Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:20][CH3:21])[CH3:19]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-chromen-2-one (2.0 g) and ethyl 2-bromobutyrate (2 mL) in DMF was added anhydrous potassium carbonate (8.5 g). The resulting reaction mixture was stirred at room temperature for 72 hours, then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and conc. in vacuo to provide colorless oil, which was purified by column chromatography to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-yl) -butyric acid ethyl ester as a white solid, MS: 275[M−H].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)c1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)c3cccnc3)ccc2n1
Yield: 80 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (71 mg, 0.22 mmol) was converted, using nicotinic acid instead of cyclopropylacetic acid, to the title compound (63 mg, 80%) which was obtained as an off-white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH2:36]([OH:39])[C:37]#[CH:38]>[Pd](Cl)Cl.C(NCC)C>[OH:39][CH2:36][C:37]#[C:38][C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:34][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.17 g (1.0 mmole) of palladium chloride, 0.5 g (2.0 mmole) of triphenylphosphine, 0.1 g (0.5 mmole) of cuprous iodide, 15 g (43 mmole) of 5-chloro-2-iodobenzophenone and 60 ml of diethylamine was stirred at room temperature for 20 min. In one portion 6.0 g (107 mmole) of propargyl alcohol was added, and the resulting mixture was stirred for 24 hr. The solvent was removed at reduced pressure and the residue was dissolved in ether. The ether solution was washed with water, dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give the product as a red oil.
Reaction SMILES: [Mg].CI.[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:14])[CH3:13])[C:6]=1[NH2:7].[CH2:15](Cl)Cl>C(OCC)C>[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:15])([OH:14])[CH3:13])[C:6]=1[NH2:7]
Reactant: CC(=O)c1cccc(C)c1N
Reactant: ClCCl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: Cc1cccc(C(C)(C)O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In this example 234.93 g (9.66 moles) of magnesium was placed under nitrogen and then mixed with 583 ml of ethyl ether at room temperature. A small amount of methyl iodide was then added with gentle stirring followed by the addition of another 468 ml of ethyl ether. A methyl iodide solution containing 1,371.72 g (9.66 moles) of methyl iodide in 468 ml of ethyl ether was slowly added at reflux over a 21/4-21/2-hour period. (During this period the mixture was diluted with another 583 ml of ethyl ether to reduce the reaction rate.) The mixture was cooled to room temperature and then a solution containing 433.9 g of 2-methyl-6-acetylaniline dissolved in 698 ml of ethyl ether was slowly added over 11/4-11/2 hours. During this addition the temperature of the mixture was maintained at about or below 25° C. The mixture was then stirred at room temperature for another hour. Three liters of methylene chloride was then added at about 25° C. and the reaction was then quenched by the addition of solid ammonium chloride and water. The mixture was then allowed to stand overnight (about 15 hours). The ether phase of the mixture was then separated and filtered. The water phase was mixed with three liters of methylene chloride filtered. The methylene chloride filtrate and the ethyl ether filtrate were each evaporated affording 2-methyl-6-(1-methyl-1-hydroxyethyl)-aniline.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:18])[CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[Br:19].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:18])[CH2:12][NH:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:6][C:5]=1[Br:19]
Reactant: CC(C)(C)NCC(=O)c1cc(F)c(N)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)NCC(O)c1cc(F)c(N)c(Br)c1

Procedure:
m.p. of the hydrochloride: 207°-208° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-tert.butylamino-5'-fluoroacetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[CH:11][C:10]2[C:9](=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][N:17](/[CH:19]=[C:8]1/[C:9](=[O:13])[C:10]2[CH:11]=[N:12][C:3]([NH:2][CH3:1])=[N:4][C:5]=2[CH2:6][CH2:7]/1)[CH3:18]
Reactant: CNc1ncc2c(n1)CCCC2=O
Reactant: COC(OC)N(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Yield: 43.1 %

Procedure:
To a solution of 2-(methylamino)-7,8-dihydroquinazolin-5(6H)-one (0.2 g, 1 mmol) in toluene (3 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.35 mL, 2.9 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was refluxed for 16 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give the desired product (0.1 g, 38%) as solid. 1H NMR (CDCl3, 400 MHz): δ 8.84 (bs, 1H), 7.62 (s, 1H), 5.68 (bs, 1H), 3.15 (s, 6H), 3.12 (d, J=6.0 Hz, 3H), 3.10-3.05 (m, 2H), 3.03-2.98 (m, 2H). LCMS [M+H]: 233.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)[C@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[CH2:43][OH:44])[C:37](O)=[O:38].[NH2:64][C@@H:65]([CH2:72][C:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1)[C:66]([C@@:68]1([CH3:71])[CH2:70][O:69]1)=[O:67]>CN(C=O)C>[C:73]1([CH2:72][C@H:65]([NH:64][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH2:43][OH:44])[C@H:35]([OH:34])[C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)[C:66]([C@@:68]2([CH3:71])[CH2:70][O:69]2)=[O:67])[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCCC2)CO1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Sequentially HATU (537 mg, 1.41 mmol) and DIEA (1.02 mL, 5.88 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoic acid (500 mg, 1.18 mmol) and (S)-2-amino-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 364 mg, 1.18 mmol) in DMF (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (DCM/MeOH=50:1 to 30:1) twice to afford (2S,3R)-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanamide (500 mg, 57% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, J=7.5 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 5.61 (d, J=4.5 Hz, 1H), 5.40-5.38 (m, 1H), 5.23-5.21 (m, 1H), 5.04-5.02 (m, 1H), 4.62-4.51 (m, 1H), 4.45-4.35 (m, 2H), 3.71 (s, 3H), 3.68-3.41 (m, 6H), 3.33 (s, 1H), 3.21 (d, J=5.1 Hz, 1H), 2.97-2.80 (m, 3H), 2.39-2.21 (m, 4H), 2.11-1.71 (m, 4H), 1.56-1.40 (m, 4H), 1.26 (s, 3H), 1.28-1.22 (m, 1H). MS(EI) for C31H44N4O9, found 617.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(#N)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:16]1[CH2:17][CH2:18][CH:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:12][N:11]=2)[CH2:14][CH2:15]1
Reactant: Fc1ccc(-c2nnc(C3CCNCC3)o2)cc1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (160 mg, 0.55 mmol) in acetonitrile (15 mL) was added triethylamine (0.192 mL, 1.4 mmol), then methyl 2-bromoacetate (0.066 mL, 0.715 mmol). The mixture was stirred overnight at room temperature for 8 h. The white precipitate was filtered, washed with acetonitrile, then ether. The mother liquor which contained the desired product was evaporated yielding the title compound as a white solid (100 mg) which was used without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 8.03 (dd, J=9.09, 5.05 Hz, 2H) 7.19 (t, J=8.59 Hz, 2H) 3.74 (s, 3H) 3.30 (s, 2H) 2.93-3.10 (m, 3H) 2.35-2.54 (m, 2H) 2.12 (dd, 4H). MS (m/z, MH+): 320.5
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (53 mg, 0.13 mmol), glycine (2.06 g, 27.5 mmol) and NaOMe solution (41 mL, 20.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 53 mg of the title compound. MS: (+) m/z 458.10 (M+1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3,5-dichlorophenyl boronic acid according to Procedure A. A white solid: mp 245-246° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.77 (m, 2H), 7.67-7.64 (m, 2H), 7.56 (bs, 1H), 6.96 (d, 1H, J=7.98 Hz), 1.7 (s, 6H); MS (EI) m/z 321 ([M+H]+, 40%); Anal. Calc. For C16H13Cl2NO2: C, 59.32, H, 4.11, N, 4.32. Found: C, 59.13, H, 4.29, N, 4.17.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]([CH2:19]O)([CH2:17]O)[CH3:16]>>[CH3:14][C:15]1([CH3:19])[CH2:17][O:10][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)[O:11][CH2:16]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2cccc(C(F)(F)F)c2)OC1
Yield: 58 %

Procedure:
The title compound (58%, crystals) was prepared from 3-trifluoromethylphenylboronic acid and neopentylglycol.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:2][C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of diisopropylamine (8.65 ml, 61.8 mmol) in dry THF (100 ml) at −20° C. under nitrogen was added a 2.5M solution of nBuLi in hexanes (23.7 ml, 59.2 mmol) dropwise. The solution was allowed to warm to 0° C. over 20 min, and then-cooled to −70° C. A solution of methyl-2-(4-chlorophenyl)acetate (9.5 g, 51.5 mmol) in THF (5 ml) was added dropwise over 5 min, and the whole then stirred for 30 min. lodoacetonitrile (5.03 ml, 69.5 mmol) was then added slowly, and the combined solution allowed to warm to room temperature over 72 h. Saturated aq. NaHCO3 solution (20 ml) was added, the mixture was concentrated to about 50 ml under vacuum, and then treated with 1 N HCl (100 ml). The mixture was extracted with EtOAc (120 ml) which was dried (MgSO4) and evaporated to give a dark brown oil, which was purified by column chromatography using 2:1 DCM:pentane as eluant to give the title product (8.6 g, 75%); 1HNMR (400 MHz, CDCl3) δ: 2.80 (dd, 1H), 3.00 (d, 1H), 3.73 (s, 3H), 3.92 (dd, 1H), 7.22 (d, 2H), 7.37 (d, 2H).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][O:28][CH3:29].O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH2:26][CH2:27][O:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCn1cc(C=O)c(-c2ccc(OC(C)C)cc2)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (655 mg, 4.6 mmol) in acetonitrile (6 ml) was stirred at 0-5° C. for 1 hr. 1-bromo-2-methoxyethane (195 mg, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL) and extracted with EtOAc (50 mL×3). The combined extracts was washed with brine (100 mL), dried and concentrated under vacuum (360 mg, yield 72%). The crude material was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.O>[Cl:12][C:4]1[N:3]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)nc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (970 mg, 4.66 mmol) in DMF (5 mL), K2CO3 (3.20 g, 23.0 mmol) was added, followed by addition of morpholine (0.410 mL, 4.60 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3×10 mL). The organic layers were combined, dried (Na2SO4) and concentrated. The resulting residue was purified on silica (0:100-50:50 EtOAc-hexanes) to yield 6-chloro-2-morpholin-4-yl-3-nitro-pyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 5.99-6.20 (m, 3H), 3.72-3.82 (m, 4H), 3.40-3.50 (m, 4H).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C(Cl)Cl>[C:19](=[O:20])([O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[O:10][C@@H:2]1[CH2:1][O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]12
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4:3,6-dianhydro-D-mannitol (3.00 g, 20.5 mmol) and triethylamine (3.15 ml, 22.6 mmol) in DCM (100 ml), 4-nitrophenyl chloroformate (4.55 g, 22.6 g) was added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was washed with a 5% solution of sodium dihydrogen phosphate (2×50 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[C:12](Cl)[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1C(OC(C)(C)C)=O)[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[C:12]([N:35]3[CH2:34][CH2:33][NH:32][C@@H:31]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:36]3)[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Nc1ncccc1C(=O)c1nc(Cl)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H]1CN(c2ccc(C(F)(F)F)c(C(=O)c3cccnc3N)n2)CCN1
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
A microwave vial was charged with (2-aminopyridin-3-yl)(6-chloro-3-(trifluoromethyl)pyridin-2-yl)methanone (2.12 g, 7.028 mmol), potassium carbonate (1.166 g, 8.434 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (1.874 g, 7.731 mmol) and dimethylformamide (4 mL). The reaction mixture was heated under microwave irradiation at 90° C. for 50 minutes. The reaction mixture was cooled down to room temperature and partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) and trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and partitioned between dichloromethane and a saturated solution of sodium carbonate. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (2.203 g, 77% yield).
Reaction SMILES: C([C:5]([N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:15][C:14]1=[O:30])([CH2:9][CH2:10][O:11][CH3:12])[C:6]([OH:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]([C:16]2[C:17]([O:19][CH3:20])=[CH:18][N:13]([CH:5]([CH2:9][CH2:10][O:11][CH3:12])[C:6]([OH:8])=[O:7])[C:14](=[O:30])[CH:15]=2)[CH:26]=1
Reactant: COCCC(C(=O)O)(n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
1.99 g (4.60 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) in 46 ml of dichloromethane and 13.3 ml (172 mmol) of TFA were reacted according to General Method 6A. Yield: 1.58 g (91% of theory)
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[OH:1][C:2]1[C:3]([C:12]([NH:14][NH:15][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1cc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NNC(=O)c1cc2ccccc2cc1O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer and a stirrer was charged with 60.6 g (0.3 mol) of 3-hydroxy-2-naphthohydrazide, 36.9 g (0.45 mol) of sodium acetate and 800 ml of acetic acid and heated to 30° C. Dropwise added thereto was 50.6 g (0.36 mol) of benzoyl chloride in one hour while stirring, and stirring was continued at 30° C. for one hour. After finishing the reaction, the reaction liquid was added to 1.5 liter of deionized water and crystal was filtered off. After washing sufficiently the crystal with 1 liter of deionized water and 500 ml of methanol, it was dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:8]=2[N:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[C:33]2[C:28](=[C:29](Br)[CH:30]=[CH:31][CH:32]=2)[N:27]=[N:26][C:25]=1[C:35]([NH2:37])=[O:36]>>[NH2:23][C:24]1[C:33]2[C:28](=[C:29]([C:12]3[CH:11]=[CH:10][C:9]4[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[N:7][C:8]=4[CH:13]=3)[CH:30]=[CH:31][CH:32]=2)[N:27]=[N:26][C:25]=1[C:35]([NH2:37])=[O:36]
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CC(C)(C)n1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)n1cnc2cc(-c3cccc4c(N)c(C(N)=O)nnc34)ccc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 1-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 1.85 (s, 9 H), 7.58 (m, 1 H), 7.76-7.83 (m, 1 H), 7.88 (d, J=8 Hz, 1 H), 7.91-7.96 (m, 2 H), 8.29 (m, 1 H), 8.32 (s, 1 H); ESI-MS m/z [M+H]+ 361.3.