Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C4C=NC=NC=4)[CH2:21][CH2:20]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[O:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[C:46](Cl)=[O:47].O>ClCCl>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:46]([C:42]4[O:41][CH:45]=[CH:44][CH:43]=4)=[O:47])[CH2:23][CH2:24]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2]
Reactant: O=C(Cl)c1ccco1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3cncnc3)CC1)C2=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)c3ccco3)CC1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
Compound 32 (800 mg, 1.92 mmol) obtained in Example 32 was suspended in dichloromethane (15 mL), and the mixture was stirred at room temperature for 4 hours after adding N,N-diisopropylethylamine (1.16 mL, 6.71 mmol) and 2-furoyl chloride (226 μL, 2.30 mmol). Thereafter, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography, and crystallized from diethyl ether to give the title compound (Compound 35) (601 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20](C(C(F)(F)F)=O)[C:21]([C:23]([F:26])([F:25])[F:24])=O.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:20])[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH2Cl2 (100 mL) was added dropwise (CF3CO)2O (10.5 mL, 75.54 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h. 2N HCl (60 mL) was then added. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (MH+-Boc) 183.1, (MH+-C4H9) 227.1; NMR (300 MHz, CDCl3): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).
Reaction SMILES: [Na].[N+:2]([CH:5]([CH3:7])[CH3:6])([O-:4])=[O:3].[CH:8]1[CH:9]=[CH:10][C:11]([CH:16]=[O:17])=[C:12]([CH:14]=[O:15])[CH:13]=1.OS(O)(=O)=O.[CH3:23]O>O>[CH3:23][O:15][CH:14]1[C:12]2[C:11](=[CH:10][CH:9]=[CH:8][CH:13]=2)[CH:16]([C:5]([CH3:7])([N+:2]([O-:4])=[O:3])[CH3:6])[O:17]1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CO
Reactant: O=Cc1ccccc1C=O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: COC1OC(C(C)(C)[N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium metal (12.4 g, 0.539 g atm) is added to MeOH, (1 L) at 10° C. over 90 min. When a clear solution is obtained the cold water bath is removed and 2-nitropropane (256 mL, 2.85 mol) is added, followed by orthophthalaldehyde (120 g, 0.895 mol). The resulting solution is stirred at rt overnight. The solution is acidified by adding 1 N H2SO4 to pH 2. White solids precipitate. The mixture is filtered, and the filter cake is washed with MeOH and discarded. The filtrate is stirred at rt for 3 h and then made basic by adding 3 N NaOH. The solution is then concentrated in vacuo to remove the MeOH. The resulting aqueous solution is extracted twice with Et2O. The combined organic layers are washed once with water, dried (MgSO4) and concentrated in vacuo. Kugelrohr distillation of remaining solvent at 50° C. (oil pump vacuum) leaves 195 g (106% of theoretical, 86% pure by GC) of a brown liquid, which is used as such in the next step. The ratio of diastereoisomers is 1:1 (1H NMR). A portion of the crude material can be purified by flash chromatography over silica gel (9:1 cyclohexane/EtOAc) to give pure 71 as a pale yellow oil. 1H NMR(CDCl3) 7.42-7.36(m, 3), 7.17-7.12(m, 1), 6.25 and 5.88(isomer I, d and dd, 1 total, J=2.4, 0.6, respectively), 6.01 and 5.72 (isomer II, s and d, 1 total, J=0.6), 3.58 and 3.37 (isomers I and II, respectively, 2s, 3 total), 1.57 and 1.56 and 1.55 and 1.48 (4s, 6 total); 13C NMR (CDCl3) 138.77, 138.51, 137.57, 129.82, 129.67, 129.21, 129.13, 123.41, 122.09, 107.32, 107.01, 90.52, 86.77, 56.14, 54.03, 22.51, 22.14, 21.73, 20.96; IR (neat) 1543, 1464, 1398, 1373, 1348, 1113, 1094, 1026, 974, 756;MS, m/z 206 [(M+H)+, base peak], 190, 149; Anal. Calcd for C12H15NO2 : C,60.75; H,6.37; N,5.90. Found: C,60.48; H,6.28;N,6.00.
Reaction SMILES: [CH:1]1([N:4]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[S:33][C:34]2[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=2[C:36]=1[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=2)=[CH:42][CH:41]=1)=[O:38]>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH:1]1([N:4]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:31][C:32]2[S:33][C:34]3[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=3[C:36]=2[C:37]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:56][CH:57]=3)=[CH:44][CH:45]=2)=[O:38])=[O:12])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 3.00 g of 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoic acid, 0.70 mL of oxalyl chloride, 33 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 33 mL of dichloromethane was added to a mixture of 0.70 mL of pyridine, 3.33 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 33 mL of dichloromethane, followed by stirring at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) and column chromatography (ethyl acetate) using NH silica gel in this order. The obtained solid was washed with ethanol to obtain 4.82 g of methyl 4-{2-[4-({[2-({3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][S:17][CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[Li+].[OH-].C1COCC1>CO>[CH3:18][S:17][CH2:16][CH2:15][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1cc2ccccc2c(CCSC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCc1nc(C(=O)O)cc2ccccc12
Yield: 91.7 %

Procedure:
1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid was prepared according to General Procedure B using 49 mg (0.187 mmol) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid methyl ester, 0.28 mL of 2 N aq. LiOH, 2 mL of THF and 0.5 mL of methanol stirring at room temperature for 1 h. 42.4 mg (91%) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid was obtained. LCMS: 248 (M+1)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[ClH:29].[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][C:15]3[N:16]=[C:27]([C:26]4[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:31][CH:30]=4)[O:18][N:17]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: N=C(CCCC1CCN(C2CCCC2)CC1)NO
Product: CS(=O)(=O)c1ccc(-c2nc(CCCC3CCN(C4CCCC4)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-cyclopentylpiperidin-4-yl)-N-hydroxybutyramidine and 4-methylsulfonylbenzoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 94.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-epoxypyrrolidine (yield 94.7%) was obtained and 1-benzyl-3-pyrroline was not recovered.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[C:11]([Cl:14])(Cl)Cl.[C]=[O:16].Cl>[Fe](Cl)(Cl)Cl.C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: Fc1cc(F)c(F)c(C(Cl)(Cl)Cl)c1F
Reactant: [C]=O
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O=CO
Product: O=C(Cl)c1c(F)c(F)cc(F)c1F
Temperature: 60 °C

Procedure:
268 g of 2,3,5,6-tetrafluorobenzotrichloride were placed in a 0.5 1 four necked flask. After addition of 5.4 g of iron(III) chloride, the mixture was heated to 60° C. with stirring. 46 g of formic acid were metered in over 6 hours at 60°-65° C. Vigorous gas development (carbon monoxide, hydrogen chloride) began immediately. The gas stream was fed to an absorption tower via a cooler. After addition was complete, the mixture was further stirred for two more hours at 60° C. The product was then distilled under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:12]([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C>O1CCCC1>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[CH3:12])=[CH:5][N:4]=1
Reactant: Nc1ncc(C(=O)Cl)cc1Cl
Reactant: O=C([O-])CC(=O)[O-]
Agent: CCC(C)(CC)O[Mg+2]
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N)c(Cl)c1
Yield: 84.4 %

Procedure:
7.2 g (37.5 mmol) of 5-chloro-6-aminonicotinoyl chloride in 10 ml of absolute tetrahydrofuran are added to a boiling solution of 8.55 g (37.5 mmol) of diethyl ethoxymagnesium-malonate (prepared in accordance with Org. Synth. Coll. Vol. IV (1963), 285) in 120 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. After neutralization with 2N sulphuric acid, the organic phase is separated off and evaporated. The residue is heated under reflux in a mixture of 30 ml of glacial acetic acid, 20 ml of water and 5 ml of concentrated sulphuric acid for 4 hours. The mixture is stirred into ice-water, brought to pH 4 and extracted with ethyl acetate. Drying and evaporation gives 5.4 g (85%) of the title compound, melting point: 188° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.[CH3:22][O-:23].[Na+]>CC(N(C)C)=O>[CH3:20][N:19]([CH3:21])[CH2:18][C:17]#[C:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([N:8]([C:5]2[N:6]=[N:7][C:2]([O:23][CH3:22])=[CH:3][CH:4]=2)[CH3:9])[CH2:11][CH2:12]1
Reactant: CN(C)CC#C[C@H]1CC[C@H](N(C)c2ccc(Cl)nn2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(N(C)[C@H]2CC[C@H](C#CCN(C)C)CC2)nn1
Temperature: 80 °C

Procedure:
A solution of 92.1 mg (0.3 mmol) of trans-(6-Chloro-pyridazin-3-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexyl]-methyl-amine in 0.6 ml DMA was treated with 0.56 ml (3 mmol) of sodium methylate (5.4 M in MeOH) and heated at 80° C. for 54 h. The reaction was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 97:3) yielded 67 mg (74%) of pure trans-[4-(3-Dimethylamino-prop-1-ynyl)-cyclohexyl]-(6-methoxy-pyridazin-3-yl)-methyl-amine, MS: 303 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH:6][S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[C:3]#[CH:4].C([Mg]Br)C.[CH:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>C1COCC1>[OH:29][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]#[C:3][C:2]([CH3:1])([NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:8])=[O:9])[CH3:5]
Reactant: CCCCCCCC=O
Reactant: C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Agent: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC(O)C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In 2 ml of THF was dissolved 1.185 g (5 mmole) of 3-methyl-3-tosylamino-1-butyne, and a THF solution of ethylmagnesium bromide (12 mmole) was added thereto at room temperature, followed by refluxing for 1 hour. After cooling the solution to 0° C., a solution of 1.25 ml (8 mmole) of n -octanal in 3 ml of THF was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with a hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and water, and then dried. The solvent was removed by distillation, and the residual oily substance was purified by column chromatography to obtain 1.37 g (percent yield: 75%) of 5-hydroxy-2-methyl-2-tosylamino-3-dodecyne.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[N:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=O)=O.Cl.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.C(O)(=O)C>C(O)C>[CH2:21]([N:28]1[C:11](=[O:13])[C:10]2[CH:15]=[CH:16][CH:17]=[N:18][C:9]=2[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccnc1C(=O)c1ccccn1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccnc2c(-c2ccccn2)nn1Cc1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-picolinoyl nicotinate, compound 6, (130 mg, 0.54 mmol), benzylhydrazine dihydrochloride (146 mg, 0.81 mmol), diisopropylethylamine (104 mg, 0.81 mmol), and ethanol (5 mL) was heated overnight at 75° C. To the reaction mixture was added acetic acid (46 μL, 0.81 mmol). The reaction mixture was heated at 75° C. for 2 h and then 100° C. for 2 h. After cooling the excess solvent was removed under reduced pressure. The residue was partitioned between 15 mL of ethyl acetate and 10% aqueous sodium carbonate. The aqueous fraction was further extracted with 2×15 mL of ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase flash chromatography eluting with 0-5% methanol in dichloromethane over 20 minutes. Like fractions containing product were combined and concentrated under reduced pressure to give 6-benzyl-8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one, RL-10 (44 mg, 0.13 mmol). 1H NMR (400 MHz, Chloroform-d) δ 9.11 (dd, J=4.5, 1.8 Hz, 2H), 8.89 (d, J=3.9 Hz, 2H), 8.77 (dd, J=8.1, 1.8 Hz, 1H), 7.91 (s, 2H), 7.68 (dd, J=8.1, 4.5 Hz, 1H), 7.49 (dd, J=25.2, 5.7 Hz, 3H), 7.37-7.24 (m, 5H), 5.53 (s, 2H). LCMS: (M+H)+, 316.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][N:9]=[C:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:8][N:9]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Cc1ccc2c(O)noc2n1
Reactant: CC1CCN(C(=O)Cl)CC1
Product: Cc1ccc2c(OC(=O)N3CCC(C)CC3)noc2n1

Procedure:
In analogy to example 1, 140 mg (0.93 mmol) of 6-methylisoxazolo[5,4-b]pyridin-3-ol were reacted with 181 mg (1.12 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 135 mg (53%), M+H+: 276.10.
Reaction SMILES: [C:1]([O:9][CH:10]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:27]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(C(=O)C(OC(=O)c2ccccc2)c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(-c3ccccc3)oc2-c2ccc(C)cc2)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-oxo-1,2-di(p-tolyl)ethyl benzoate is dissolved in 10 ml of dimethylformamide in a reactor. 0.22 g of thiourea (2 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 5 hours. The solution is poured onto a water/ice mixture. The precipitated product is washed with water, filtered through a sintered glass filter under vacuum and placed overnight in a desiccator before being purified on a column of silica gel with dichloromethane as elutent.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[CH2:17][CH2:18][CH2:19][C:20](=O)[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[CH3:17][C:18]12[CH2:19][CH2:20][CH2:21][N:1]1[C:2]1[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=1[C:7](=[O:8])[NH:9]2
Reactant: CC(=O)CCCCl
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CC12CCCN1c1nc(N3CCOCC3)sc1C(=O)N2
Yield: 10 %

Procedure:
A stirred solution of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.99 mmol), 5-chloro-2-pentanone (0.5 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) in DCE (4 mL) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.03 g, 10%) as an off-white solid. δH (DMSO-d6) 7.29 (1H, s), 3.73-3.64 (4H, m), 3.57-3.39 (6H, m), 2.08-1.96 (2H, m), 1.93-1.83 (2H, m), 1.36 (3H, s). LCMS (ES+) 295.2 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[N:13]=[C:12]([CH3:22])[CH:11]=1)(=O)C.Cl>CO>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)=[CH:11][C:12]([CH3:22])=[N:13]1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1C
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2ccccc2C)n1

Procedure:
1-Acetyl-2-[1-(2-methylphenyl)-3-methyl-5-pyrazolyl]amino-2-imidazoline (7.0 g.) was treated with HCl in methanol as described in Example II to give 4.6 g. of product, mp 168°-169°.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:22]([O:21][C:19]([C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:12][NH:8][CH2:9]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccn1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CNC[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-benzyl-trans-3-ethoxycarbonyl-4-(2-pyridyl)pyrrolidine from step 2 above (5.0 g, 16 mmol) and 10% Pd on carbon (750 mg) in ethanol (30 mL) containing acetic acid (3 mL) was shaken under an atmosphere of hydrogen (40 psi) on a Parr apparatus at ambient temperature for 18 h. The catalyst was removed by filtration and the filtrate solvents were removed in vacuo. The residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an oil (3.3 g; HPLC RT=2.43 min, method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(=O)(O)(O)O.[H][H]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 12.3 gm (42.7 millimols) of 4-(4'-chloro-4-biphenylyl)-4-oxo-butyric acid in 150 ml of acetic acid was admixed with 4 ml of orthophosphoric acid of 89% and hydrogenated in the presence of 4 gm of palladium/barium sulfate (5%) at a hydrogen pressure of 5 atmospheres and at room temperature. The catalyst was vacuum-filtered off, and the solvent was evaporated. The residue was dissolved in ether, the organic phase was washed with water and evaporated to dryness. The free acid thus obtained was dissolved again in ethyl acetate, the solution was filtered and mixed with a small excess of cyclohexylamine. Yield: 9.5 gm (62.5% of theory); m.p. 187°-190° C. (cyclohexylamine salt). Melting point of the free acid: 136°-137° C.