Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[CH2:8]2.N1CCCC1.O.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[CH:8]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc2c1CCC(=O)C2
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Yield: 43.8 %

Procedure:
28 g (0.16 mol) of 5-methoxy-2-tetralone and 12.5 g (14.5 ml, 0.175 mol) of pyrrolidine were dissolved in 150 ml of toluene. The mixture was boiled on a water separator for 2 hours, cooled, treated with 31.7 g (0.19 mol) of ethyl bromoacetate and boiled under reflux for 2 hours. The mixture was then concentrated, dissolved in 150 ml of ethanol/water (5:1) and again boiled under reflux for 2 hours. The solvent was distilled off in a vacuum and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution, dried with MgSO4, filtered and concentrated. The residue was dissolved in ether, treated with active charcoal and recrystallized. There were obtained 18.4 g of ethyl rac-1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-napthylacetate as white crystals. A further 10.3 g of white crystals could be obtained from the mother liquors by chromatography over silica gel with cyclohexane/ethyl acetate (4:1). Total yield: 28.7 g (68%) of white crystals with m.p. 36°-40°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:44]([O:46][C:47](=[O:66])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=1)[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:44]([O:46][C:47](=[O:66])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([C:9]2[C:10]([F:12])=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[CH:7]=[N:6][CH:5]=[CH:4]3)[CH:50]=1)[CH3:45]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Oc1c(F)cc(F)c2ccncc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(-c2c(F)cc(F)c3ccncc23)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled suspension of 5,7-difluoro-isoquinolin-8-ol (200 mg, 1.10 mmol, 1.00 eq.) in DCM (10 mL), NEt3 (0.46 mL, 3.31 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (0.29 mL, 1.66 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (20 mL) and washed with sat. aq. NaHCO3 soln. (2×10 mL). The org. layer was dried over MgSO4 and concentrated in vacuo. To a mixture under N2 of the resulting triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (354 mg, 1.10 mmol, 1.00 eq.), and sodium carbonate (468 mg, 4.42 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (10 mL), tetrakis(triphenylphosphine) palladium (0) (64 mg, 0.06 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])[O:6][CH2:7][CH3:8])#[N:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[C:1]#[N:2])=[O:19]
Reactant: CCOC(=N)c1ccccc1C#N
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccccc1C#N

Procedure:
starting from ethyl o-cyanobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-o-cyanobenzimidate and therefrom with methylhydrazine there is obtained 3-(o-cyanophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 96.5°-99° C.
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:5]([OH:7])=O.OC(C(F)(F)F)=O.[NH2:31][CH:32]([CH2:46][CH3:47])[CH:33]([C:35]1[O:36][C:37]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[N:38][N:39]=1)[OH:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[OH:34][CH:33]([C:35]1[O:36][C:37]([C:40]2[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=2)=[N:38][N:39]=1)[CH:32]([NH:31][C:5](=[O:7])[CH:4]([CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH2:3][C:2](=[O:1])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:46][CH3:47]
Reactant: CCC(N)C(O)c1nnc(-c2ccncc2)o1
Reactant: O=C(O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(=O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(-c2ccncc2)o1
Reaction time: 14 h
Yield: 126 %

Procedure:
To a stirred mixture of 4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (102 mg, 0.3 mmol), 2-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol TFA salt (105 mg), prepared as in reference 18, and HOBt (55 mg, 0.36 mmol) in MeCl2 (5 ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine (0.25 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 210 mg of N-{1-[Hydroxy-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide. MS: 554.2(M−1), 555.8(M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(C(C)C)cc1Br
Product: COc1ccc(C(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 83.6 %

Procedure:
With 20.0 g of the compound obtained in Step 230-1 and 10.6 g of 5-chloroisatin as starting materials, 16.2 g of the title compound (pale yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)CCC(=O)c1c(C)[nH]c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCc1c(C)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of methyl 4-(2-methylindol-3-yl)-4-oxobutyrate (2.0 g) in tetrahydrofuran (50 ml) was added a 1M solution of boran in tetrahydrofuran (16.5 ml) at 0° C. After stirred at 0° C. for 30 minutes, the mixture was poured into a mixture of ethyl acetate and brine. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was purified by column chromatography on silica gel (50 g) eluting with chloroform to give methyl 4-(2-methylindol-3-yl)butyrate (1.67 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1.Cl.[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46]Cl)[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH2:46][CH2:45][N:42]3[CH2:43][CH2:44][O:39][CH2:40][CH2:41]3)[C:18]3[C:23]([C:24]=2[CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2Cl)CC1
Agent: Cl
Product: O=C(c1c(C(c2ccccc2)c2ccccc2)c2ccccc2n1CCN1CCOCC1)N1CCN(c2ccccc2Cl)CC1
Yield: 74.2 %

Procedure:
Substantially the same procedure as in Example 89 was repeated using Compound 88 (1.0 g, 1.98 mmol) obtained in Example 88 and 2-morpholinoethylchloride hydrochloride (385 mg, 2.07 mmol) to give 0.91 g (yield: 74%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:9][C:8]([C:7]1[CH:6]=[C:5]([C:11]([O:13][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])[CH:4]=[C:3]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:2]=1[O:1][CH2:14][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(C(=O)O)c(O)c(C(=O)O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Compound 13 (22.6 g, 0.1 mol), benzyl chloride (57 g, 0.46 mol) and anhydrous potassium carbonate (120 g, 0.87 mol) were mixed in dry DMF (500 mL). The mixture was heated at 75° C. while stirring under nitrogen overnight. TLC confirmed that the reaction was complete. The reaction mixture was cooled, filtered, and the filtrate was evaporated to remove the volatiles. The residue was dissolved in 1 L of recycling [?] methylene chloride and a silica gel plug was used to remove some impurities with low Rf. The fully benzyl-protected product was obtained as a thick, yellow oil after removing the solvent: raw yield 53 g (90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)[C:5]([F:17])=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:7]=[C:2]([NH:1][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)N1CCN(c2nc(N)ccc2F)CC1
Product: CCOC(=O)C(=CNc1ccc(F)c(N2CCN(C(C)=O)CC2)n1)C(=O)OCC
Yield: 86.7 %

Procedure:
A mixture of 6-amino-2-(4-acetyl-1-piperazinyl)-3-fluoropyridine (23.9 g) and diethyl ethoxymethylenemalonate (22.7 g) is heated for 5 hours with stirring. After cooling, the precipitate is collected by filtration, and recrystallized from ethanol to give 35.5 g of diethyl N-[6-(4-acetyl-1-piperazinyl)-5-fluoro-2-pyridyl)aminomethylenemalonate (m.p. 164°-165° C.).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[C:11]#[C:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1cccc(C#Cc2c(-c3ccccc3)noc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
3-(5-Methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid methyl ester (600 mg, 1.89 mmol) was treated with ethanol (12 mL) and aqueous sodium hydroxide (1 M, 7.56 mL, 7.56 mmol). The reaction mixture was heated for 1.5 h at 80° C. After concentration and dilution with water (9 mL) the pH was adjusted to 1.5 by adding hydrochloric acid (1 M, 8 mL). The resulting suspension was stirred for 30 min at 0° C. and filtered. Washing with ice-cold water (10 mL) and drying afforded the title compound (546 mg, 95%) as a light brown solid. MS: m/e=304.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13](=O)[CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6]2.[CH3:17][NH2:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]([NH:18][CH3:17])[CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6]2
Reactant: CN
Reactant: CCC(=O)C1CCCc2cc(OC)ccc21
Product: CCC(NC)C1CCCc2cc(OC)ccc21

Procedure:
Using the product of Example 105 with the procedure described in Example 98 but replacing the ethylamine with methylamine gave the desired product.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH:16]1([C:19](=N)OCC)[CH2:18][CH2:17]1.C(O)C.N>CO>[CH:16]1([C:19]2[NH:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:8][C:9]=3[N:14]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=N)C1CC1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: c1cn(Cc2ccc3[nH]c(C4CC4)nc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of 3.3 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 2.88 parts of ethyl cyclopropanecarboximidate hydrochloride and 64 parts of ethanol was stirred first for 4 hours at room temperature and further for 1 hour at reflux. The reaction mixture was cooled, treated with methanol, saturated with ammonia, and evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol (92:8 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate, yielding 2.57 parts (61.6%) of 2-cyclopropyl-5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole; mp. 184.3° C. (compound 168).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:18][OH:19])[CH2:10]2.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH:18]=[O:19])[CH2:10]2
Reactant: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@H](C=O)Cc1cccc(F)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]isoindolin-1-one (0.8 g, 2.001 mmol) in methylene chloride (10 mL, 200 mmol) at 0° C. was added Dess-Martin periodinane (1.02 g, 2.40 mmol). The reaction mixture was stirred at room temperature for 1 h, and then quenched with 1 N NaOH aqueous solution, and extracted with DCM (2×). The combined organic phases were washed with water, brine and dried over Na2SO4, filtered and concentrated under reduced pressure to give 685 mg (86% yield) of the desired product as yellowish solid. LC/MS found: 398.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=O)=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:28][N:29]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19][CH2:18][CH2:17][C:16]([C:20]([NH:41][C:40]4[CH:42]=[CH:43][C:37]([CH2:36][N:29]([CH3:28])[CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:38][CH:39]=4)=[O:22])=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
In THF (15.3 ml) was dissolved 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic acid (510 mg). To the mixture were added under ice-cooling thionyl chloride (0.11 ml) and DMF (one drop), and the mixture was stirred at room temperature for 1 hour. To a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (389 mg) and triethylamine (0.87 ml) in THF (15.3 ml) was added the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) to give 7-(4-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzothiepine-4-carboxamide (512 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:16]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[N:22]=[C:21]([NH:31][CH3:32])[N:20]=1)[CH3:17].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:29][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([NH:31][CH3:32])[N:20]=[C:19]3[O:18][CH2:16][CH3:17])[C:9](=[O:11])[N:10]=1
Reactant: O=C1CSC(NCc2ccccc2Cl)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-benzylamino)-thiazol-4-one (example 13a, 38.5. mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 45 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a brown solid: 43.2 mg (59.5%), MS: m/e 454 (MH+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1.C(N(CC)CC)C>CO>[CH3:2][N:3]([CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Reactant: CNC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)CCOc1cc(-c2ccccc2)on1
Yield: 62.9 %

Procedure:
After dimethylamine hydrochloride (815 mg) was dissolved in methanol (50 ml), 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and triethylamine (2.8 ml) were added thereto, followed by reflux of the resulting mixture for 8 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ether (20 ml), and the solution was washed with a diluted aqueous NaCl solution (20 ml), followed by drying of the organic layer over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (146 mg, 63%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[C:4]([F:18])[CH:3]=1.N1CCCCC1.[CH3:25][CH:26](C(O)=O)[C:27](O)=[O:28].C(O)(=O)C>N1C=CC=CC=1>[F:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:27](=[O:28])[C:26]([CH3:25])=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:10]1
Reactant: CC(C(=O)O)C(=O)O
Reactant: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
Under a stream of nitrogen gas, 0.295 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone), compound 3-1 was dissolved in 2.0 ml of pyridine. To this solution were added 0.113 ml of piperidine and 0.295 g of methylmalonic acid, and the mixture was heated to 70° C. and stirred for 2.5 hours. Then, 2.0 ml of acetic acid was added, and stirring was further continued at 130° C. for 7 hours. The reaction solution was left cooling to room temperature and concentrated under reduced pressure. The residue was diluted with 100 ml of diethyl ether. The diluted solution was washed twice with 20 ml of 3 N hydrochloric acid and once with 30 ml of saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 0.184 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one, compound 5-1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][NH:13][C:14]([NH:16][NH2:17])=[O:15].C(=O)(O)[O-].[Na+].C(=O)=O>CO>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][NH:13][C:14]([NH:16][NH:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[O:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NNC(=O)NN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NNC(=O)NNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 65 °C

Procedure:
190.5 g (1.0 mole) p-toluene sulfonyl chloride, 45 g (0.5 mole) carbohydrazide, 84 g (1.0 mole) sodium bicarbonate and 1000 ml methanol were placed in a 2 liter flask. The mixture was stirred and heated to reflux (65° C) for 90 minutes. Carbon dioxide evolution was complete at this point. The solid product and sodium chloride were filtered off. The material was suspended in water to dissolve the sodium chloride and the residual solid product was filtered off, washed well with water, and dried at 60° C. Yield: 139 g -- Dec. temp. 232° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[NH:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2[nH]ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.