Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[C:23]#[N:24]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=4)[C:23]#[N:24])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1C#N
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1C#N
Yield: 72 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 5-(chloromethyl)-2-methoxybenzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 72%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH:41][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:40]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 83.8 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.59 g, 1.43 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.29 g, 1.72 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight undr argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a bown solid product, 0.65 g, 83.8% yield. MS: 540.8 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.26 (s, 1 Hz), 10.86 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.01 (s, 1H), 7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 7.13-7.11 (m, 1H), 6.88-6.84 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.19-4.14 (m, 2H), 3.37-3.33 (m, 3H), 3.15 (m, 2H), 3.01-2.99 (m, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.78-1.77 (m, 2H), 1.33 (d, 3H, J=6.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[N:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CC(O)C>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[N:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1NC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2nc3ccc(-c4ccccc4F)nn3c2C)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a mixture of N-(5-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (0.100 g, 0.280 mmol), 4-fluorophenylboronic acid (0.420 mmol), Na2CO3 (0.840 mmol), 2-propanol (9 mL) and water (3 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0280). The mixture is heated at 80° C. for 12 hours, diluted with sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.073 g, 62%) as a yellow solid: Rf 0.29 (1:1 EtOAc:hexanes); LCMS (m/z)=417.5 [M+H]+, tR=2.71 min. (compound same as Example 312)
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CC([O-])(C)C.[K+].F[C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1.O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: OCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCC(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2,2-difluoroethanol (0.178 mL, 2.82 mmol) and KOtBu (0.319 g, 2.70 mmol) in 10 mL THF was stirred for 5 min, then ethyl 2-fluoro-5-nitrobenzoate (0.500 g, 2.35 mmol) was added and it was stirred at rt overnight. Additional 60 μL 2,2-difluoroethanol and 110 mg KOtBu were added and it was stirred for 2 h. The mixture was diluted with H2O, concentrated i.vac. and extracted 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated to furnish the subtitle compound. Yield: 0.52 g (81%); TLC: Rf=0.85 (silica gel, DCM:EtOH 99:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=O)[C:36]([F:39])([F:38])[F:37]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.74 g), anhydrous potassium carbonate (1.26 g) and methanol (30 ml) was added at room temperature 1-bromo-3,3,3-trifluoropropan-2-one (1.74 g), and the mixture was stirred at the same temperature for 0.5 hours. To the mixture was added anhydrous potassium carbonate (1.26 g), and the mixture was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in acetic acid (20 ml). To the solution was added concentrated sulfuric acid (1 ml), and the mixture was refluxed for 20 minutes. To the reaction solution was added water (120 ml), and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with sodium hydrogen carbonate solution and concentrated. The residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (1.02 g) as oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[CH3:20][N:21]([CH:23]=O)[CH3:22]>>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:1]/[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: CN(C)C=O
Reactant: CSc1nc(C)c(C#N)c(Nc2cccc(C)c2)n1
Product: CSc1nc(/C=C/N(C)C)c(C#N)c(Nc2cccc(C)c2)n1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-methyl-6-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile (1.32 g, 4.89 mmol) in DMF (8 mL) was added DMF dimethyl acetyl (1.16 g, 9.75 mmol), and the reaction mixture was stirred at 110° C. for 1.5 h. The mixture was concentrated and the residue was dissolved into EtOAc (30 mL). The solution was washed with water and organic layer was collected. The aqueous layer was extracted with EtOAc (2×). The combined extract was dried over Na2SO4, filtered, and concentrated to give the crude enamine product (1.47 g). MS: M(C17H19N5S)=325.44, (M+1)+=326.1
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:33].Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36]/[N:35]=[C:8](/[C:6]1[CH:5]=[CH:4][C:3](=[O:33])[N:2]([CH3:1])[CH:7]=1)\[CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[O:25])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1

Procedure:
In analogy to example 151, step 3, 1-methyl-5-{3-[4-(morpholine-4-carbonyl)-phenyl]-3-o-tolyl-propionyl}-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=460.4 [M+H]+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:10]1[CH2:14]OC[CH2:11]1>C(OCC)C.[Ti]>[C:2]1([C@@H:1]([OH:8])[CH2:14][CH:10]=[CH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1
Agent: [Ti]
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 1.25 mmol of the titanium compound of Example 2b in 60 ml of diethyl ether is cooled to -74° C., and 0.1 ml (1.0 mmol) of freshly distilled benzaldehyde is added. The slightly yellow, clear solution is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added and the mixture is warmed to RT, stirred for a further hour at this temperature, filtered with suction and concentrated on a rotary evaporator. The crude product (0.80 g of a clear colourless oil) is flash-chromatographed (60 g of silica gel, 35 cm long, cross-section 2 cm, 5 ml/fraction, 0.4 bar, 10:1 toluene/ethanol). 0.098 g of product is obtained. Yield: 66%, ee: 93%.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O>CO>[Br:11][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4](=[O:10])[NH:5][C:6]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(C)[nH]c1=O
Solvent: CO
Product: CCc1cc(Br)c(C)[nH]c1=O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 3-ethyl-6-methyl-1H-pyridin-2-one (23.92 g, 174.4 mmol) and N-bromosuccinimide (32.67 g, 183.5 mmol) in methanol (450 ml) was stirred under nitrogen at room temperature. A thick suspension formed after some hours and was stirred at RT for a further 24 h. The reaction mixture was concentrated to one half to one third of the original volume and diluted with 200 ml of water. The mixture was cooled in an ice bath with stirring and then filtered with suction. The residue was washed with cold water and dried at 65° C. 35.93 g (95%) of 5-bromo-3-ethyl-6-methyl-1H-pyridin-2-one were obtained in the form of a beige powder.
Reaction SMILES: O.[CH2:2]([SH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[CH2:2]([S:10][CH2:14][CH2:13][CH2:12][C:11]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCS
Solvent: O
Solvent: CCO
Product: CCCCCCCCSCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An apparatus was provided including a two liter, 4-neck, round bottom flask equipped with an alcohol thermometer, an overhead mechanical stirrer, a water-cooled condenser and a nitrogen purge. Into this reactor gradually were added 23 g of sodium into 1,200 ml of absolute ethanol previously added. After all of the sodium had reacted the solution was stirred overnight under a slow nitrogen flow. 1-octanethiol, 146.28 g, was added to the mixture and an addition funnel and heating mantel were added to the reactor. In 200 ml of ethanol, 129.13 g of butyrolactone was added dropwise to the ethanol solution at reflux temperature. The resulting mixture was heated at reflux overnight. The ethanol was then removed from the reaction mixture and the residue was dissolved in water. The aqueous solution was washed with methylene chloride. The aqueous solution was then added to an ice/sulfuric acid mixture and the product extracted with methylene chloride. The methylene chloride solution was washed with water, dried with sodium sulfate, filtered and concentrated under vacuum with heating. The liquid product solidified upon cooling to room temperature. There was provided 219 g of 4-(n-octylthio)butyric acid. The solid exhibited a melting point of 33°-34.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-:27].[Na+].Cl>FC(F)(F)C(O)=O.O>[OH:27][C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 4 h

Procedure:
A solution of 4-{3-[3-[2-(1-Cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (3.7 g., 0.01 mole) in trifluoroacetic acid (20 ml.) is allowed to stand at 25° C. for 4 hours. Excess trifluoroacetic acid is then removed by evaporation at reduced pressure. The oily residue is dissolved in a solution of sodium hydroxide (2.0 g., 0.05 mole) in water (40 ml.). The basic solution is acidified with 2 N hydrochloric acid. The title compound precipitates as a solid. Recrystallization from acetonitrile-water yields the purified title compound, m.p. 147°-148° C.
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[CH:15][N+:16]([O-:18])=[O:17]>N1C=CC=CC=1>[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[C:15]([N+:16]([O-:18])=[O:17])[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: CN1CCNC1=C[N+](=O)[O-]
Solvent: c1ccncc1
Product: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
14.6 g of phenylsulfenyl chloride was added dropwise to a cooled, stirred solution of 14.3 g of Compound 1 in 250 ml of pyridine. The mixture was allowed to stand overnight at room temperature, then excess pyridine was recovered on a rotary evaporator. The residue was treated with 250 ml of water and the mixture extracted with methylene chloride. The combined extracts were dried and the solvent evaporated to give a crystalline solid which was triturated with ethyl acetate, then ethanol, to yield 25, as a yellow solid, melting point: 170° - 173°.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C>[Br:18][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 1.0 g (3.94 mmol) of 2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone and 20 mL of glacial acetic acid was added 1.0 g (5.6 mmol) N-bromosuccinimide and the mixture was left to stir at room temperature for 16 h. The reaction was poured onto ice water and vacuum filtered, washing well with water. The crude product was recrystallized from ethyl acetate to yield 1.05 g (83.5%) of 5-bromo-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO)δ7.6 (3H, m); 8.15 (2H, m).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C1COCC1.Cl[C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:15])=[CH:12][C:11]=1[N+:24]([O-:26])=[O:25]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:13]1[CH:22]=[CH:23][C:10]([NH:3][CH2:1][CH3:2])=[C:11]([N+:24]([O-:26])=[O:25])[CH:12]=1
Reactant: CN(C)CCNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1ccc(C(=O)NCCN(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 73 %

Procedure:
To 2.0 M solution of ethylamine in THF (8 mL, 16 mmol) slowly added 4-chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide (0.40 g, 1.5 mmol). After heating at 65° C. for 16 h, the reaction mixture was cooled, concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to afford the title compound (0.30 g, 73%) as a yellow solid. 1H-NMR (CD30D): δ 8.75 (1H, d), 8.32 (1H, br s), 7.98 (1H, dd), 7.08 (1H, d), 3.58-3.64 (3H, m), 3.43-3.51 (2H, m), 2.94 (2H, br t), 2.62 (6H, s), 1.35 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=O.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH3:14])=[O:13]
Reactant: COc1ccccc1C=CC(=O)O
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)C=Cc1ccccc1OC

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-methoxyphenyl)-acrylic acid and 4-heptylamine. MS (M+H, 276.2).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(Cl)Cl.[C:64]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)([CH3:67])([CH3:66])[CH3:65]>>[C:64]([C:68]1[CH:69]=[CH:70][C:71]([CH2:72][NH:73][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)=[CH:74][CH:75]=1)([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CNC(=O)c2ccc(S(=O)(=O)Nc3nccs3)cc2)cc1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
4-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 99, 1.30E3 mg, 0.00300 mol), HBTU (1400.8 mg, 0.0031671 mol) and Et3N (1.07 mL, 0.00766 mol) were mixed in methylene chloride (10 mL, 0.2 mol). 4-tert-butylbenzylamine (424.1 mg, 0.002598 mol) was added and the reaction stirred overnight. The reaction was washed with saturated sodium bicarbonate (aq) followed by 0.5N HCl. The organic phase was separated and dried over magnesium sulfate, then treated with activated carbon and filtered through a Celite pad. The solvent was removed in vacuo to give an oily residue. The residue was triturated with DCM and the solid collected by filtration. LCMS analysis of the solid revealed cleavage of the dimethoxybenzyl protection group had occurred. The gray solid was saved. The filtrate was purified by column chromatography, chloroform to 10% MeOH in chloroform gradient eluent. Product fractions were combined and evaporated to an oily residue. The residue was triturated with methylene chloride and beige solid collected. The solid products from steps 4 and 5 were combined and dissolved in 1N NaOH (aq). The solution was washed 3× with diethyl ether. The basic aqueous phase was treated with activated carbon and filtered through a Celite pad. The pale yellow filtrate was slowly acidified to pH 2-3 with 6N HCl (aq). The resultant precipitate was collected by filtration. Vacuum drying yielded 511 mg of product as a white powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(NC(=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCC(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and acetophenone (II), MS (m/e) 420, 375, 315, 301,287 and 283; IR (neat) 1684, 1597, 1581, 1449, 1392, 1369, 1251 and 1164 cm-1 ; NMR (CDCl3) 7.97, 7.56, 7.45, 4.18, 3.39, 2.60, 2.33 and 1.30 δ.
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:5]1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]=[C:29]1S(C)(=O)=O.O>CN(C=O)C>[F:21][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:29]3[N:28]([CH2:27][CH2:26][O:25][CH3:24])[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[N:30]=3)=[CH:16][CH:15]=2)=[N:5]1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cc(F)cnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(Oc2ccc(-c3nn(CC(F)F)c4cc(F)cnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a stirred solution of 4-[1-(2,2-difluoroethyl)-6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (47 mg) in DMF (4 mL) was added NaH (60% in oil, 4.23 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (32.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of tert-butyl (Z)-4-(3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl)piperidine-1-carboxylate (0.0802 g, 0.207 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0302 g, 0.207 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-((Z)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0724 g, 68%).