Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[C:13]1([C@H:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:11]([O:10][C:6]([C:7]#[C:8][C@:24]1([OH:25])[CH2:23][CH2:22][CH2:21][NH:20][C@H:19]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])[CH3:12]
Reactant: C#CC(=O)OCC
Reactant: O=C1CCCN[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#C[C@]1(O)CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (55.4 ml, 1.4 M in hexanes, 77.6 mmol) was added dropwise to a stirred solution of ethyl propiolate (7.9 ml, 77.7 mmol) in tetrahydrofuran (200 ml), keeping the temperature of the reaction below −65° C. The mixture was stirred for 10 min and a solution of (2S)-2-phenyl-3-piperidone in tetrahydrofuran (50 ml) added dropwise at −72° C. over 15 min. The reaction mixture was stirred at this temperature for 40 min, quenched with acetic acid (10 ml) and warm up to room temperature. Solvent was removed in vacuo. The residue was treated with saturated aqueous NaHCO3 (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (210 g, hexane:diethyl ether 5-40%) to afford the product (11.9 g, 83%, 96% ee) as a colourless oil.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]([O-:11])(=[S:10])[CH3:9]>>[C:8]([O:11][CH:2]1[CH2:3][C:4](=[O:6])[NH:5][C:1]1=[O:7])(=[S:10])[CH3:9]
Reactant: O=C1C=CC(=O)N1
Reactant: CC([O-])=S
Product: CC(=S)OC1CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 43.1 %

Procedure:
Maleimide (5.0 g., 0.051 mole) was added to 10 ml. (0.14 mole) thioacetate acid cooled to 0° C. under nitrogen. The mixture was stirred at 0° C. for 70 min., then filtered. The filtrate was diluted with 70 ml. ethyl acetate and the resulting solution was washed with 50 ml. saturated aqueous sodium bicarbonate solution and 50 ml. saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow oil (5.4 g). The crude product was purified by flash chromatography on silica gel (350 g.), eluting with 1:3 ethyl acetate-hexane, to yield 3.81 g (43%) of the title compound as a white solid. The NMR spectrum of the title compound as a deuterochloroform solution had peaks at 2.38 (s) and 2.3-3.54 (m) (total 5H); 4.24 (m, 1H); and 8.86 (b, 1H)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CN([C:24]([O:28][N:29]1N=NC2C=CC=C[C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([N:29]([O:28][CH3:24])[CH3:30])=[O:10]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a solution of 2-bromo-pyridine-4-carboxylic acid (11.83 g, 58.56 mmol) in DMSO (100 mL) are added HOBt (9.49 g, 70.30 mmol) and HBTU (26.70 g, 70.30 mmol). The mixture is stirred at room temperature for 20 min, then N,O-dimethylhydroxylamine HCl (6.28 g, 64.41 mmol) and diisopropylethylamine (22.72 g, 175.68 mmol) are added to the mixture. After stirring at room temperature for 3 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 10%˜40%) to give 2-Bromo-N-methoxy-N-methyl-isonicotinamide (12.4 g, 86%) as a white solid. M/Z=245.0
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[S:9]1(=[O:15])[CH2:12][C:11]([CH3:14])([NH2:13])[CH2:10]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH3:36])[C:27]([N:33]=S=O)=[C:28]([CH:32]=1)[C:29](Cl)=[O:30].O>O1CCCC1>[NH2:33][C:27]1[C:26]([CH3:36])=[CH:25][C:24]([Cl:23])=[CH:32][C:28]=1[C:29]([NH:13][C:11]1([CH3:14])[CH2:12][S:9](=[O:15])(=[O:8])[CH2:10]1)=[O:30]
Reactant: CC1(N)CS(=O)(=O)C1
Reactant: Cc1cc(Cl)cc(C(=O)Cl)c1N=S=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NC2(C)CS(=O)(=O)C2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 1,1-dioxo-3-methyl-3-thietanamine trifluoroacetic acid salt [the product of step 1] (598 mg, 2.40 mmol) and triethylamine (0.836 ml, 6.00 mmol) in tetrahydrofuran (6 ml) cooled at 0-5° C. is added a solution of 5-chloro-3-methyl-2-sulfinylaminobenzoyl chloride [the product of step 2] (600 mg, 2.4 mmol) in tetrahydrofuran (4 ml). The reaction mixture is stirred at room temperature overnight, and then poured into water. After extraction with ethyl acetate, the combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated. The crude product is purified by column chromatography on silica gel (ethyl acetate/hexane 1:4) to afford the title benzamide [compound D54 from Table D] (410 mg, 56%) as a white solid with a melting point of 79-82° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C>Cl>[CH2:17]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1c1cccs1
Agent: Cl
Product: O=C(O)C1CN(Cc2ccccc2)CCC1c1cccs1
Yield: 100 %

Procedure:
The product from step b) (6.83 g, 20.7 mmol) was treated with 4 M HCl (400 ml) at 100° C. for 16 hours. Next, the reaction was evaporated to dryness, azeotroped with toluene (2×50 ml) and placed on the high vacuum to give the subtitle compound (7 g, 100%). MS calculated for C17H19NO2S−H 300, observed 300.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:43][C:44]1[CH:45]=[C:46]([C:54]2[CH:63]=[CH:62][C:61]3[C:56](=[C:57]([NH2:64])[CH:58]=[CH:59][CH:60]=3)[N:55]=2)[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1>CN(C=O)C.O>[F:43][C:44]1[CH:45]=[C:46]([C:54]2[CH:63]=[CH:62][C:61]3[C:56](=[C:57]([NH:64][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:9])[CH:58]=[CH:59][CH:60]=3)[N:55]=2)[CH:47]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:49]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12)c1cnccn1
Yield: 40.3 %

Procedure:
2-pyrazine carboxylic acid (0.065 g, 0.51 mmol) was combined with DIPEA (0.140 mL, 0.811 mmol) and HATU (0.200 g, 0.51 mmol) in 5 mL DMF. The mixture was stirred at room temperature for ten minutes, at which time 2-(3-fluoro-5-(trifluoromethyl)phenyl)quinolin-8-amine (0.12 g, 0.391 mmol) was added. The mixture was stirred at room temperature for 18 hours before 10 mL water was added. The resulting precipitate was collected by filtration, and the solids were triturated in methanol to yield N-(2-(3-fluoro-5-(trifluoromethyl)phenyl)quinolin-8-yl)pyrazine-2-carboxamide as a beige solid (0.065 g, 31% yield). MS (ESI) calcd for C21H12F4N4O (m/z): 412.09. found: 413 [M+1].
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[N:18]=[C:17](O)[CH:16]=[N:15]2)=[CH:10][CH:9]=1.CI.O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[N:18]=[C:17]([O:4][CH3:1])[CH:16]=[N:15]2)=[CH:12][CH:13]=1
Reactant: Oc1cnn(-c2ccc(Br)cc2)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1cnn(-c2ccc(Br)cc2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Cesium carbonate (4.5 g, 13.7 mmol) was added to a solution of 2-(4-bromophenyl)-2H-1,2,3-triazol-4-ol (1.1 g, 4.6 mmol) and methyl iodide (0.36 mL, 5.7 mmol) in THF (50 mL). The reaction was heated to 60° C. and stirred at this temperature for 16 h. Water (20 mL) was added to the reaction, and the resulting mixture was extracted with EtOAc (2×150 mL). The combined organic phases were dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford the title compound as a tan solid (1.1 g, 95%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.98 (s, 3 H) 7.39 (s, 1 H) 7.55-7.62 (m, 2 H) 7.79-7.86 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:11]=[C:12]([O:14]CC2C=CC=CC=2)[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:11]=[C:12]([OH:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)cc(-c2cccc(F)c2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(O)cc(-c2cccc(F)c2)c1
Yield: 96 %

Procedure:
5-Benzyloxy-3′-fluoro-biphenyl-3-carboxylic acid tert-butyl ester (4.1 g) was dissolved in EtOH (50 mL) and hydrogenated in Parr apparatus over 10% Pd/C (410 mg) for 1 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to yield the title compound (3.0 g, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cncc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2-methoxyphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:16])[CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=2)=[CH:4][CH:3]=1>[Pt]=O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:9]([CH3:16])[CH2:10][CH:11]([NH2:13])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cn1cc([N+](=O)[O-])cc1-c1ccc(F)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CN1CC(N)CC1c1ccc(F)cc1
Yield: 7.5 %

Procedure:
To 2-(4-fluorophenyl)-1-methyl-4-nitro-1H-pyrrole (200 mg, 1.03 mmol) synthesized in Reference Synthesis Example 246, acetic acid (2.0 mL) and platinum oxide (20.0 mg) were added and the resultant solution was stirred under hydrogen atmosphere at room temperature for 3 days. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography (chloroform/methanol=1/0→1/1) to obtain the title compound (15.0 mg, yield 7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>O1CCCC1>[Cl:16][C:17]1([C:20]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1(Cl)CC1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2(Cl)CC2)cc1
Temperature: 60 °C
Yield: 73.1 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 100 ml of absolute tetrahydrofuran by stirring and heating to 60° C. The solution is allowed to cool to room temperature, 4.15 g (29.9 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride are added dropwise and the reaction solution is then stirred for 6 hours at room temperature. It is then concentrated to half its volume and 200 ml of water are added. The precipitate which forms is filtered off, washed with water and recrystallized from methanol, giving 5.5 g (73% of theory) of 6-[p-(1-chlorocyclopropylcarbonylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless crystals, of melting point 189°-190° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:19][N:20]1[CH2:24][C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[N:33]=3)[N:28]=[CH:27][CH:26]=2)[O:22][C:21]1=[O:37])[CH2:3][NH:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:16][CH2:15][C:14](=[O:17])[NH:13][C:12]=2[CH:18]=1)(=[O:7])=[O:6].CC1(C)O[C@H](CN)CO1>>[OH:1][C@@H:2]([CH2:19][N:20]1[CH2:24][C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[N:33]=3)[N:28]=[CH:27][CH:26]=2)[O:22][C:21]1=[O:37])[CH2:3][NH:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:16][CH2:15][C:14](=[O:17])[NH:13][C:12]=2[CH:18]=1)(=[O:6])=[O:7]
Reactant: COc1ccc2nccc([C@@H]3CN(C[C@@H](O)CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Agent: CC1(C)OC[C@@H](CN)O1
Product: COc1ccc2nccc([C@@H]3CN(C[C@H](O)CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1

Procedure:
The title compound was prepared using the same procedure as 3-Oxo-3,4-dihydro-2H benzo[1,4]thiazine-6-sulfonic acid {(R)-2-hydroxy-3-[(R)-5-(6-methoxy-[1,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl}-amide (GSK-203344A) except substituting C-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine for C-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine. 1H NMR (400 MHz, CDCl3): δ8.72 (d, J=4.5 Hz, 1H); 8.19 (d, J=9.1 Hz, 1H); 7.59 (d, J=4.6 Hz, 1H); 7.35-7.42 (overlapping signals (3H); 7.11 (d, J=9.1 Hz, 1H); 6.30 (m, 1H); 4.54 (t, J=9.4 Hz, 1H); 4.01-4.08 (m, 1H); 3.99 (s, 3H); 3.58 (dd, J=8.8, 7.5 Hz, 1H); 3.49 (dd, J=14.6, 7.0 Hz, 1H); 3.44 (s, 2H); 3.27 (dd, J=14.7, 3:6 Hz, 1H); 3.08 (dd, J=13.4, 3.8 Hz, 1H); 2.99 (dd, J=13.1, 6.3 Hz, 1H); 2.62 (m, 1H). MS (ES) m/e 546 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[N+:23]([O-])=O)[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.CO.O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C.[Fe]>[NH2:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9]1)[C:19]#[N:20]
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Compound (153a) (5.00 g), cesium carbonate (6.72 g), and 4-chloro-3-nitrobenzonitrile (3.21 g) were suspended in acetonitrile (50 mL), followed by stirring at 70° C. for 4 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 4-{(4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-nitrobenzonitrile (7.19 g, 98%). The obtained 4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-nitrobenzonitrile (7.19 g) was suspended in THF (50 mL), MeOH (50 mL), and water (50 mL), and ammonium chloride (7.20 g) and iron powder (8.76 g) were added to the resulting suspension, followed by stirring at 80° C. for 2 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The solvent of the filtrate was distilled away, and water was added to the residue. Insoluble matters were collected by filtration and dried under reduced pressure to obtain compound (158a) (6.44 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[CH2:6][NH:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([F:15])([F:16])[CH2:6][N:7]([C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=1)[CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNCCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(CCc1cccs1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.3 %

Procedure:
A solution of 0.98 g (0.0037 mole) of 2,2-difluoro-3-(2-thiophen-2-yl-ethylamino)-propionic acid ethyl ester in 1 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.72 g (0.0037 mole) of 2,4-dichloro-5-nitro-pyrimidine, 1.3 g (0.15 mole) of sodium bicarbonate and 10 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.53 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-thiophen-2-yl-ethyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-269) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[CH:3]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(C)c1nn(Cc2cccc(Br)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2cccc(-c3ccc(N4CCN(C)CC4)nc3)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 65.8 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 79, 31 mg, 0.073 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (22.16 mg, 0.073 mmol), potassium carbonate (303 mg, 2.192 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with 1N HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[5-hydroxy-6-(1 -methylethyl)-2-({3-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (32 mg, 0.048 mmol, 65.7% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1H), 12.98 (br. s., 1H), 10.18 (t, J=5.56 Hz, 1 H), 9.71 (br. s., 1H), 8.46 (d, J=2.27 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 7.52-7.61 (m, 2H), 7.42 (t, J=8.08 Hz, 1H), 7.23 (d, J=7.58 Hz, 1H), 7.07 (d, J=9.09 Hz, 1H), 5.32 (s, 2H), 4.48 (d, J=12.63 Hz, 2H), 4.09 (d, J=5.56 Hz, 2H), 3.52 (d, J=10.36 Hz, 2H), 3.00-3.26 (m, 5H), 2.86 (d, J=4.04 Hz, 3H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 521 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[F:14][CH:15]([F:19])[C:16]([O-])=[O:17]>C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:17])[CH:15]([F:19])[F:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C([O-])C(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,5-dibromopyridine (16 g, 67 mmol) in toluene (150 mL) was added 2.5 N solution of n-BuLi (27 mL, 67 mmol) dropwise at −78° C. The resulting solution was stirred at −78° C. for 1 hour before the addition of 2,2-difluoroacetate (10 g, 80 mmol). After stirred at ambient temperature overnight, the reaction solution was diluted with saturated aqueous NH4Cl solution (80 mL) at 0° C., and then extracted with ethyl acetate (2×100 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 5-10% ethyl acetate in hexane to afford the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.08 (d, J=6.0 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.05 (t, J=54.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[CH:3]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][N:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:20]=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cn1cc(Br)c2ccncc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)c2ccncc2c1=O
Yield: 69.5 %

Procedure:
A mixture of 4-bromo-2-methyl-2,7-naphthyridin-1-one (50 mg, 0.21 mmol), [3-(methanesulfonamido)phenyl]boronic acid (68 mg, 0.31 mmol), Pd(dppf)Cl2 (15.3 mg, 0.021 mmol) and aqueous K3PO4 (1 M, 0.3 mL, 0.3 mmol) in dioxane (3 mL) was microwaved at 90° C. for 40 min. Purification by silica gel chromatography (PE:EA=100:1 to 1:1) followed by preparative HPLC gave the title compound (48.1 mg, 69.8%) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 9.56 (s, 1H), 8.68 (d, J=6.4 Hz, 1H), 7.96 (s, 1H), 7.81 (d, J=6.4 Hz, 1 H), 7.51 (t, J=7.6 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.34 (d, J=1.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 3.71 (s, 3H), 3.03 (s, 3H). LCMS: 330.0 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[N:9]=[C:8]([CH:10]([OH:13])CO)[CH:7]=[C:6]([CH3:14])[CH:5]=1)[CH3:2]>C1COCC1.O.CC(=O)OCC>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([CH:10]=[O:13])[CH:7]=[C:6]([CH3:14])[CH:5]=1)[CH3:16]
Reactant: CCN(CC)c1cc(C)cc(C(O)CO)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)c1cc(C)cc(C=O)n1
Reaction time: 16 h
Yield: 90.7 %

Procedure:
A solution of diethyl-(4-methyl-6-vinyl-pyridin-2-yl)-amine (457 mg, 2.40 mmol), N-methyl-morpholine-N-oxide (885 mg), and OsO4 (5 mg, 20 μmol, 200 μL of a 2.5% solution in tert.-butanol) in acetone (16 mL) and water (2 mL) is stirred at rt for 18 h. The mixture is diluted with EA (200 mL) and washed with water (50 mL). The org. extract is dried over MgSO4, filtered and concentrated to give crude 1-(6-diethylamino-4-methyl-pyridin-2-yl)ethane-1,2-diol (550 mg) as a brown oil; LC-MS: tR=0.55 min, [M+1]+=225.03. 1H NMR (CDCl3): δ 1.20 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 3.51 (q, J=7.0 Hz, 4H), 3.71 (dd, J=11.3, 5.8 Hz, 1H), 3.75 (s br, 1H), 3.88 (dd, J=11.0, 3.8 Hz, 1H), 4.62 (t, J=4.8 Hz, 1H), 6.22 (s, 1H), 6.33 (s, 1H). A solution of the above crude 1-(6-diethylamino-4-methyl-pyridin-2-yl)-ethane-1,2-diol (550 mg, 2.45 mmol) and NaIO4 (857 mg, 4.01 mmol) in THF (18 mL) and water (3 mL) is stirred at rt for 7 h before another portion of NaIO4 (524 mg, 2.45 mmol) is added. Stirring is continued for 16 h. The mixture is diluted with EA, washed with water, dried over MgSO4, filtered and concentrated to give crude 6-diethylamino-4-methyl-pyridine-2-carbaldehyde (427 mg) as a green oil; LC-MS: tR=0.55 min, [M+1]+=193.01; 1H NMR (CDCl3): δ 1.22 (t, J=7.0 Hz, 6H), 2.34 (s, 3H), 3.60 (q, J=7.0 Hz, 4H), 6.49 (s, 1H), 7.04 (s, 1H), 9.89 (s, 1H).