Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][C:28]1[CH:29]=[C:22]([F:21])[CH:23]=[C:24]([C:25]#[N:26])[CH:27]=1
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(F)cc(C#N)c2)c1
Temperature: 120 °C

Procedure:
To a solution of ethyl 4-chloro-3-hydroxyphenylacetate (34a; 1.4 g; 6.5 mmol) and NMP (13 mL) was added potassium carbonate (2.7 g; 19.6 mmol) and 1.2 g of 3,5-difluorobenzonitrile (1.2 g; 8.5 mmol). The reaction mixture was heated to 120° C. and monitored by TLC. After 3.5 h an additional 0.9 g of K2CO3 was added and at 5.5 h an additional 0.9 g of K2CO3 and 0.3 g of 3,5-difluorobenzonitrile was added. After 8 h of heating the reaction was cooled to rt and the reaction mixture was filtered through a pad of CELITE® and the solid cake was washed well with EtOAc. The filtrate was washed with 2 portions of 2N HCl 1N NaOH, water and brine. The organic extract was dried (MgSO4), filtered and evaporated to yield 1.3 g of the ether 35a.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 78.3 %

Procedure:
(R)-8-(Benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)-quinolin-2(1H)-one (5.0 g, 10.2 mmol) was dissolved in dimethyl formamide (90 mL) and water (10 mL). Sodium iodide (1.7 g, 11.3 mmol) and sodium azide (0.7 g, 11.3 mmol) were added sequentially. The reaction mixture was stirred at RT until all the solid was in solution. The solution was heated at 80° C. for 40 hours then cooled to RT and diluted with water (300 mL). The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude residue was recrystallised from ethyl acetate and iso-hexane to afford the desired compound, (3.6 g, 78%), used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[NH2:26][CH2:25][CH2:24][NH:27][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: NCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCN)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (100 mg, 0.26 mmol, 1.00 equiv) in DCM (5 mL). This was followed by the addition of a solution of ethane-1,2-diamine (307 mg, 5.11 mmol, 19.96 equiv) in DCM/DMF (10/1 mL). The resulting solution was stirred for 5 h at room temperature. The mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl acetate and washed with 2×10 mL of water and then 1×10 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 90 mg (76%) of N-(2-aminoethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: Cl.[C:2]([CH:5]1[CH:10]2[CH:6]1[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)(=[O:4])[NH2:3].C(Cl)[Cl:19]>CO>[ClH:19].[CH:6]12[CH:5]([C:2]([NH2:3])=[O:4])[CH:10]1[CH2:9][NH:8][CH2:7]2
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Agent: Cl
Solvent: CO
Product: NC(=O)C1C2CNCC21
Reaction time: 3 h
Yield: 100 %

Procedure:
1.25 M hydrochloric acid solution (9.76 mL, 12.2 mmol) dissolved in methanol was added dropwise to the tert-butyl 6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (177 mg, 0.784 mmol) prepared in Example 4 and stirred for 3 hours. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=15:1). After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 127 mg (100%) of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][CH2:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CCCI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 38.2 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (20 mg, 0.077 mmol), potassium carbonate (107 mg, 0.77 mmol) and propyl iodide (0.023 mL, 0.23 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. After cooling the reaction was diluted with dichloromethane, washed with water (3 times) and saturated brine, filtered and concentrated. Silica gel chromatography using a mixture of hexanes, ethyl acetate, and dichloromethane (3.5:0.5:4) followed by trituration with diethyl ether and hexanes afforded 9 mg (40%) of 3-(2-pyridyl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ −8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H) 7.39 (s, 1H), 4.06 (t, 2H), 1.88 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2C)[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=NO)[CH:5]=[CH:6][CH:7]=1.C1(B(O)[OH:33])C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Product: O=C(CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1

Procedure:
In analogy to example 1, step 1, from (E)-3-(3-bromo-phenyl)-1-pyridin-4-yl-propenone (example 11) and phenylboronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=380.1 ([M+H]+, 1Br).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]([C:12]1[CH:28]=[CH:27][C:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C>C1C=CC=CC=1>[O:5]([C:12]1[CH:28]=[CH:27][C:15]([N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CC(=O)N(Cc1ccc2c(c1)OCO2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 ml of acetyl chloride dissolved in 10 ml of anhydrous benzene is added dropwise at 0° - 5° C in the course of one hour, with stirring, to a solution of 12.7 g of 4-phenoxy-N-(3,4-methylenedioxybenzyl)-aniline and 6 g of N-ethyl-diisopropylamine in 100 ml of anhydrous benzene. The whole is subsequently heated to room temperature and stirred for a further 8 hours. The precipitated N-ethyl-diisopropylamine-hydrochloride is separated by filtration; the filtrate is washed with 10% sodium carbonate solution and then with water. After drying of the organic phase by means of sodium sulphate, the benzene is distilled off in vacuo, and the residue recrystallised in hexane to obtain 4-phenoxy-N-acetyl-N-(3,4-methylenedioxybenzyl)-aniline, M.P. 75° - 76° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.Cl.[NH+]1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc(OC)cc2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cc(O)cc2ccccc12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Methyl 3-methoxy-1-naphthalenecarboxylate (Bin Ye and Terrence R. Burke, Tetrahedron, 52, 9963-9970 (1996)) (8.13 g, 37.6 mmol) and pyridinium hydrochloride (217 g, 1.88 mol) was heated to 200° C. for 30 min. After cooling to room temperature, 1N HCl was added and the precipitate was filtered and washed with water to give the title compound (6.67 g, 94%) as a yellow solid. 1H-NMR (DMSO-d6): 13.16 (s, 1H), 10.03 (s, 1H), 8.73 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.37 (m, 3H); MS m/z 187 (M−H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][CH2:20][S:21][C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:41])[N:4]([CH3:42])[C:3]1=[O:43].BrC1C=C(C=C([Cl:53])C=1)C#N>>[Cl:53][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([C:10]2[N:9]([CH2:19][CH2:20][S:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:8]=[C:7]3[C:6]=2[C:5](=[O:41])[N:4]([CH3:42])[C:3](=[O:43])[N:2]3[CH3:1])[CH:18]=1)[C:14]#[N:15]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: N#Cc1cc(Cl)cc(Br)c1
Product: Cn1c(=O)c2c(-c3cc(Cl)cc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate GA step 1) by replacing bromobenzonitrile with 3-bromo-5-chlorobenzonitrile;
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(I)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (4.1 mL) was added to a solution mixture of methyl 2-(benzyloxy)-4-iodobenzoate (1.0 g) in dioxane (5.0 mL) and methanol (5.0 mL), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 2.5 with 6.0 mol/L hydrochloric acid under ice-cooling, ethyl acetate was added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the resulting solid substance was collected by filtration to obtain 0.93 g of 2-(benzyloxy)-4-iodobenzoic acid as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=2[C:16]#[N:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=2[C:16]#[N:17])=[CH:5][CH:4]=1)(=[O:30])=[O:29]
Reactant: N#Cc1cccc(Oc2ccc(CO)cc2)c1C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(Oc2cccc(C#N)c2C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 3-[4-(hydroxymethyl)phenoxy]phthalonitrile (900 mg, 3.9 mmol) prepared according to procedures described in literature, and triethylamine (0.75 ml, 5.8 mmol) in anhydrous CH2Cl2 (50 ml), kept at 0° C. under stirring and in an inert atmosphere, methylsulfonylchloride was added (0.33 ml, 4.3 mmol). The mixture was stirred at 0° C. for 1 hour, then it was diluted with CH2Cl2 (50 ml) and washed with 1% HCl solution (60 ml), then with brine (50 ml), the organic layer was dried on Na2SO4 and the solvent was evaporated. 1.1 g (93%) of the title compound were obtained as a viscous fluid that crystallized on standing.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:33](=[O:34])C1>ClCCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C@@H:12]([C:13]([CH3:16])([CH3:14])[CH3:15])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:33]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1)C(C)(C)C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of the product of Example 111-4 in 1,2-dichloroethane (1325 mL) was treated with triethylamine (37.5 mL, 269 mmol, 1.25 equivalents) and N,N-disuccinimidyl carbonate (68.9 g, 269 mmol, 1.25 eq). The reaction mixture was stirred at 20° C. overnight, washed with 10% Na2CO3 (2×1.5 L). The aqueous was back-extracted with dichloromethane (600 mL). The organics were combined and washed with 1.5 L of brine. The organic layer was concentrated to yield 76.8 gm of crude material. 1H NMR (CDCl3): δ 7.15-7.3(m, 5H), 4.25-4.4(m, 3H), 3.75(m, 1H), 3.67(residual dichloroethane), 3.48(m, 1H), 3.1(m, 2H), 1.4(s, 9H), 1.0(s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=1)[N:5]=[CH:4][NH:3][C:2]2=[O:1])([O-:17])=[O:16]
Reactant: O=C(O)c1cccc2c(=O)[nH]cnc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c(=O)[nH]cnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a suspension of 4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (500 mg, 2.63 mmol) in 3 mL of sulfuric acid at 0° C., fuming nitric acid was added portionly. The resulting mixture was then stirred at 60° C. overnight. After cooling to rt, the reaction mixture was poured into ice-water slowly. The yellow precipitate was collected by filtration, and washing with water as the desired product in 84% yield. 1HNMR (in DMSO): 8.60 (s, 1H), 8.89 (d, J=2.6 Hz, 1H), 8.91 (d, J=2.6 Hz, 1H). Mass: M+H+: 236.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([O:28][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.19 g, 22.5 mmol) and 3-(1-cyanocyclopropyl)-N-(5-hydroxy-2-methylphenyl)benzamide (6.00 g, 20.5 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.25 g, 30.8 mmol) and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→40/60), and the obtained solution was concentrated under reduced pressure to give the title compound (9.08 g, quantitatively) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:9]([C:17](OCC)=[O:18])=[N:8]2)=[CH:4][CH:3]=1.[NH3:24]>CO>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:9]([C:17](=[O:18])[NH2:24])=[N:8]2)=[CH:4][CH:3]=1
Reactant: CCCCOc1cc(C(=O)OCC)nn1Cc1ccc(Cl)cc1
Reactant: N
Solvent: CO
Product: CCCCOc1cc(C(N)=O)nn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
A mixture consisting of 6.7 g of 1-(p-chlorobenzyl)-3-ethoxycarbonyl-5-n-butoxypyrazole, 30 ml of a 28% aqueous ammonia solution and 30 ml of methanol was placed in an autoclave and heated at a temperature of 60°C for 2 hours. After completion of the reaction, the solvent was removed by distillation and the residue was recrystallized from methanol-petroleum ether to give 5.3 g (86.2% yield) of 1-(p-chlorobenzyl)-3-carbamoyl-5-n-butoxypyrazole as colorless needles having a melting point of 137° - 138°C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:25]3[CH2:26][CH:27]=[C:28]([C:31]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[CH2:29][CH2:30]3)[O:18][C:17]=2[CH:19]=1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: COc1ccc2c(c1)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2

Procedure:
[(2R)-7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (1.5 g, 4.3 mmole) was dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 30 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 4.0 mmole) added, followed by sodium bicarbonate (1.0 g), and the mixture was refluxed under nitrogen for 18 hours. The solvent was removed under vacuum and the residue partitioned between 400 mL each of methylene chloride and water. The layers were separated and the organic phase was washed with water and saturated sodium chloride solution, dried over potassium carbonate and filtered. The filtrate was evaporated to a foam (1.6 g). Chromatography on silica gel using 4% methanol in chloroform as eluant gave 0.20 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 166–168° C.
Reaction SMILES: N#N.[CH:3](/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>C(Cl)Cl.O>[Si:22]([O:17][CH2:16][C:14]1[N:15]=[C:11](/[CH:3]=[CH:4]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:12][CH:13]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1coc(/C=C/c2ccccc2)n1
Agent: N#N
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-(2-styryloxazol-4-yl)methanol (5.40 g, 26.8 mmol) in CH2Cl2 (56.0 mL) was treated at rt with tert-butylchlorodimethylsilane (8.52 g, 53.67 mmol) followed by imidazole (3.69 g, 53.67 mmol) and the resulting suspension was stirred for 1 h at rt. Water was added. The aq. layer was extracted with and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (gradient from hept to 9:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 07: tR=1.08 min, [M+H]+=316.13.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([F:20])[C:13]=1[NH:21][NH2:22]>CN1C(=O)CCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[N:21]([C:13]3[C:14]([F:20])=[C:15]([F:19])[CH:16]=[C:17]([F:18])[C:12]=3[F:11])[N:22]=[CH:4][C:3]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1c(F)c(F)cc(F)c1F
Solvent: CN1CCCC1=O
Product: Fc1cc(F)c(F)c(-n2ncc3c(I)ccnc32)c1F
Temperature: 184 °C
Yield: 104.3 %

Procedure:
To a 15 mL pressure bottle was added 2-fluoro-4-iodonicotinaldehyde (710 mg, 2.83 mmol), (2,3,5,6-tetrafluorophenyl)hydrazine (509 mg, 2.83 mmol), and anhydrous NMP (4 mL). The reaction mixture was flushed with argon, securely capped, and heated at 184° C. for 2.75 h. The reaction mixture was partitioned with ethyl acetate (300 mL), water (125 mL), and brine (50 mL). The organic layer was washed with water (4×40 mL) and brine (75 mL) and the combined aqueous layers were extracted with additional ethyl acetate (300 mL). The second organic layer was washed with water (4×60 mL), and brine (100 mL), and the combined organic layers were dried over sodium sulfate, and evaporated in vacuo to give 1.16 g (quantitative yield) of the title compound as a tan solid. LC/MS (Condition B): ret. T=3.92 min, (M+H)+ 393.89.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29])(C)(C)C.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([C:24]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 150 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A mixture of anthranilamide (0.15 g, 1.10 mmol), 4-[2(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.340 g, 1.101 mmol), sodium hydrogensulfite (0.126 g, 1.101 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The solid was collected by filtration, washed with water (10 mL×3) and dried under high vacuum to provide desired compound (328 mg, 70%), as a white solid. A solution of the above described compound (0.316 g, 0.745 mmol) in THF (3 mL) was cooled to 0° C. under nitrogen and TBAF (1.5 mL, 1.49 mmol) was added, followed by stirring at room temperature for 1 h. The reaction mixture was diluted with cold water (30 mL), the white precipitate was filtered off, washed with water (15 mL×3) and MeOH (20 mL×3) and dried under high vacuum, to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (150 mg, 65%), as a white solid. Selected data: MS (ES) m/z: 311.04; MP 260-261° C.