Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CN(C)[CH:6]=[CH:7][C:8]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1)=O.C(=O)(O)O.[C:21]1([NH:27][C:28]([NH2:30])=[NH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C>[NH:27]([C:28]1[N:30]=[C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CN(C)C=CC(=O)c1cncn1C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: Cn1cncc1-c1ccnc(Nc2ccccc2)n1
Yield: 64 %

Procedure:
Sodium methoxide (2.63 g, 48.7 mmol) was added to a solution of 5-(3-dimethylaminoprop-2-en-1-oyl)-1-methylimidazole Method 4; 2.91 g, 16.2 mmol) and phenylguanidine hydrogen carbonate (3.52 g, 17.9 mmol) in 2-propanol (14 ml) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was allowed to cool and partitioned between EtOAc and saturated aqueous sodium, hydrogen carbonate solution. The organic phase was separated, dried and the solvent removed by evaporation. The residue was purified by column chromatography eluting with DCM and 7M methanolic ammonia solution (97:3) to give the title compound 2.57 g, (64%) as a solid. M/z: 252.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[O:20])[C:8](=[CH:21]O)[CH:7]1[CH3:23])=[O:5])[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([NH:24][CH:21]=[C:8]2[C:9](=[O:20])[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]2[CH3:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNc2ccccc2)C1C

Procedure:
Starting with 3.2 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid ethyl ester and 1.0 g. of aniline in 30 ml. of benzene and employing the reaction procedures of Example 5 provides 3.2 g. of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8](C2C=CC(Cl)=C(Cl)C=2)[N:7]=1)=[O:5].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][N:3]([CH3:21])[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([C:24]2[CH:25]=[C:26]([S:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=2[CH3:22])[N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1nc(-c2ccc(Cl)c(Cl)c2)cnc1N
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1B(O)O
Product: CON(C)C(=O)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N

Procedure:
This compound is prepared in an analogous manner to intermediate B substituting 3,4 dichlorophenyl boronic acid with 2-methyl-5-(N-morpholinylsulfonyl) phenyl boronic acid in step 2. The title compound is obtained as an off-white solid. [M+H]+ 422.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>C(O)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[CH:6][C:7]2[NH:10][C:11]3[C:12]([C:8]=2[CH:9]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:17]
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]c3ccccc3c2c1
Yield: 123.9 %

Procedure:
A mixture of dicylcohexylphosphino-2′,3′-dimethoxy biphenyl (17 mg, 0.04 mmol), palladium(II) acetate (5 mg, 0.02 mmol) in toluene (20 mL) was degassed with argon gas for 15 min. To the resulting mixture was added aniline (136 mg, 1.4 mmol), K3PO4 (636 mg, 3.0 mmol), and 4-bromobenzoic acid methyl ester (300 mg, 1.4 mmol) and stirring was continued at reflux temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 15% ethyl acetate in hexane as eluent) to afford 200 mg (63.4% Yield) of 4-phenylamino-benzoic acid methyl ester. A stirred solution of 4-phenylamino-benzoic acid methyl ester (98 mg, 0.43 mmol), Palladium acetate (193 mg, 0.86 mmol) in acetic acid (2 mL) was heated at 110° C. for 15 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 10% ethyl acetate in hexane as eluent) to afford 120 mg (60.3% Yield) of 9H-carbazole-3-carboxylic acid methyl ester. LiOH.H2O (680 mg, 16.2 mmol) was added to a stirred solution of 9H-carbazole-3-carboxylic acid methyl ester (120 mg, 0.53 mmol) in the mixture of methanol (1 mL), THF (3 mL) and H2O (1 mL). The reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was concentrated. The residue was diluted with water, acidified with aqueous 10% aqueous HCl solution, filtered the solid to afford 104 mg (92.85% Yields) of 9H-carbazole-3-carboxylic acid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:31](OC(C)(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])[CH:17]=[CH:31][N:32]([CH3:34])[CH3:33])=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Temperature: 80 °C
Yield: 69 %

Procedure:
To 1-[7-(cyclopentylamino)-2-(4fluorophenyl)pyrazolo[1,5- c]pyrimidin-3-yl]ethanone (200 mg, 0.59 mmol) was added 1,1 -di-tert-butoxy-N,N-dimethylmethanamine (4 mL) and the mixture heated to 80° C. for 30 minutes. The reaction was let cool to room temperature and was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water and brine. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica chromatography eluting with ethyl acetate to yield 160 mg (69%) of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one. 1H NMR (CDCl3): δ 7.77 (m, 4H), 7.44 (d, 1H), 7.19 (t, 2H), 6.41 (d, 1H), 5.09 (d, 1H), 4.57 (m,1H), 3.07 (m, 3H), 2.60 (m, 3H), 2.25 (m, 2H), 1.85 (m, 6H). MS m/z 394 (M+1).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](O)[CH2:17][OH:18].[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>CC(C)=O>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH:10]1([N:9]2[CH2:16][CH2:17][O:18][C:8]2=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCCO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Product: C1CCC(N=C2OCCN2C2CCCCC2)CC1
Yield: 102.9 %

Procedure:
A mixture of 41.2 g of dicyclohexylcarbodiimide and 7 g of ethylene glycol was heated on a water bath for 2 hours. After removing the precipitate of dicyclohexyl urea formed, the resulting oily product was dissolved in acetone and to the acetone solution was added an acetone solution containing 9 g of oxalic acid to obtain 35 g of Compound (1) with a melting point of 130° - 133°C.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:22]1([N:28]2[C:32]([SH:33])=[N:31][N:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:22]1([N:28]2[C:32]([S:33][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[C:10]([O:17][CH3:18])[C:11]=4[CH2:15][CH3:16])[S:4]3(=[O:6])=[O:5])=[N:31][N:30]=[N:29]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCc1c(OC)cc(OC)c2c1C(=O)N(CCl)S2(=O)=O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OC)cc(OC)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 74 %

Procedure:
A solution of 2-chloromethyl-4-ethyl-5,7-dimethoxysaccharin (Example 22L, 0.4 g) and 1-phenyltetrazol-5-thiol sodium salt (0.28 g) in dimethylformamide (3 mL) was heated at 110° C. for two hours, then poured into water. Recrystallization of the resulting solid from ethanol-water afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxysaccharin, 0.44 g, 74% yield, mp 162°-164° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:7]([CH:14]3[CH2:16][CH2:15]3)[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:24](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:25]>>[CH:14]1([C:7]2[C:8]([CH3:13])([CH3:12])[O:9][C:10]3[C:5]([C:6]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:4][CH:3]=[C:2]([NH:25][C:24](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:11]=3)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C1CC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C1CC1)=C2c1ccc(F)cc1

Procedure:
The compound obtained in (1) described above (112 mg) and tert-butyl carbamate (240 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (117 mg) as a pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCNCC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCNCC4)cc3)cc2)cc1)c1ccc(N2CCNCC2)cc1

Procedure:
Compound 317 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-piperazinobenzoate. [M+H]+ calcd for C35H37N6O3: 589.29; found: 589.07.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][OH:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCOCc1cccnc1

Procedure:
1-tert-Butoxycarbonyl-2(S)-(2-hydroxyethyl)-4-(1-naphthoyl)piperazine (0.300 g, 0.780 mmol) was reacted with sodium hydride (0.312 g, 60% dispersion in oil, 7.8 mmol) and 3-chloromethylpyridine (0.497 g, 3.9 mmol) according to the procedure described in Example 7, Step C. The crude product was chromatographed on silica gel with 3% methanol in chloroform. The title compound was obtained as an oil, (0.180 g).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.8 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 3-methyl-4-[(4-phenylphenyl)methyl]piperazine-1-carboxylate (600 mg, 1.64 mmol, 1.00 equiv), dichloromethane (25 mL). Trifluoroacetic acid (1 mL) was added dropwise. The resulting solution was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure to yield 532 mg (crude) of 2-methyl-1-[(4-phenylphenyl)methyl]piperazine as brown oil. LCMS (ESI, m/z): 267 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:13](N)[CH2:14][NH2:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:10]2[NH:15][CH2:14][CH2:13][N:11]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)C#N)c1
Reactant: NCCN
Product: COc1cccc(C(C)C2=NCCN2)c1

Procedure:
rac-2-[1-(3-Methoxy-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-methoxyphenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): yellow oil; MS (ISP): 205.3 ((M+H)+.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH:9]=O)([O-:3])=[O:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])([O-:3])=[O:2]
Reactant: O=CC=Cc1cccc([N+](=O)[O-])c1
Reactant: NNC(N)=S
Product: NC(=S)NN=CC=Cc1cccc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
The compound is prepared according to the method described in Example 1A from 3-nitrocinnamaldehyde (2.2 mmol) (Org. Lett. 5(5), 777-780, 2003) and from thiosemicarbazide (2.2 mmol). Yield 88%.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[C:7]1[C:16]2[O+]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1.[NH4+:29]>O>[C:17]1([C:14]2[CH:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]3[CH2:10][CH2:9][CH2:8][C:7](=[O:6])[C:16]=3[N:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH4+]
Reactant: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)[o+]c21
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)nc21

Procedure:
12.44 g of 5,6,7,8-tetrahydro-8-oxo-2,4-diphenyl-1-benzopyryliumtetrafluoroborate (32 mmol) is suspended in 80 ml of distilled water and a solution of 25 g of ammonium carbaminate (320 mmol) in 200 ml of distilled water is added with stirring. After stirring at room temperature for 24 h, the solution is extracted by suction via a nutsche, washed with distilled water and dried by suction. The cream-coloured powder is washed in portions with diethyl ether and dried at 50° C. in a vacuum drying cabinet to constant weight: 8.39 g of ivory-coloured product (87.5%) with a melting point of 177-178° C. (decomposition). IR (ATR): The CO valence vibration band can be seen at 1700 cm−1. 1H-NMR (500 MHz, CDCl3): δ=8.09 (d, 2H, o-H of 2-phenyl), 7.79 (s, 1H, H3), 7.56-7.33 (m, 8H, arom. H), 2.92 (t, 2H, J=5.75 Hz), 2.83 (t, 2H, J =6.56 Hz), 2.10 (p, 2H, J=5.75 Hz, J=6.56 Hz).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:25]4[CH:26]=[C:21]([N:19]([CH3:20])[CH3:18])[CH:22]=[CH:23][CH:24]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1cccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)c1
Temperature: 140 °C
Yield: 10.2 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.13 g, 0.36 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol), 3-(N,N-dimethylamino)phenylboronic acid (68 mg, 0.41 mmol), cesium carbonate (235 mg, 0.72 mmol, 2.0 eq), and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8). The obtained residue was crystallized from methanol:1,2-dichloroethane (1:1, 1.5 mL) and filtered to give {3-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-dimethyl-amine as a white solid (13 mg, 10% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:22]
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (200 mg, 0.77 mmol) and 3-methylsulphonylaniline hydrochloride (80 mg, 0.39 mmol, Acros) afforded a crude reaction product mixture, which was partitioned between EtOAc (100 mL) and 1 N NaOH (50 mL). The organic layer was washed with 1 N NaOH (50 mL), water (50 mL), satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (9:1 CH2Cl2/EtOAc) provided the title product as a white solid. MS (ESI, pos. ion) m/z: 394 (M+1). MP: 204–205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH:20]([CH3:22])[CH2:21][C:15]=3[N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH:20]([CH3:22])[CH2:21][C:15]=3[N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)COC(C)C3)c(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(-c2nc3c([nH]2)COC(C)C3)cc1C(=O)O
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate (compound 464.7, 100 mg, 0.330 mmol, 1.00 equiv) in methanol (10 mL). A solution of lithium hydroxide (76 mg, 3.17 mmol, 10.0 equiv) in water (10 mL) was added and the resulting solution was stiffed for 4 h at room temperature. The mixture was concentrated in vacuo and then aqueous HCl was added until the pH was 5-6. The mixture was adjusted to pH 5-6 with aqueous HCl and then the resulting mixture was concentrated in vacuo. MeOH (5 mL) was added to the residue and the solids were removed by filtration. The filtrate was concentrated in vacuo to obtain the title compound as a yellow solid (60 mg, 63%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:19][CH2:13][C:12]([C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][O:9][C:10]=1[C:15]([F:17])([F:18])[F:16])=[O:14]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccccc2)noc1C(F)(F)F
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1c(-c2ccccc2)noc1C(F)(F)F
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of 1-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-ethanone (2.88 g, 11 mmol) in chloroform (11 mL) and AcOH (0.6 mL) at 48° C. was added a solution of bromine (0.61 mL, 12 mmol) in chloroform (3.5 mL) over 5 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 4:1) afforded the title compound (2.2 g, 59%) which was obtained as a light yellow oil. MS: m/e=334.3/336.4 [M+H]+.
Reaction SMILES: [CH2:1](N(C/C=C/C#CC(C)(C)C)CCNCCOC1C=CC=C(C2C=CSC=2)C=1)C.C(=O)C.[CH2:33]([N:35]([CH2:53]/[CH:54]=[CH:55]/[C:56]#[C:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:36][CH2:37][NH:38][CH2:39]/[CH:40]=[CH:41]/[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]2[CH:52]=[CH:51][S:50][CH:49]=2)[CH:43]=1)[CH3:34].C=O>>[CH2:33]([N:35]([CH2:53]/[CH:54]=[CH:55]/[C:56]#[C:57][C:58]([CH3:60])([CH3:59])[CH3:61])[CH2:36][CH2:37][N:38]([CH3:1])[CH2:39]/[CH:40]=[CH:41]/[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]2[CH:52]=[CH:51][S:50][CH:49]=2)[CH:43]=1)[CH3:34]
Reactant: CCN(C/C=C/C#CC(C)(C)C)CCNCCOc1cccc(-c2ccsc2)c1
Reactant: CCN(C/C=C/C#CC(C)(C)C)CCNC/C=C/c1cccc(-c2ccsc2)c1
Agent: C=O
Agent: CC=O
Product: CCN(C/C=C/C#CC(C)(C)C)CCN(C)C/C=C/c1cccc(-c2ccsc2)c1

Procedure:
Compounds of Examples 81 and 82 were obtained by performing the same reaction as in Example 80 except that (E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[2-[3-(3-thienyl)phenoxy]ethyl]ethylenediamine or acetaldehyde was used instead of the starting compound, (E, E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]ethylenedi-amine or formalin, which was used in the above-mentioned reaction.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[CH2:28][CH2:27]1)=[O:25])=O)(C)(C)C.Cl>C(O)C>[Cl:23][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH:9]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=4[CH3:39])[CH2:28][CH2:27]3)=[O:25])[CH2:10]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)CCN3C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)CCN3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-chloro-benzenesulfonyl)-2-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (2.18 g) in ethanol (21.8 mL) was added a saturated solution of HCl in ethanol (21.8 mL) at 0° C. The reaction mixture was stirred at ambient temperature overnight, the solution was concentrated and the residue dissolved in a mixture of NaHCO3 solution and ethyl acetate. The inorganic phase was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to yield [4-(3-chloro-benzenesulfonyl)-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone as crude product (1.79 g), MS: 477.0 ([M+H, 1Cl]+).