Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1([CH2:26]OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1([CH2:26][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH3:17])[C:11]=2[CH3:16])[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Reactant: Cc1c(O)ccc(OCc2ccccc2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(OCc3ccccc3)c(C)c2C)CC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A suspension of 4-benzyloxy-2,3-dimethyl-phenol (960 mg), 1-methanesulfonyloxymethyl-cyclopropanecarboxylic acid ethyl ester, prepared as in Step 1 (890 mg) and cesium carbonate (1.5 g) in DMF (20 mL) was stirred at 130 ° C for 6 h, and the mixture was partitioned between EtOAc and water. The organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 10% EtOAc in hexane to give 0.78 g of 1-(4-benzyloxy-2,3-dimethyl-phenoxymethyl)-cyclopropanecarboxylic acid ethyl ester as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]3[CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, cyclopropylamine (2.40 g, 0.042 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the residue was recrystallized from isopropyl alcohol with refrigeration. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. over the weekend to give 2.4 g (53%) of title compound, mp 231°-232° C.
Reaction SMILES: [N+]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-])=O.[H][H].O>CO.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][CH2:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: [H][H]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2OCN1CCO[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)N(CCO)CO2
Yield: 97.4 %

Procedure:
A solution of 42 g (0.148 mole) of the compound of Example 1 in 6,300 ml of methanol was combined with 10% Pd/C, and the resulting mixture was placed in a hydrogen atmosphere having a head of water, at room temperature. At the end of the reaction, the suspension was filtered on celite and the solution obtained was evaporated under vacuum. The resulting crude product was taken up with ethyl ether and filtered under vacuum, thus yielding 30 g of 6-amino-2,3-dihydro-3-(2'-hydroxyethyl)-4H-1,3-benzoxazin-4-one. m.p. 94°-96° C. (ethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1>>[O:17]1[CH:21]=[CH:20][C:19]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:18]1
Reactant: O=Cc1ccoc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccoc2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-furaldehyde gave the title compound as a yellow solid m.p.: 130° C.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1B(O)O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(C)cnc2C)c(OC)c1
Temperature: 75 °C

Procedure:
A mixture of 3-chloro-2,5-dimethyl-pyrazine (283 mg, 2.0 mmol), 2,4-dimethoxyphenylboronic acid (455 mg, 2.5 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in DME (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 75° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, and washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (25% ethyl acetate in hexanes) yields 3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazine as an oil MS: 245.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=O)[CH3:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:20][C:17]1[S:16][C:15]([C:12](=[N:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH3:13])=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(C)s1
Reactant: Nc1ccccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=Nc1ccccc1C(F)(F)F)c1ccc(C)s1
Yield: 87.5 %

Procedure:
A solution of 2-(trifluoromethyl)aniline (4.0 q, 25 mmol), 2-acetyl-5-methylthiophene (4.4 g, 31 mmol), and p-toluenesulfonic acid (50 mg) in toluene (30 mL) was heated under reflux with azeotropic removal of water for 10 hours. Then the mixture was concentrated on a rotary evaporator, and the oily residue was distilled under reduced pressure to give 6.2 g (88%) of ketimine 12q as an oil (bp 128°-130° C./0.3 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](Cl)=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:9])[C:4]=1[Cl:8])=[O:21])[CH3:20]
Reactant: Clc1sc(Cl)c(Cl)c1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)c1sc(Cl)c(Cl)c1Cl
Temperature: -18 °C
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
To tetrachlorothiophene (2.0 g, 9.0 mmol) in an oven dried 50 mL flask, evacuated and flushed with nitrogen, was added anhydrous diethyl ether (12 ml). The resulting solution was cooled to −18° C., then n-butyllithium (1.6 M in hexane) (5.6 ml, 9.0 mmol) was added dropwise via a syringe. After stirring for 10 min at −18° C., diethyl oxalate (1.4 ml, 9.9 mmol) was added dropwise. Stirring was continued for 30 min, then the reaction mixture was quenched with 1N HCl. The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. Purification was performed by column chromatography using hexane/ethyl acetate (20:1) to provide (3,4,5-trichlorothiophen-2-yl)-oxo-acetic acid ethyl ester as a yellow solid (0.93 g, 47%). MS (M+H)+: 288.92; 1H NMR (300 MHz, CDCl3) δ4.44 (2H, q, J=7.1 Hz), 1.43 (3H, t, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ173.72, 161.82, 136.83, 133.16, 127.30, 126.53, 63.76, 14.11.
Reaction SMILES: [C:1]([CH2:3][C:4]([O-:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH:9]([CH3:11])[CH3:10].S(=O)(=O)(O)O>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])#[N:2]
Reactant: N#CCC(=O)[O-]
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Product: CC(C)CCOC(=O)CC#N

Procedure:
Using the procedure of Example 1, cyanoacetate acid (85.5 g; 1.00 mol) and isoamyl alcohol (176 g; 2 mol) are reacted in the presence of sulfuric acid (0.49 g; 0.005 mol). Isoamyl cyanoacetate (bp 133/20 mm of Hg) is recovered as a clear liquid. The yield was 150 g (97% of theoretical) and its purity was >99% (GC assay).
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][N:21]=1)[CH2:14][OH:15].O[C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH3:31][Si:2]([CH3:1])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:19]=[CH:20][N:21]=1)[CH2:14][O:15][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(CO)Cc1nccn1COCC[Si](C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1CC(COc1ccc(C=O)cc1)Cc1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
To a tetrahydrofuran (2 mL) solution of the compound (120 mg) produced in Example 18 and a 4-hydroxybenzaldehyde (31 mg), triphenylphosphine (81 mg) and diethylazodicarboxylate (175 μL) were added in this order. The reaction solution was stirred at room temperature for 15 hours. To the reaction solution, water (20 mL) was added. The aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed with saturated sodium chloride solution (50 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=80:20→0:100→ethyl acetate:methanol: 28% aqueous ammonia=100:0:0→80:20:2) to obtain the title compound (85 mg) having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)[N:3]=1.NC(N)=[S:20].Br>C(O)(=O)C>[N:4]1([CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([SH:20])([CH2:11]4)[CH2:9]2)[CH2:15]3)[CH:5]=[CH:6][CH:2]=[N:3]1
Reactant: NC(N)=S
Reactant: Brc1ccn(CC23CC4CC(CC(C4)C2)C3)n1
Agent: Br
Solvent: CC(=O)O
Product: SC12CC3CC(C1)CC(Cn1cccn1)(C3)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 26A (2.0 g) and thiourea (2.0 g) in a solvent mixture of acetic acid (20 mL) and 48% aqueous HBr solution (10 mL) was heated to 100° C. for 24 hours. The reaction was concentrated to dryness, and the residue was dissolved in 20% v/v ethanol in water (100 mL). Solid sodium hydroxide (10 g) was added, and the mixture was stirred overnight. The solution was acidified to pH 1 with concentrated HCl solution, and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 10-50% ethyl acetate in hexane, to give the title product.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:9]=[N:10][N:11]=2)[C:5](Cl)=[N:6][CH:7]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([N:9]=[N:10][N:11]=2)[C:5]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c2nnnn12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3nnnn23)CC1
Temperature: 30 °C
Yield: 93.9 %

Procedure:
A 250 mL round bottom flask was charged with 8-bromo-5-chlorotetrazolo[1,5-c]pyrimidine (10 g, 42.7 mmol), tert-butyl piperazine-1-carboxylate (11.9 g, 64 mmol), triethylamine (13 g, 0.13 mol) and ethanol (200 mL). The resulting mixture was heated at 30° C. for 2 h under N2 and then cooled to room temperature. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo, to afford 15.4 g (94%) of the product as an off-white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2-:10].[Na+].C1(C)C(C)=CC=CC=1>O>[NH2:10][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=1
Reactant: CCCc1ccncc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCc1ccnc(N)c1

Procedure:
75 g (0.62M) of 4-n-propylpyridine and 28 g (0.73M) of sodium amide were added to 250 ml of xylene, and the mixture was heated under reflux for 10 hr. Water was added in small portions to the reaction mixture under ice cooling to decompose excess sodium amide, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate and then purified by column chromatography (dichloromethanemethanol 50:1→20:1). The yield was 33 g. (blackish purple solid)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][CH2:25][O:26][CH3:27])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COCCBr
Product: COCCN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-bromo-2-methoxyethane. MS 362 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.59 μM.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:4]2[C:5]([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13](=[O:15])[C:3]=12)=[O:7]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O
Solvent: CC(=O)O
Product: O=C1c2c(Cl)cc(Cl)c(Cl)c2C(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
3,4,6-Trichlorophthalic acid (500 g, 1.86 moles), glacial acetic acid (4 L), and aniline (175 mL, 1.92 moles) were charged to a 12 L 3-neck flask equipped with a condenser, a stirrer and a thermometer. The mixture was heated with stirring and maintained at 100°-101° C. for 2 hours, then cooled to room temperature and filtered. The filter cake was washed with cold water and vacuum dried (70° C., 0.2 mmHg) for 24 hours to yield 590.7 g of 97.5% pure 3,4,6-trichloro-N-phenylphthalimide (m.p. 199°-200° C.).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[CH:26]([CH2:30][CH2:31][CH3:32])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[CH:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CCCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CCCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=492.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([Li])CCC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](OCC)=[O:19]>O1CCCC1.CCCCCC.[Cl-].[NH4+]>[NH:4]1[CH:3]=[C:2]([C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[O:19])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: CCOC(=O)c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1cn[nH]c1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
To a solution of 4-iodopyrazole (1.0 g) in tetrahydrofuran (10 mL), a solution of n-butyllithium in hexane (2.6 M, 4.8 mL) was added dropwise at −10° C. and stirred at room temperature for 1 hour. The reaction mixture was cooled to −10° C. and ethyl picolinate (0.86 g) was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane:ethyl acetate=1:1 to 1:2) to give the titled compound (0.090 g) as a colorless solid.
Reaction SMILES: [CH:1]([N:4]1[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]2[C:6]([CH2:7][C:8]([CH3:25])([CH3:24])[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11]2)=[N:5]1)([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:13]2[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]3[C:12]=2[CH2:11][C:10]([CH3:22])([CH3:23])[NH:9][C:8]([CH3:24])([CH3:25])[CH2:7]3)=[CH:29][CH:28]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CC(C)(C)NC(C)(C)C2
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CC(C)(C)NC(C)(C)C2
Yield: 59.4 %

Procedure:
The title compound (100 mg) was prepared as in Example 296 using 196 mg of trifluoro-methanesulfonic acid 2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester and 100 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C20H28FN3, 329.23. found, m/z 330.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.27 (m, 4H), 4.31 (m, 1H), 3.10 (s, 2H), 2.70 (s, 2H), 1.47-1.34 (m, 18H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].N(=[CH:8][C:9]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=1)=[O:10])O>O>[CH3:17][O:16][C:15]1[CH:14]=[C:13]2[C:12](=[CH:19][CH:18]=1)[NH:11][C:9](=[O:10])[C:8]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(NC(=O)C=NO)cc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 60 °C
Yield: 65 %

Procedure:
Concentrated sulfuric acid (45 mL) containing 5 mL of water was warmed to 60° C. and 8.6 g of N-(2-hydroximinoacetyl)anisidine was added in one portion. The stirred mixture was heated to 93° C. for 10 minutes and then allowed to cool to room temperature. The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluting with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid. The 1.1 g of 2-hydrazino-carbonylmethyl-4-anisidine was refluxed for 1 hour in 20 mL of 1N sodium hydroxide. The mixture was cooled, acidified to pH 2 with concentrated hydrochloric acid and extracted 3 times with 25 mL of ethyl acetate each time. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of 5-methoxy-2-oxindole as a yellow solid. The combined yield was 1.5 g or 33%.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:19])[CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1cccnc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Yield: 18.5 %

Procedure:
To a solution of 2.1 g (0.090 mole) of sodium metal in 100 ml of ethanol, was added 10.0 g (0.075 mole) of 2-oxindole, followed by 13.6 g (0.090 mole) of ethyl nicotinate. The resulting slurry was heated under reflux for 3 hours and then the mixture was cooled and filtered. The residue was discarded, and the filtrate was evaporated in vacuo. The residue thus obtained was dissolved in ca. 150 ml of water, and the aqueous solution was washed with chloroform. To the aqueous solution was then added 5.8 ml of glacial acetic acid and the resulting mixture was cooled in an ice-bath. The solid was recovered by filtration and recrystallized from ethanol to give 3.3 g of the title compound as yellow needles, m.p. 169°-170° C. Analysis: Calcd. for C14H10N2O2 : C, 70.58; H, 4.23; N, 11.76%. Found: C, 70.66; H, 4.41; N, 11.73%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17]([NH:12][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[C:2]=1[Cl:1])=[O:18]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)c3cc(Cl)cc(Cl)c3)ccc2s1
Yield: 60 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 3,5-dichlorobenzoyl chloride (122 mg, 0.56 mmol) in presence of triethylamine (0.5 mL) according to method A gave 3,5-Dichloro-N-(4-chloro-2-methyl-benzothiazol-5-yl)-benzamide (66 mg, 0.15 mmol, 60% yield) as a off-white powder after crystallisation in hexane/DCM.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][S:30]([C:28]2[S:29][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[CH:26][CH:27]=2)(=[O:31])=[O:32])[CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: NCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Product: O=S(=O)(NCCN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 12 h
Yield: 7.6 %

Procedure:
To a solution of 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.213 g) [in CH2Cl2 (10 ml)] was added a solution of the product of Example 4, Step (b) (0.210 g) [in CH2Cl2 (5 ml) and pyridine (0.066 ml)]. The reaction was left to stir for 12 hrs. The reaction mixture was washed with saturated aqueous NaCl solution and the organics separated and dried and then filtered. The solvents were evaporated and the product purified by using reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} give the title compound as a solid (0.03 g).