Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Zn]C.[C:4]1(C)C=CC=CC=1.Br[C:12]1[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].[NH4+].[Cl-]>O1CCOCC1.CO>[F:18][C:17]1[C:12]([CH3:4])=[C:13]([N+:21]([O-:23])=[O:22])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1F
Reactant: Cc1ccccc1
Agent: C[Zn]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(C)c1F
Temperature: 55 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Dimethylzinc (67 ml of a 2M toluene) was slowly added to a mixture of 2-bromo-3-fluoro-4-methoxy-1-nitro-benzene (12.0 g) and palladium-(diphenylphosphinoferrocenyl)-dichloride-methylene dichloride complex (1.65 g) in dioxane (300 ml) at 40° C. The mixture was stirred at 55° C. during 2 hours. After cooling to room temperature, MeOH (80 ml) was slowly added followed by aqueous NH4Cl soln. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to provide 2-fluoro-1-methoxy-3-methyl-4-nitro-benzene (10.5 g, 90% purity) as a light yellow solid used as such in Step 3. 1H NMR (CDCl3) δ ppm: 7.89 (1H, dd); 6.86 (1H, dd); 3.96 (3H, s); 2.53 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23](OC)[O:24]C)[CH:20]=[CH:19][C:18]=3[N+:28]([O-:30])=[O:29])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=3[N+:28]([O-:30])=[O:29])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A mixture of 4.43 g (9.9 mmole) of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2a), 80 mL of acetonitrile and 20 mL of 1 M hydrochloric acid was heated at 60 degrees for 2 hours. The mixture was diluted with 200 mL of ice-water. The precipitate was collected by filtration, washed with water, and air dried to give 3.3 g of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b) as an orange solid.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].COC(OC)OC.F[B-](F)(F)F.[Li+].C([O-])(O)=O.[Na+]>CC(=O)OCC>[CH3:18][C:17]1([C:15]2[O:16][C:12]([CH2:11][N:8]3[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]3)=[CH:13][CH:14]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: CC(=O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Reactant: OCCO
Agent: F[B-](F)(F)F
Agent: N#N
Agent: O=C([O-])O
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Cn3ncc([N+](=O)[O-])n3)o2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark under inert atmosphere (N2), a solution of 1-[5-(4-nitro-[1,2,3]triazol-2-ylmethyl)-furan-2-yl]-ethanone (180 mg, 0.76 mmol) in ethylene glycol (0.85 mL, 15.24 mmol) was treated with trimethylorthoformate (0.17 mL, 1.52 mmol) and lithium tetrafluoroborate (14 mg, 0.15 mmol). The resulting mixture was heated to 95° C. overnight. The reaction mixture was allowed to cool to rt. NaHCO3 (10 mL) and EA (10 mL) were added and the aq. phase was extracted with EA (2×10 mL). The combined org. extracts were washed with brine (10 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:30 hept-EA) gave the title compound as a colorless oil: TLC:rf (60:30 hept-EA)=0.31. LC-MS-conditions 02: tR=0.94 min; [M+H]+=281.01.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:17]S(CC(C)C)=O)([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:5][C:4]=1[F:24])#[N:2].[ClH:25].O1CCOCC1>CO>[ClH:25].[ClH:25].[NH2:17][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:24])[CH:5]=1)([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:10]
Reactant: CC(C)CS(=O)NC(C)(c1cccnc1)c1ccc(C#N)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)(c1cccnc1)c1ccc(C#N)c(F)c1
Reaction time: 4 h

Procedure:
N-[1-(4-cyano-3-fluoro-phenyl)-1-(3-pyridyl)-ethyl]-2-methylpropanesulfinamide (0.080 g, 0.232 mmol) was dissolved in MeOH (5 mL) and treated with 4M HCl solution in dioxane (0.58 mL, 2.32 mmol). The solution was stirred for 4 h, concentrated to dryness, and azeotroped with CH2Cl2 and Et2O to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:16])C.C(O)(=O)C>[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: CCCCC(CC)COC(=O)CCN(CC)CC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 2.34 g (10 mmol) of p-iodoanisole, 2.57 g (10 mmol) of 2-ethylhexyl β-diethylamino-propionate, 0.9 g (15 mmol) of acetic acid and 15 mg of palladium on charcoal (5%) is stirred at 150° C. for 2 hours. Therafter, the mixture is worked up as in Example 1. 2-Ethylhexyl p-methoxycinnamate is obtained in 93% yield.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCc1nc2ccccc2o1
Reactant: Fc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1cccnc1C#CCCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.2 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (28 mg, 0.148 mol) and triethylamine (8.30 mL, 59.20 mmol), were added 3-fluoro-2-iodopyridine (660 mg, 2.96 mmol) and Pd(PPh3)2Cl2 (104 mg, 0.148 mmol) under N2. A yellow suspension was obtained. After a 5 minutes of stirring at room temperature, was added a solution 2-(But-3-ynyl)benzo[d]oxazole (compound 8(A), 510 mg, 3 mmol) in triethylamine (0.2 mL) under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and heated at 50° C. overnight under N2. Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 50 g, Cyclohexane/AcOEt:60/40 as eluent) following by C18 chromatography (Prepacked column 15 g, H2O/CH3CN: from 80/20 to 40/600 as eluent) to afford 120 mg of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole (Yield: 15%) as white powder (Mp=86-88° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH:39]=[C:38]([CH2:40][CH3:41])[S:37][C:9]=2[N:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])=[CH:25][CH:24]=2)[C:11](=[O:21])[C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC.CN(C)C=O>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)=O>[CH2:40]([C:38]1[S:37][C:9]2[N:10]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[C:11](=[O:21])[C:12]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]=2[CH:39]=1)[CH3:41]
Reactant: CCc1cc2c(OS(=O)(=O)C(F)(F)F)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCc1cc2cc(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a mixture of 7-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-5-(2-phenylethyl)-6,7-dihydrothieno[2,3-b]pyridin-4-yl trifluoromethanesulfonate (1 g), palladium acetate (0.018 g), triphenylphosphine (0.042 g), tributylamine (1.18 mL) and N,N-dimethylformamide (20 mL) was added formic acid (0.12 mL), and the mixture was stirred under argon atmosphere at 70° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.34 g, 45%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1.C(C1C=C(O)C(=CC=1)O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([C:8]12[CH2:13][CH2:12][CH:11]([CH:10]=[CH:9]1)[CH:3]1[CH:2]2[C:1](=[O:7])[NH:5][C:4]1=[O:6])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1=CC=CCC1
Reactant: O=C1C=CC(=O)N1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
13.5 g (0.138 mol) of maleimide and 25.3 g (0.17 mol) of ethyl 1,3-cyclohexadiene-1-carboxylate are heated under reflux with 1.4 g of 4-(tert-butyl)-pyrocatechol in 275 ml of toluene overnight The mixture is concentrated and the residue is recrystallized from isopropanol.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([Cl:12])[C:8]([CH2:10]O)=[CH:9][C:3]=2[O:2]1.P(Br)(Br)[Br:14]>C(OCC)C>[Br:14][CH2:10][C:8]1[C:7]([Cl:12])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1
Reactant: OCc1cc2c(cc1Cl)OCO2
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Clc1cc2c(cc1CBr)OCO2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2.5 g of 6-chloropiperonyl alcohol are dissolved in 80 ml of ethyl ether. The solution is cooled to 0° C. and then 1.9 ml of PBr3 are added. The mixture is stirred at ambient temperature for 18 hours. It is poured onto ice and then extraction is carried out with AcOEt. The organic phase is washed with a saturated NaCl solution. 3.3 g of powder are obtained.
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=2)=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:4][C:3]#[CH:2])=[N:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: C#CCBr
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
2 mL (80% in toluene, 18.5 mmol) 3-bromo-propyne are added to a suspension of 3.8 g (18.5 mmol) 5-(4-chloro-phenyl)-pyridin-2-ol and 5.1 g (37 mmol) K2CO3 in 50 mL DMF and the reaction mixture is stirred for 64 h at RT. The mixture is evaporated down i. vac., the residue is combined with 80 mL water, extracted with 150 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:13][CH2:21][CH3:22])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask was placed 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (6.0 g, 23 mmol) in anhydrous DMF (22.8 mL). Potassium carbonate (6.3 g, 46 mmol) was then added followed by iodoethane (2.73 mL, 34.2 mmol). The resulting suspension was stirred at 60° C. for 2 h. The mixture was poured into 100 mL water and extracted with 200 mL of ethyl ether. The organic layers were separated, combined and washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated to 6.0 g of tan oil. LCMS calculated for C11H13BrClO2 (M+H)+: m/z=293.0; Found: 293.0
Reaction SMILES: [CH3:1][N:2]([CH3:30])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:22])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[C:7]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:5])=[O:4].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[Si:23]([C:7]1[N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:30])[CH3:1])[CH:10]=[C:9]([CH:11]([O:22][C:37](=[O:39])[CH3:38])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=1)([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccnc3ccccc23)nc1[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To 2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (example 8, step A) (0.750 g, 1.62 mmol) in 8 ml of anhydrous toluene at 0° C., pyridine (0.16 ml, 1.94 mmol) was added followed by acetyl chloride (0.14 ml, 1.94 mmol). The solution was stirred at room temperature for two hours. It was cooled to 0° C. and ice cubes were added. The reaction mixture was partitioned between toluene (5 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and column purified (hexanes:EtOAc; 1:4) to give 0.84 g (100%) of the product.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CO

Procedure:
N-BOC-(S)-proline (Sigma Chemical Co., 12.97 g, 60.02 mmol) was dissolved in anhydrous THF and brought to 0° C. with stirring. Borane/THF complex was added dropwise via syringe over a 10 minute period. The reaction mixture was stirred at room temperature for 1 hour, then the reaction was quenched slowly with saturated NaHCO3 and stirred for an additional hour. The solvent was removed in vacuo, and the residue was diluted with H2O. The desired compound was extracted from the aqueous phase with Et2O (3×). The organic layer was then washed with brine (2×) dried (MgSO4) and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.Br[CH2:74][C:75]1[CH:82]=[CH:81][C:78]([C:79]#[N:80])=[CH:77][C:76]=1[F:83]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:74][C:75]3[CH:82]=[CH:81][C:78]([C:79]#[N:80])=[CH:77][C:76]=3[F:83])[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown sticky solid (31%). MS (Turbo Spray): m/z=428.2 (M+H).
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.N1N=C(S(Cl)(=O)=O)NC=1>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1nnc[nH]1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (295 mg, 1.3 mmol) and 4H-1,2,4-triazole-3-sulfonyl chloride (218 mg, 1.3 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-25%) of MeOH/EtOAc, to give benzamide II-7 (176 mg, 38%) as a white powder: mp (MeOH/EtOAc) 266-269° C.; 1H NMR δ 14.79 (s, 1H, NH), 10.39 (s, 1H, CONH), 8.94 (d, J=2.2 Hz, 1H, H-2″), 8.78 (s, 1H, H-5′), 8.71 (br s, 1H, NHSO2), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.19 (ddd, J=8.3, 2.5, 1.5 Hz, 1H, H-4″), 7.93 (d, J=8.3 Hz, 2H, H-2, H-6), 7.46 (br d, J=8.3 Hz, 2H, H-3, H-5), 7.39 (dd, J=8.3, 4.7 Hz, 1H, H-5″), 4.30 (br d, J=4.7 Hz, 2H, CH2N); 13C NMR δ 165.6, 161.8, 145.7, 144.5, 142.0, 135.8, 133.1, 127.7 (2), 127.3 (2), 127.2, 123.5, 45.9, 1 resonance not observed; MS m/z 359.6 (MH+, 100%). Anal. calcd for C15H14N6O3S: C, 50.27; H, 3.94; N, 23.45. Found: C, 50.35; H, 3.82; N, 23.42%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2C#N)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(C2CCCNC2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
To a stirred solution of tert-butyl 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.170 g, 0.431 mmol) in dioxane (30 mL) was added 4N HCl in dioxane (3 mL). The mixture was stirred at room temperature for 12 hrs. The resulting precipitates were collected by filtration and the filtrate was washed with dioxane to give 2-amino-6-(2-hydroxyphenyl)-4-(3-piperidinyl)-nicotinonitrile hydrochloride (0.075 g, yield; 53%).
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[C:27]2[C:26](=[CH:6][C:7]3[C:8]([CH:5]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCC2=C(C1)C(=O)c1cc3ccccc3cc1C2=O
Yield: 81.2 %

Procedure:
A mixture of 240 mg (1.1 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 220 mg (1.0 mmol) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in 20 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 18 hours. The solution was evaporated to dryness, the yellow residue was stirred with 10 ml of diethyl ether and the mixture was subsequently filtered to give 260 mg (81%) of methyl rac-1,2,3,4,5,12-hexahydro-5,12-dioxonaphthacene-2-carboxylate in the form of a bright yellow solid of melting point 173°-174° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:21][O:22]C(=O)C)([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[O:9])[CH3:7])(=O)C.[OH-].[Na+].C(O)C>O>[OH:4][CH2:5][C:6]([CH2:21][OH:22])([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1)=[O:9])[CH3:7]
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CO)(CO)C(=O)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
Then, 22 g (0.06 mole) of p-(1,1-bis(acetoxymethyl)ethylcarbonylamino)benzenesulfonamide, 4.8 g (0.12 mole) of sodium hydroxide, 50 ml of ethanol and 50 ml of water were introduced into a 300 ml three-necked flask equipped with a stirring machine and a condenser and refluxed while heating for 2 hours. The reaction mixture was poured into 1 l of water while stirring, then stirred for 30 minutes and filtered to give white solid of p-(1,1-bis(hydroxymethyl)ethylcarbonylamino)benzenesulfonamide. The white solid was purified by recrystallization from ethanol (yield 11 g).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][C:20](Cl)=[O:21].O>CC(C)=O.O>[Cl:18][CH2:19][C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:21]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1NC(=O)CCl
Reaction time: 2 h

Procedure:
38 Grams of methyl anthranilate and 35 g of potassium carbonate were dissolved in 300 ml of a mixture of acetone-water (2:1), then to this solution was added dropwise 30 g of chloroacetyl chloride under an ice-cooled condition with stirring. After completion of the addition, the reaction was carried out at a room temperature for 2 hours, then 200 ml of water was added to the reaction mixture, and the mixture obtained was ice-cooled, and the crystals precipitated were collected by filtration. The crystals collected were washed with water and ethanol, and recrystallized from methanol to obtain 48.6 g of methyl o-(α-chloroacetylamino)benzoate in the form of colorless needle-like crystals. Melting point: 97°-99° C.
Reaction SMILES: [CH2:1]([S:5]([N-:8][Si](C)(C)C)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([NH:20][C@H:21]([C:25](F)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C1C=CC=CN=1)C>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:5]([NH:8][C:25](=[O:26])[C@H:21]([CH:22]([CH3:23])[CH3:24])[NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: CCCCS(=O)(=O)[N-][Si](C)(C)C
Agent: CN(C)c1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-butanesulfonyl-N-trimethylsilylamide (prepared according to the procedure described in Example 8) (1.72 g, 8.28 mmol), t-butoxycarbonylvaline fluoride (1.01 g, 4.6 mmol), and dimethylaminopyridine (220 mg, 1.84 mmol) in tetrahydrofuran (25 ml) is stirred at room temperature for 1 hour. The mixture is diluted with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material is chromatographed on silica gel with ethyl acetate/hexane (3:1) to give N-butanesulfonyl-(t-butoxycarbonyl)valineamide.