutyl-4-phenyl-1(2H)-isoquinolinone hydrochloride (0.05 g, 81%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(OC(=O)C)(=[O:17])C.C(N(CCCC)CCCC)CCC.[Cl-].[NH4+]>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[O:11][C:12](=[O:17])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCCl
Product: O=C1C=C(c2cccc(Cl)c2)C(=O)O1
Reaction time: 0.5 h

Procedure:
To a flask was added ethyl 2-(3-chlorophenyl)-2-oxoacetate (1.8 g, 8.47 mmol) and acetic anhydride (1.60 ml, 16.93 mmol) in DCE (5 ml) at RT. To the resulting solution was added titanium(IV) chloride (16.93 ml, 16.93 mmol) and tributylamine (2.42 ml, 10.16 mmol). The solution was heated to reflux for 12 hours. The solution was then cooled in ice, and a solution of ammonium chloride was added. The mixture was stirred for 30 min. LC/MS indicated all starting material was gone. The solution was washed with 1×NH4Cl, 1N HCl, water, dried and concentrated in vacuo to provide 3-(3-chlorophenyl)furan-2,5-dione which was used as is in the next reaction. LC/MS, m/e 209 (M+1). HPLC Rt, 2.89 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: O1[CH:5]2[C:6]3[C:7]4[C:12]([C:13]5[C:18]([C:19]=3[CH:2]1[CH:3]=[CH:4]2)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[CH:9][CH:8]=4.[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.BrC1C=CC=C(I)C=1.C(N(CC)CC)C>[Zn].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.C1(C)C=CC=CC=1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13]=3[CH:14]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc(I)cc1
Reactant: C1=CC2OC1c1c2c2ccccc2c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Brc1cccc(I)c1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Brc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
Temperature: 110 °C
Yield: 62 %

Procedure:
Compound A (4.0 g, 16.4 mmol), zinc (10.72 g, 163.9 mmol), PdCl2(PPh3)2 (1.16 g, 1.7 mmol), and 1-bromo-4-iodobenzene (4.64 g, 16.4 mmol) or 1-bromo-3-iodobenzene were charged in a two-necked bottle. The bottle was then vacuumed and purged with nitrogen, and dried toluene (100 mL) and triethyl amine (23.0 mL, 165.9 mmol) were added to the bottle. The mixture in the bottle was heated to 110° C. for reaction for 24 hours, and the resulting was filtered to remove metal. The filtrate was condensed to remove the solvent, and then purified by chromatography with hexanes to obtain B (3.90 g, yield=62%) as white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])=[CH:2]1.CC1C(O)=C(CN)C(COP(O)(O)=O)=C[N:18]=1.P([O-])([O-])([O-])=O>O>[NH2:18][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Reactant: Cc1ncc(COP(=O)(O)O)c(CN)c1O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 37 °C
Reaction time: 2 h

Procedure:
To a solution containing 20.3 g (100 mmol) of indole-3-pyruvic acid and 26.5 g (100 mmol) of pyridoxamine-5-phosphate in 1000 ml of distilled water buffered at pH 6.5 with 0.5M phosphate buffer and maintained at 37° C., is added 50 mg of the monoclonal antibodies prepared according to Example 15. The reaction mixture is gently agitated for 2 hours. The monoclonal antibodies are then recovered by ultrafiltration. Dialysis of the reaction mixture followed by lyophilization yields the product L-tryptophan.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccccc1F
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1F

Procedure:
Prepared according to procedure A using 2-fluoroaniline (17 mL, 180 mmol), pyridine (29 mL, 360 mmol) and diethyl methylmalonate (46 mL, 270 mmol). The crude was purified by column chromatography on silica (using a gradient of hexane:EtOAc, 1:0 to 4:1 as eluent) to give ethyl 3-(2-fluorophenylamino)-2-methyl-3-oxopropanoate as a light brown solid. Mass Spectrum (ESI) m/e=239.9 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[NH2:10])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: NNc1cccc(Br)c1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 3-bromophenylhydrazine hydrochloride (15 g, 67 mmol) in anhydrous THF (360 mL) was added LiHMDS (1.0 M solution in THF, 127 mL, 127 mmol) dropwise over a period of 1 h at 0° C. The reaction mixture was stirred for 30 min while warming to room temperature. The flask was recooled to −78° C., and MeI (4.1 mL, 67 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. and then was quenched with water (600 mL). The aqueous layer was extracted with methylene chloride (3×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 60:40) gave the title compound (10.2 g, 76%) as yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=3.5 Hz, 1H), 7.08 (t, J=13.5 Hz, 1H), 6.91-6.86 (m, 2H), 3.69 (br s, 2H), 3.11 (s, 3H).
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C([O:41][C:42](=[O:48])[C@H:43]([CH:45]([CH3:47])[CH3:46])[NH2:44])(C)(C)C.C(OC(=O)[C@@H](C(C)C)N)(C)(C)C>>[CH3:46][CH:45]([CH3:47])[C@H:43]([NH:44][S:33]([C:20]1[CH:21]=[CH:22][C:23]2[O:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:31][C:32]=2[CH:19]=1)(=[O:35])=[O:34])[C:42]([OH:48])=[O:41]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Agent: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: CC(C)[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (D)-valine-t-butyl ester, (S)-3-methyl-2-(phenoxathiine-2-sulfonylamino)-butyric acid is obtained as an off-white solid; mp 171-175° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 3.42 g (20 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene, 2.67 mL (21 mmol) of 1-ethylpiperazine and 5.14 mL (30 mmol) of diisopropylethylamine in 25 mL of acetonitrile is heated for 2.5 hours at 85°C. and then for 1 hour at 95°C., and is then stirred overnight while allowing to return to room temperature. The acetonitrile is evaporated off and the residue is then taken up in 50 mL of ether and 25 mL of water. The aqueous phase is extracted with ether. The organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. The oil obtained is triturated in an ether/cyclohexane mixture (1/1) and the precipitate is isolated by filtration, rinsed with pentane and dried in an oven. 4.1 g of the expected product are finally obtained. Yield=77%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:22][CH:23]=2)=[O:36])=[CH:30][CH:31]=1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)cc1
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: CO
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(NC(=O)c5ccc(F)cc5)cc4)cc23)CC1
Yield: 29.4 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-(4-fluorobenzamido)benzene (0.217 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.093 g, 29%) as an amorphous solid. FDMS m/e=427 (M+). EA calculated for C27H26N3OF: C, 75.85; H, 6.13; N, 9.83. Found: C, 75.55; H, 6.18; N, 9.73.
Reaction SMILES: [Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[SH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[CH3:15][C:16](=[O:19])[CH2:17][CH3:18]>C1COCC1.CCOCC>[Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[SH:9][C:10]1[S:11][C:12]([C:16]([OH:19])([CH2:17][CH3:18])[CH3:15])=[CH:13][N:14]=1
Reactant: CCC(C)=O
Reactant: Sc1nccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C)(O)c1cnc(S)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of LDA (59 mmol) in THF was prepared at −10° C. and cooled to −78° C. To the LDA was added a solution of 2-mercaptothiazole (3.00 g, 25.6 mmol) in 5 mL of THF. After 15-20 min of stirring a solution of 2-butanone (2.23 mL, 38.4 mmol) was added, and the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with ether and washed successively with aq. 2N HCl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was washed with Et2O to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:27](O)=[O:28])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:27]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:28])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (275 μl) was condensed with Boc-3-(1-naphthyl)-L-alanine (970 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-[Boc-3-(1-naphthyl)-L-alanyl]morpholine (1.18 g) as a white powder (yield quantitative). After Boc group elimination with TFA, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (620 mg) as obtained in Reference Example 8 to yield the title compound (compound 79; 1.09 g) as a white powder (yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(N)c1cccc(Br)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A mixture of 1-(3-bromophenyl)ethanamine (1.0 g, 5.0 mmol), 2,4-difluoro-1-nitrobenzene (0.8 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (20 mL) was stirred for 18 h and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo to yield the title compounds as a yellow oil (1.25 g, 74%). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1H), 8.25 (m, 1H), 7.48 (s, 1H), 7.41 (m, 1H), 7.25 (m, 2H), 6.36 (m, 1H), 6.24 (m, 1H), 4.55 (m, 1H), 1.63 (d, 3H). MS (ESI) m/z: Calculated: 338; Observed: 339 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (76 mg, 0.264 mmol), 3-(pyrimidin-2-yl)aniline (64 mg, 0.375 mmol), K2CO3 (90 mg, 0.652 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg, 0.131 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (43 mg). MS 441.2 (M+H); UV 201.1, 249.3, 301.5 nm; t 0.462 min.