Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO.O>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=[N:24][OH:25])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCn1c(=O)c(C=NO)c(OC)c2cc(C)ccc21

Procedure:
A solution of 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 1 g), hydroxylamine hydrochloride (0.3 g) and sodium acetate (0.3 g) in methanol (20 ml) was stirred for 3hrs. The mixture was then diluted with water and extracted with methylene chloride. The extracts were dried, evaporated and the resulting solid was crystallized from ether-hexane to give 1-hexyl-3-oximinomethyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 316 (M.+); NMR (CDCl3): δ3.98 (s, 3H, OCH3), 8.54 (s, 1H, CH=N).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@@:10]3([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:25]1([CH2:28][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@:10]3([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:27][CH2:26]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 3,14-dimethoxy-8α-methylmorphinan-6-one hydrochloride (26) (0.83 g, 2.36 mmol), cyclopropylmethyl bromide (0.51 g 3.78 mmol), anhydrous sodium carbonate (1.6 g, 15.09 mmol) and ethanol (20 ml) was refluxed at oil bath temperature of 110° C. for 18 hours with stirring under a nitrogen atmosphere. The resulting product was filtered and the residue washed with ethanol (3×35 ml). The filtrate was concentrated under reduced pressure give 0.689 g of a solid product which was purified by chromatography on silica gel using graded methanol/chloroform mixtures to provide 0.362 g (41.5% theory) of 17-cyclopropylmethyl-3,14-dimethoxy-8α-methylmorphinan-6-one (30) as a tan foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B.O1CCCC1>CO.O1CCCC1>[NH2:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(OCCO)c(N)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(NCc2ccccc2)ccc1OCCO
Reaction time: 7 h

Procedure:
2.66 g (10 mmol) of 2-(2,4-diaminophenoxy)ethanol and 1.06 g (10 mmol) of benzaldehyde were dissolved in methanol (dried over molecular sieve). After addition of 10 mg of molecular sieve, the reaction mixture was allowed to agitate 7 hours. Then, 20 mL of a solution of borane-tetrahydrofuran com-plex (1 M in tetrahydrofuran) was added at 0° C., and the reaction mixture was allowed to agitate one hour at room temperature. At the end of the reaction, the reaction mixture was filtered and hydrolyzed. The precipitate was filtered off, washed with water and then dried.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][C:25]3([CH3:30])[CH3:29])=[CH:8][C:6]=2[N:7]=1
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC1(C)CN(S(C)(=O)=O)CCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-3,3-dimethyl-piperazine using procedure C yielded 2-chloro-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [Na].[F:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[CH:23](I)([CH3:25])[CH3:24].[OH-].[Na+]>CN(C=O)C>[F:2][C:3]1[CH:19]=[CH:18][C:6]([N:7]([CH:23]([CH3:25])[CH3:24])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: CC(C)I
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
4′-Fluoro-2′-nitro-p-toluenesulfonanilide sodium salt (66.46 g (200 mmol)) was dissolved in DMF (66 ml). To this, under heating in an oil bath kept at 120° C., isopropyl iodide (102.0 g (600 mmol)) was added over a period of 20 minutes. The resulting mixture was left to cool to room temperature, mixed with 1% aqueous sodium hydroxide solution and stirred. The resulting crystals were filtered, washed with water and ethanol, successively. The crude crystals thus obtained were recrystallized from ethyl acetate to give 30.58 g (43%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[C@@H:18]12[CH2:24][C@@H:21]([CH:22]=[CH:23]1)[CH2:20][C@H:19]2[CH2:25][C:26](O)=[O:27]>>[C@@H:18]12[CH2:24][C@@H:21]([CH:22]=[CH:23]1)[CH2:20][C@H:19]2[CH2:25][C:26]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17])=[O:27]
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Reactant: Nn1nc(-c2cccs2)c2ccccc2c1=O
Product: O=C(C[C@@H]1C[C@@H]2C=C[C@H]1C2)Nn1nc(-c2cccs2)c2ccccc2c1=O

Procedure:
The product from Example 10B and 2-((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.41 (dd, J=7.8, 1.4 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.92-8.10 (m, 2H), 7.80 (dd, J=5.1, 1.1 Hz, 1H), 7.65 (dd, J=3.6, 1.1 Hz, 1H), 7.29 (dd, J=5.1, 3.6 Hz, 1H), 6.23 (dd, J=5.7, 3.0 Hz, 1H), 6.07 (dd, J=5.7, 2.8 Hz, 1H), 2.89-2.92 (m, 1H), 2.77-2.81 (m, 1H), 2.42-2.50 (m, 1H), 2.10 (dd, J=14.3, 7.9 Hz, 1H), 2.08 (dd, J=14.1, 8.0 Hz, 1H), 1.91 (ddd, J=11.5, 9.0, 3.8 Hz, 1H), 1.34-1.37 (m, 1H), 1.27 (d, J=8.1 Hz, 1H), 0.61 (ddd, J=11.5, 4.3, 2.5 Hz, 1H); MS (APCI) M/Z 392 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][C:29]2([C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:32]2)[CH2:28][CH2:27]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:26]1[CH2:27][CH2:28][C:29]2([C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:32]2)[CH2:30][CH2:31]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)CN(C(=O)OC(C)(C)C)c3ccccc34)cnc12
Yield: 79.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.363 g, 1.07 mmol) obtained in Example 21, step 4 and tert-butyl spiro[indoline-3,4′-piperidine]-1-carboxylate (0.370 g, 1.28 mmmol) obtained in Reference Example 8, the title compound (0.518 g, 79%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:16]([Cl:19])([Cl:18])=[CH2:17].Cl>C(Cl)Cl>[Cl:18][C:16]([Cl:19])=[CH:17][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2Cl2 (5 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (0.64 g, 4.76 mmol) in CH2Cl2 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.88 g, 68% ) as a light yellow oil: 1H-NMR (CDCl3, 300 MHz) δ8.38, d, J=8.4, 1H). 7.40 (d, J=8.4, 1H), 7.10 (s, 1H); Rf=0.5 (4:1 Hex:EtOAc).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-hydroxy-3-trifluoromethylphenyl)ethanone (2.01 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (2.70 g) and chloromethyl methyl ether (1.10 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.33 g) as a pale yellow oily substance.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)#[N:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN(C)C=O>O>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: CCCCC(C#N)(CCCCCBr)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C#N)(CCCCCn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 47.8 %

Procedure:
A mixture of 6-cyano-6-(2,4-dichlorophenyl)decyl bromide (14.2g., 0.036 mole) imidazole (10g., 0.15 mole) and 5 ml. N,N-dimethylformamide is heated at 120° C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are dried over magnesium sulfate and filtered. Into the ethereal solution is bubbled dry hydrogen chloride gas until no more oily precipitate forms. The solvent is then decanted and the oily residue is taken up in acetone and neutralized with dilute ammonium hydroxide solution. The purified free base is extracted into ether and dried over magnesium sulfate. When the solvent is evaporated, a total of 6.5 g. (47.8%) of product is obtained, which is identified by nmr.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]([Sn](CCCC)(CCCC)CCCC)=[CH2:10]>C1(C)C=CC=CC=1>[CH:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)=[CH2:10]
Reactant: O=Cc1cc(Br)cs1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1csc(C=O)c1

Procedure:
A solution of 5.0 g of 4-bromothiophene-2-carbaldehyde, 11.4 ml of vinyltributyltin, and 3.6 g of tetrakistriphenylphosphine palladium in 100 ml of toluene was heated at 110° C. for 4 hours under a sealed tube condition. The organic layer was extracted with ethyl acetate and washed with water. In addition, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.4 g of 4-vinylthiophene-2-carbaldehyde as a brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([S:15]Cl)=[O:14]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][C:13](=[O:14])[S:15][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nsc(=O)o2)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxybenzamide (0.30 g, 1.10 mmol) in toluene (10 ml) was added chlorocarbonylsulfenyl chloride (0.80 ml, 9.92 mmol). The resulting reaction mixture was refluxed at 80° C. for 3 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed with twice with water, twice with 5% NaHCO3, again with water, and was dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.475 g) that was carried forward to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2nc(Br)cnc21
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (from Ark Pharm, cat# AK-23813, 1.00 g, 5.05 mmol) in tetrahydrofuran (10 mL), NaH (60% w/w dispersion form in mineral oil, 283 mg, 7.07 mmol) was added at 0° C. After 0.5 hour, benzenesulfonyl chloride (644 μL, 5.05 mmol) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (1.50 g, 88%). LCMS calculated for C12H9BrN3O2S (M+H)+: m/z=339.2. Found: 339.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11]
Reactant: C=CC(=O)OC
Reactant: Cc1c[nH]c2c(Br)cc(F)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/c1cc(F)cc2c(C)c[nH]c12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of 7-Bromo-5-fluoro-3-methyl-1H-indole, [which was prepared analogous to I-30, according to the method of Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (870 mg, 3.8 mmol) and methyl acrylate (819 mg, 9.5 mmol) in triethylamine (4 ml), palladium(II) acetate (112 mg, 0.5 mmol) and tri-o-tolylphosphine (428 mg, 1.42 mmol) was added under argon at rt The reaction mixture was stirred at 100° C. for 3 hrs in a sealed pressure tube and then cooled to rt The reaction mixture was diluted with CH2Cl2 (70 ml), washed with water (3×40 ml), brine, and dried over sodium sulfate. After removal of solvent, the residue purified by column chromatography on silica gel with methanol/dichloromethane as an eluent to give 690 mg of compound I-33 as a solid. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:15][CH:16]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)N1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 65 °C

Procedure:
Isopropylpiperazine (2.3 g, 17.94 mmol), 2-chloro-5-chloromethylpyridine (3.2 g, 19.73 mmol) and K2CO3 (26.91 g, 3.713 mmol) were mixed in EtOH (50 mL) a strongly exothermic reaction. The reaction was heated further for 12 hours at 65° C. The reaction mixture was filtered and evaporated. The crude product was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:29]([F:31])([F:32])[F:30])[CH:11]=3)=[O:22])=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: C#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cc2cn[nH]c2c(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 530 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-5-ethynyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of N,N-dimethylformamide, is added 465 mg (3.48 mmol) of bicyclopropyl-1-ylamine hydrochloride and 485 μL (3.48 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 3:7) affords 200 mg (31% over two steps) of the product as white solid; LC/MS:554/556 (M+H)+, m.p.: 246-248° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:20](Cl)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1.Cl>COCCOCCOC>[Cl:11][C:12]1[C:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)c1cc(Oc2ccc(Cl)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 10 °C

Procedure:
To 30 ml of dry diglyme under a nitrogen atmosphere was added 0.960 g (0.02 mol) of sodium hydride dispersion in mineral oil (50%). The solution was cooled to 10° C. and 1.28 g (0.01M) 4-chlorophenol in 15 ml of dry diglyme was added dropwise while maintaining the temperature at 10° C. This was followed by the dropwise addition of 2.36 g (0.01 mol) of 4,5-dichloro-2-nitrobenzoic acid in 15 ml of dry diglyme. The reaction mixture was then heated to 153° C. (oil bath) for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature and poured into an ice/water mixture. The pH was then adjusted to 1.5 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, and the organic layer dried over anhydrous magnesium sulfate. The solvent was removed and the crude solid triturated with hexane, followed by recrystallization from carbon tetrachloride to give the title compound: yield 1.65 g (50%) m.p. 160°-162° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:3]=1.Cl[C:15]1[CH:20]=CC(C#C)=CN=1>>[C:15]([C:2]1[N:6]([CH3:7])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:3]=1)#[CH:20]
Reactant: Cn1c(Br)cnc1N1CCOCC1
Reactant: C#Cc1ccc(Cl)nc1
Product: C#Cc1cnc(N2CCOCC2)n1C

Procedure:
4-(5-Ethynyl-1-methyl-1H-imidazol-2-yl)-morpholine was prepared from 4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccc(C)c(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1
Yield: 64.2 %

Procedure:
As described for Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is reacted with 0.303 g (1.8 mmol) of 2,5-dimethylbenzoyl chloride in 10 ml of dichloromethane. The product is recrystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 213°-216° C. Anal. Calc'd for C30H26N2O2 : C,80.7; H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][Si:18]([C:21]#[C:22][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8])([CH3:20])[CH3:19]
Reactant: N#Cc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cncc(C#N)c1
Temperature: 25 °C
Yield: 109.3 %

Procedure:
Combine 5-bromonicotinonitrile (10.0 g, 53.0 mmol), bis(triphenylphosphine)palladium (II) dichloride (1.86 g, 2.65 mmol), copper (I) iodide (1.04 g, 5.46 mmol) and triethylamine (50 mL, 359 mmol) in a sealed tube under nitrogen and treat with (trimethylsilyl)acetylene (8.00 mL, 56.75 mmol). Stir the resultant black reaction mixture at 70° C. for 1.7 h and cool to room temperature. Dilute the reaction mixture with ethyl acetate and wash with a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Dissolve the residue in dichloromethane and filter through a pad of diatomaceous earth/silica gel. Wash with 80:20 dichloromethane:ethyl acetate. Concentrate the filtrate to give 11.6 g of the title compound as a brownish-tan solid. This material contains minor impurities, which do not have an adverse effect on subsequent chemistry (see PREPARATION 4). The crude material is purified by silica gel chromatography, eluting with 95:5 to 85:15 hexanes:ethyl acetate to give the title compound.