Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])=[CH:15][CH:16]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 77.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methyl ester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was treated with a 0.8M aqueous lithium hydroxide solution (3.6 mL, 2.92 mmol). The reaction mixture was stirred at 25° C. for 23 h and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a cream solid. This solid was purified by triturating with diethyl ether/petroleum ether to provide pure 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (527.0 mg, 77%) as a white solid: mp 143-145° C.; EI-HRMS m/e calcd for C15H17F3O4S (M+) 350.0800, found 350.0816.
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[S:29][C:20]4=[N:21][CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=[C:19]4[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.Cl>O.C1COCC1>[Cl:11][C:9]1[CH:8]=[C:7]([C:12]2([C:30]([F:32])([F:31])[F:33])[O:16][N:15]=[C:14]([C:17]3[S:29][C:20]4=[N:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=[C:19]4[CH:18]=3)[CH2:13]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: COC(=O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Reaction time: 12 h
Yield: 73.7 %

Procedure:
Add a solution of LiOH—H2O (76 mg, 2 mmol) in water (0.5 mL) to a solution of methyl 2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylate (237 mg, 0.5 mmol) in THF (3 mL). Stir the mixture at temperature for 12 hours. After addition of 10 mL of water, acidify the mixture with concentrated HCl to PH=6˜7. Extract the resultant mixture with ethyl acetate (3×10 mL). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5-carboxylic acid as pale yellow solid (170 mg, 73.9%), which is used in next step without further purification. MS (m/z): 461 (M+1).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:12]([SH:14])[CH3:13].[Cl-].[Na+]>C1COCC1>[CH2:12]([S:14][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCS
Reactant: N#Cc1cnccc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ccncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.72 g of sodium hydride (60% oil-based) was added to a mixture of 5.0 g of 4-chloronicotinonitrile, 3 ml of ethanethiol and 36 ml of THF under ice cooling, then the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 5.72 g of 4-ethylsulfanylnicotinonitrile. 4-ethylsulfanylnicotinonitrile
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:12][S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:12]([CH2:33][C:32]1[CH:35]=[CH:36][C:29]([I:28])=[CH:30][CH:31]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)N(Cc1ccc(I)cc1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To a solution of 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (50 mg, 0.129 mmol) in anhydrous DMF (1 mL), 4-iodobenzyl bromide (46 mg, 0.154 mmol) and cesium carbonate (50 mg, 0.154 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. The reaction mixture was partitioned between water and ether. The ether layer was separated, dried (Na2SO4), concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (68 mg, 90%) as a foam. 1H NMR (CDCl3, 400 MHz): δ7.48 (d, 2H), 7.21 (m, 3H), 7.09 (d, 2H), 6.91(d, 2H), 6.45 (s, 1H), 4.60 (m, 3H), 3.81 (s, 3H), 3.38 (s, 3H), 3.17 (dd, 1H), 2.81 (dd, 1H), 2.63, 2.44, 2.14 (3s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)N)[CH3:18]>>[CH2:17]([C:19]1[CH:20]=[C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:18]
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: CCc1cc(N)ccc1OCc1ccccn1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Yield: 54.5 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (655 mg, 2.82 mmol) and 3-ethyl-4-(pyridin-2-ylmethoxy)aniline (786 mg, 3.10 mmol) to give the title compound as a white solid (625 mg, 55%); NMR spectrum: 1.20 (t, 3H), 2.66 (q, 2H), 3.79 (d, 2H), 4.30 (td, 2H), 5.21 (s, 2H), 7.02 (d, 1H), 7.36 (m, 2H), 7.43 (dd, 1H), 7.85 (td, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 8.60 (d, 1H); Mass Spectrum: 407 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[OH:30])[C:23]([NH:25][NH2:26])=[O:24]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][C:29]([OH:30])=[C:20]([Cl:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)c(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 81.8 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.02 g, 3.8 mmol) and 3-chloro-4-hydroxybenzohydrazide (711 mg, 3.8 mmol) were coupled in an analogous fashion as the procedure used for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (50 mL) followed by cooling to 0° C. and filtration to yield product as a white solid (1.36 g, 82%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.93 (d, J=2.2 Hz, 1H), 7.75 (dd, J=2.2, 8.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.67 (m, 1H), 5.55 (d, J=6.8 Hz, 1H), 4.38 (m, 1H), 4.10 (dd, J=3.1, 7.0 Hz, 1H), 2.36 (s, 3H), 1.34 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20][CH2:21][C:22]([O:24]CC)=O)[C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:31].O.C([O-])(O)=O.[Na+]>CC(O)=O.CCOC(C)=O>[OH:24][C:22]1[N:31]=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)=[N:20][CH:21]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CNC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)n1nc(-c2ncc(O)nc2-c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 24.8 %

Procedure:
A mixture of ethyl {[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]amino}acetate (14.0 g) and ammonium acetate (21.0 g) in AcOH (60 ml) was refluxed with stirring for 2 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(5-hydroxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (3.0 g) as white powder.
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[CH:12]=[CH:13][C:14](O)=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1.N1CCCC1>CO>[Br:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[O:9][C:6]1([CH2:7][CH2:8][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1)[CH2:18][C:17]2=[O:19]
Reactant: CC(C)C1CCC(=O)C1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Yield: 78.1 %

Procedure:
A mixture of 3-isopropylcyclopentanone (0.5 g, 3.962 mmol), 1-(5-bromo-2-hydroxyphenyl)ethanone (0.424 g, 1.98 mmol) and pyrrolidine (0.143 g, 1.98 mmol) in MeOH (25 mL) was refluxed overnight. The solvent was removed in vacuo to give crude 6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentan]-4-one (500 mg, 79%). 1H-NMR (CDCl3): 0.78 (m, 3H), 0.82 (m, 3H), 1.34 (m, 1H), 1.58 (m, 3H), 1.75 (m, 1H), 1.91 (m, 2H), 2.08 (m, 1H0, 2.73 (s, 2H), 6.74 (m, 1H), 7.44 (m, 1H), 7.89 (d, 1H).
Reaction SMILES: C([O:4][C@@H:5]([CH3:39])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:25])[C:19]=3[N:18]=[C:17]2[S:26][C:27]2[C:35]([N:36]([CH3:38])[CH3:37])=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:25][C:20]1[C:19]2[N:18]=[C:17]([S:26][C:27]3[C:35]([N:36]([CH3:38])[CH3:37])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[N:16]([CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C@@H:5]([OH:4])[CH3:39])[CH2:9][CH2:10]3)[C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3N(C)C)OCO4)nc3c(N)nccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3N(C)C)OCO4)nc3c(N)nccc32)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S)-1-[4-(2-{4-amino-2-[(6-(dimethylamino)-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-1-yl}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate (171 mg, 0.32 mmol) in MeOH (3.0 mL) was added K2CO3 (89 mg, 0.64 mmol) and resulting mixture was stirred for 6 h room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure and residue was purified by flash column chromatography. The product was eluted with 10% MeOH in dichloromethane. 1H NMR (DMSO-d6) δ 7.1 (d, J=5.8 Hz, 1H), 7.0 (s, 1H), 6.78 (d, J=5.8 Hz, 1H), 6.41 (s, 2H), 6.18 (s, 1H), 5.94 (s, 2H), 7.78 (d, J=7.4 Hz, 1H), 4.37 (qin, J=5.0 Hz, 1H), 4.27 (t, J=11.3 Hz, 1H), 4.09-4.2 (m, 2H), 3.16 (d, J=5.0 Hz, 1H), 2.77-2.9 (m, 1H), 2.63 (s, 6H), 2.38-2.5 (m, 1H), 1.66 (d, J=11.7 Hz, 2H), 1.53 (q, J=6.6 Hz, 2H), 1.35-1.5 (m, 1H), 1.13 (t, J=5.0 Hz, 3H), 0.85-1.1 (m, 2H); TOF-MS [M+H]+ 513.22.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[O-].[Na+].[C:22]([O-])(=[O:24])[CH3:23].[Na+].C(=O)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]2[O:24][CH:22]([CH3:23])[O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Agent: CC=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)O2)c1Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
8.0 g (27.4 mmol) of methyl 2-chloro-3-(hydroxyiminomethyl)-4-methylsulfonylbenzoate in 150 ml of methylene chloride were admixed dropwise with 16.0 g (27.4 mmol) of a 12.5% strength sodium hypochlorite solution, and a spatula-tip of sodium acetate was added. After 1 hour, 34.4 g (0.74 mol) of acetaldehyde were added a little at a time within a period of 36 hours, and the mixture was slowly heated to 55° C. The mixture was subsequently stirred at room temperature for 48 hours, washed with water, dried and concentrated. The residue was then taken up in methylene chloride, 10.0 g (0.23 mol) of acetaldehyde and a spatula-tip of sodium acetate were added and the mixture was heated under reflux for 8 hours. After 72 hours, a further 10.0 g 5 (0.23 mol) of acetaldehyde were added and the mixture was stirred at room temperature. The mixture was subsequently washed with water, dried and concentrated. The residue was passed through silica gel (eluent: isopropanol:cyclohexane=1:9). This gave 5.0 g (55% of theory) of methyl 2-chloro-3-(2-methyl-2H-1,3,4-dioxazol-5-yl)-4-methylsulfonylbenzoate.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[S:12].O1C=CN=C1.BrBr.C(=O)([O-])[O-].[Na+].[Na+]>Br>[NH2:13][C:11]1[S:12][C:2]([Br:1])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(N)=S
Agent: Br
Agent: BrBr
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1nc(N)sc1Br
Temperature: 60 °C

Procedure:
Ethyl 2-aminothiazoles-4-carboxylate (5.0 g) (prepared from ethyl bromopyruvate and thiourea by the procedure described in J. Med. Chem., 1971, 14, 1075 for the corresponding oxazole) in concentrated hydrobromic acid (9 cm3) was stirred at ambient temperature and treated dropwise with bromine (3.2 g), then heated to 60° C. for 2 hours, neutralised with sodium carbonate and the product extracted into ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give ethyl 2-amino-5-bromothiazole-4-carboxylate (1.54 g). MH+ =251; 1H NMR: δ 1.40(3H,t); 4.40(2H,t); 5.6(2H,br s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:22]([CH:19]2[CH2:21][CH2:20]2)=[O:23])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)c2)c(F)c1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(Nc2ccc([N+](=O)[O-])cc2F)ccn1)C1CC1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
Mix 2-chloro-N-(2-fluoro-4-nitro-phenyl)pyridin-4-amine (280 mg, 1.05 mmol), cyclopropanecarboxamide (267 mg, 3.15 mmol), Cs2CO3 (863 mg, 2.63 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 65 mg, 1.05 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 48 mg, 0.053 mmol] and 1,4-dioxane (6 mL) in a 50 mL round bottom flask, heat at 100° C. under N2 for 16 hrs. Cool the reaction to 25° C., add water (40 mL), extract with EtOAc (10 mL×2). Combine the organic layers; wash with brine (15 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, PE:EtOAc=7:3) affords the target compound (180 mg, 54%). MS: (M+1): 317.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([NH2:20])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([NH:20][C:42](=[O:44])[CH3:43])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(N)nc2CCN1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(NC(C)=O)nc2CCN1C(=O)OCc1ccccc1

Procedure:
To an-ice cooled solution of (±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (50 mg, 100 μmol, 1 eq.) and NEt3 (69 μL, 500 μmol, 5 eq.) in DCM (1 mL), acetyl chloride (14 μL, 200 μmol, 2 eq.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C(N)CN.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:24])([F:25])[F:26])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C(=O)NCC(F)(F)F)C(C)C)c3)c3cc(Cl)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 2-{[5-(5-chloro-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]amino}-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 1-1a (315 mg, 0.543 mmol) dissolved in a mixture of MeOH (3.0 ml) and THF (7 ml) was added ethylenediamine (0.183 ml, 2.72 mmol) followed by 1 M sodium hydroxide (1.086 ml, 1.086 mmol). The mixture was allowed to stir for ½ hr at room temperature. The reaction was quenched with 1N HCL (2.7 mL), concentrated to remove solvents and aqueous sodium bicarbonate (10 mL) added. The product was extracted into DCM, dried over sodium sulfate, concentrated and chromatographed on silica using 1-10% methanol/dichloromethane to give 135 mg desired product 1-1b as a foam. LRMS (ESI) m/z 426.1 [(M+H)+; calcd for C19H19ClF3N5O: 426.1].
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>CN(C)C=O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A mixture of 75 g (0.235 mol) of 1-(diphenylmethyl)-3-(methanesulphonyloxy)-azetidine, 47.1 g (0.254 mol) of potassium phthalimide and 800 ml of dimethylformamide was refluxed for 1½ hours, during which time a fine precipitate gradually settled out. After cooling the precipitate was filtered off and the solvent was evaporated off in vacuo, finally under a high vacuum. The colourless residue crystallised when left to stand. Yield: 78.0 g (90% of theoretical). Rf=0.95 (El N).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:59])([F:58])[C:49]1[N:57]=[C:52]2[CH2:53][NH:54][CH2:55][CH2:56][N:51]2[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:54]1[CH2:55][CH2:56][N:51]2[N:50]=[C:49]([C:48]([F:58])([F:47])[F:59])[N:57]=[C:52]2[CH2:53]1)=[O:5]
Reactant: FC(F)(F)c1nc2n(n1)CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[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: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2nc(C(F)(F)F)nc2C1
Reaction time: 12 h
Yield: 16.4 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (780 mg, 2.65 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.80 g, 4.77 mmol), 2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 19a (560 mg, 2.92 mmol, prepared according to a known method disclosed by “patent application WO2009025784”) and N,N-diisopropylethylamine (1.4 mL, 7.95 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 19 (205 mg, yield 16.4%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][C:9]3([O:16][C:5]=2[CH:4]=1)[CH2:14][CH2:13][N:12](C)[CH2:11][CH2:10]3.C(=O)([O-])[O-].[K+].[K+].ClC(OC(Cl)C)=O>ClCC(Cl)C>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][C:9]3([O:16][C:5]=2[CH:4]=1)[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3
Reactant: COc1ccc2c(c1)OC1(C=C2c2ccccc2)CCN(C)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)CCl
Product: COc1ccc2c(c1)OC1(C=C2c2ccccc2)CCNCC1
Yield: 109.2 %

Procedure:
To a stirred solution of 7-methoxy-N-methyl-4-phenylspiro[2H-1-benzopyran-2,4′-piperidine] (3.76 g, 11.71 mmol) in anhydrous 1,2-dichloropropane (150 cm3) was added potassium carbonate (4.04 g, 29.23 mmol) and the resulting suspension was cooled in an ice-bath before being treated drop-wise with 1-chloroethyl chloroformate (1.58 cm3, 14.64 mmol). The reaction mixture was heated to reflux overnight and a further portion of 1-chloroethyl chloroformate (0.8 cm3, 7.4 mmol) was added before it was heated to reflux for a further 24 h. Upon cooling, the reaction mixture was filtered through cotton wool which was subsequently washed with dichloromethane (50 cm3) and the volatiles were removed in vacuo. The resulting intermediate was treated with methyl alcohol (200 cm3) and the mixture was heated to reflux overnight. Upon cooling, the volatiles were removed in vacuo before the resulting solid was dissolved in a mixture of dichloromethane (150 cm3) and aqueous sodium carbonate solution (5%, 30 cm3). The organic layer was separated, washed with water (2×50 cm3), dried over sodium sulfate and the solvent was removed in vacuo to afford the title compound as a gum (3.93 g).