Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5].[CH2:33]([N:35]([CH2:50][CH3:51])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])[CH3:39])[CH3:34].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:50]([N:35]([CH2:33][CH3:34])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5])=[O:45])[CH3:39])[CH3:51]
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncc(-c2cccc(C(F)(F)F)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 10.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)benzamide (200 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (120 mg, 0.45 mmol, 1.00 equiv), EDCI (130 mg, 0.68 mmol, 1.50 equiv), and 4-dimethylaminopyridine (83 mg, 0.68 mmol, 1.50 equiv). The resulting solution was stirred for 10 h at 25° C. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.2 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.45 (s, 1H), 11.29 (s, 1H), 9.18 (s, 2H), 8.12-8.21 (m, 3H), 8.03 (s, 1H), 7.89-7.91 (d, J=6.6 Hz, 1H), 7.75-7.84 (m, 2H), 7.62-7.66 (m, 2H), 7.51 (s, 1H), 7.28-7.31 (d, J=8.1 Hz, 1H), 3.37 (s, 2H), 3.26 (s, 4H), 3.10-3.18 (m, 4H), 1.58-1.68 (m, 6H), 1.15-1.20 (m, 6H). MS (ES, m/z): 688.00 [M+]+.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:5][CH2:6]OC)[CH3:3].[H-].[Na+].[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].O.[O:31]1CCC[CH2:32]1>CCOCC>[CH3:3][N:2]([CH:4]([C:9]1([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)[CH2:5][CH2:6][CH2:32][O:31][CH2:23][CH2:22][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH3:1]
Reactant: C=Cc1ccncc1
Reactant: C1CCOC1
Reactant: COCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN(C)C(CCCOCCc1ccncc1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[1-(4-chlorophenyl)cyclobutyl]-3-dimethylaminopropan-1-ol (3 g prepared as described in Example 211) in tetrahydrofuran (50 ml) was added to a stirred suspension of sodium hydride (1.02 g of a 50% dispersion in mineral oil) in tetrahydrofuran (60 ml). The mixture was stirred at ambient temperature for one hour and a solution of 4-vinylpyridine (5.74 ml) in tetrahydrofuran (10 ml) was added and the mixture allowed to stand for 72 hours at ambient temperature and then heated under reflux for 48 hours. Water was added dropwise to the cooled reaction mixture which was then extracted with ether. The extracts were washed, dried and evaporated to give an oil which was dissolved in ether, filtered and the filtrate evaporated. The residue was heated at 95° C./0.5 mm Hg for 2 hours and then purified by flash chromatography on a silica column using a 9:1 mixture of light petroleum (b.p. 60°-80° C.) and propan- 2-ol as eluant followed by high performance liquid chromatography. The product was heated at 80° C./20 mm Hg for 5 hours to leave N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-4-[2-(4-pyridyl)ethoxy]butylamine as an oil the boiling point of which was not determined.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:4]([N:8]2[CH:17](O)[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4([CH3:22])[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[C:3]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:4]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4([CH3:22])[CH2:20][CH2:21]4)=[CH:13][CH:14]=3)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1N1C(=O)c2cc(C3(C)CC3)ccc2CC1O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1-n1ccc2ccc(C3(C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-hydroxy-7-(1-methyl-cyclopropyl)-3,4-dihydro-2H-isoquinolin-1-one (1.134 g, 2.2 mmol) was dissolved in 13 ml dichloromethane at room temperature; triethylamine (1.31 ml, 9.44 mmol) followed by addition of methanesulfonyl chloride (0.478 g, 4.171 mmol) were added. It was stirred for 1.5 hours at room temperature but it's already done in 10 minutes according to LCMS. The reaction mixture was extracted with dichloromethane/water; organic phase was washed with brine; dried over sodium sulfate; filtered; concentrated to give 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-7-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one (1.094 g, 2.2 mmol) MS (ESI) 520.0 (M+Na+).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[H][H].[C:15](OCC)(=[O:23])[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=O>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[F:9])[N:6]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:23])[NH:10]2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc2cc(F)c(F)cc2[nH]c1=O

Procedure:
A reaction mixture was prepared containing 8.75 g. of 4,5-difluoro-2-nitroaniline, 200 ml. of ethanol, and as a catalyst 1 g. of 10 percent palladium-on-carbon. The mixture was hydrogenated until the theoretical amount of hydrogen had been absorbed, using a low-pressure hydrogenation apparatus. The catalyst was separated by filtration using standard precautions and the product of the reaction, 4,5-difluoro-o-phenylenediamine, was reacted with diethyl mesoxalate following the procedure of Preparation 1 without further purification. The product of this reaction, ethyl 6,7-difluoro-3,4-dihydro-3-keto-2-quinoxaline carboxylate, melted at about 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12]OC(OC)(OC)C>CCOC(C)=O>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: COC(C)(OC)OC
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
To 5,6-dichloronicotinic acid (2.2 g) was added 1,1,1-trimethoxyethane (4.3 mL), followed by irradiation with microwave at 120° C. for 15 minutes. The reaction mixture was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4 and the vehicle was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=85:15 to 80:20) to obtain methyl 5,6-dichloronicotinate (2.2 g) as a white solid.
Reaction SMILES: [O-:1]O.[CH:3]1(C2C=CC=CC=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(=O)(=O)(O)[OH:16]>>[C:3]1([OH:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:3]1(=[O:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: [O-]O
Reactant: c1ccc(C2CCCCC2)cc1
Product: O=C1CCCCC1
Product: Oc1ccccc1

Procedure:
The oxidation effluent stream from the oxidation reactor 106, including cyclohexylbenzene hydroperoxide, is fed by line 110, along with a cleavage catalyst, such as sulfuric acid, in line 112 to a cleavage reactor 114. Conditions in the cleavage reactor 114 are such that cyclohexylbenzene hydroperoxide in the oxidation effluent stream is decomposed to produce phenol and cyclohexanone in a respective weight ratio of less than 2.57. The cleavage effluent stream from the cleavage reactor 114 is fed by line 116 to a separation device, for example, a conventional fractionation column 118. Fractionation column 118 is operated to divide the cleavage effluent into a first fraction composed of cyclohexanone (including, for example, no greater than 1000 wppm of phenol) that is removed in line 120 as an overhead of the fractionation column 118, and a second fraction including phenol and cyclohexanone that is removed in line 122 as a bottoms product of the fractionation column 118. The second fraction in line 122 has a phenol to cyclohexanone weight ratio that is greater than that of the cleavage effluent in line 116.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:28][OH:29]>O>[OH:29][CH2:28][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:1]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: COC(=O)c1ccncc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1ccnc(CO)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
The reaction was performed in 2 separate 1000 mL round-bottomed flasks. To a solution of methyl isonicotinate (70 g, 510.44 mmol) and sulfuric acid (2.340 mL, 43.90 mmol) in MeOH (700 mL) under reflux, was added a solution of ammonium peroxydisulfate (210 g, 918.80 mmol) in water (350 mL) over 20 min. The reaction was refluxed for 20 min and was then allowed to cool to room temperature. The solid was filtered off and washed with MeOH. MeOH was removed from the filtrate under reduced pressure and then was neutralised by cautious stepwise addition of solid Na2CO3 under ice-cooling. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4 and evaporated. The dark-brown residue was treated with cyclohexane (3×300 mL) and the cyclohexane phase was decanted. The remaining dark-brown residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns. A gradient from 25% to 100% of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(hydroxymethyl)isonicotinate (27.5 g, 32%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.90 (s, 3H), 4.78 (s, 2H), 7.57-7.90 (m, 2H), 8.64 (s, 1H). MS m/z 168 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C1COCC1>[CH2:19]([N:21]([CH2:22][CH3:23])[C:14](=[O:16])/[C:13](/[O:17][CH3:18])=[CH:12]/[CH:11]=[CH:10]/[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:20]
Reactant: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)O
Reactant: CCNCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a solution of (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoic acid (0.1 g, 0.41 mmol), diethylamine (0.042 ml, 0.41 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 nmol) in DMF/THF 1:1 (50 Ml), DCC (0.093 g, 0.45 mmol) was added at 0° C. The resulting solution was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane, washed successively with 10% HCl, saturated solution of NaHCO3 and water, dried and evaporated under vacuum. The crude material was purified by column chromatography (EtOAc/hexane 4:6) and triturated with isopropyl ether to yield 21 mg (17.2%) of the title compound as a light yellow solid, m.p.=141-143° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:29]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 59 %

Procedure:
A solution of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), benzyl bromide (0.58 mL) and cesium carbonate (1.6 g) in N,N-dimethylacetamide (15 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.0 g, 59%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1ccc2cc(Cl)cc(Cl)c2o1
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a 2 L round bottom flask fitted with a mechanical stirrer and condenser was placed 3,5-dichlorosalicylaldehyde (200.0 g, 1.05 mol, 1 equivalent), acetic anhydride (356 g, 3.49 mol) and triethylamine (95.0 g, 0.94 mol, 0.90 equivalent). The reaction solution was heated at reflux overnight. The dark brown reaction mixture was cooled to 50° C. and water (1 L) added with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). This mixture was heated to 45° C. for one hour, cooled to room temperature, filtered and the solid (fraction A) washed with EtOH (0.5 L). The combined EtOH solutions were concentrated by rotary evaporation to produce an oil (fraction B). The solid from fraction A was dissolved in methylene chloride (1.5 L) and the resulting solution passed through a pad of silica gel (1300 mL volume). The resulting dark brown solution was concentrated to an oil that was triturated with hexanes (1.3 L) to give a solid that was isolated by filtration and washed (hexanes) to give substantially pure 6,8-dichlorocoumarin (163 g). An additional 31 g of product was obtained by treating the oil (fraction B) in a similar fashion; the oil was dissolved in methylene chloride (0.5 L) passed through a silica pad (0.5 L volume) and triturated with hexanes. The total isolated yield is 194 g or 86% of the brown solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13]([C:26]([C:25]2[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=2[O:23][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:12][CH2:11]3)=[CH:18][CH:19]=1
Reactant: Fc1ccc(COc2ccc3c(c2)CCNC3)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-(4-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline (CA [620606-78-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 498.4 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][OH:13])[CH:6]=[C:5]2[CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([CH2:12][OH:13])[CH:6]=[C:5]4[CH3:14])=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(CO)nc2ccc(I)cc12
Product: Cc1cc(CO)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
The product was obtained analogously to Example 7.1 e starting from (6-iodo-4-methylquinolin-2-yl)methanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 50 mg (19% of theoretical); C24H17ClN2O (M=384.857); calc.: molpeak (M+H)+: 385/387 (Cl); found: molpeak (M+H)+: 385/387 (Cl); HPLC-MS: 5.50 minutes (method B).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH2:28][CH3:29])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2]
Reactant: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12 g. of 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxycarbanilic acid ethyl ester and 2 g. of sodium hydride (50% dispersion in oil) in 100 ml. of absolute dimethylformamide was stirred at room temperature for 4 hours and then treated with 6.5 g. of ethyl iodide. After stirring at room temperature for 30 minutes, the dimethylformamide was removed at 60° C. under vacuum. The residue was taken up in 250 ml. of water and the precipitated product extracted with two 600 ml. portions of ethyl acetate. The ethyl acetate extract was washed with two 300 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on 350 g. of silica gel using ethyl acetate/alcohol (3:1) and there was obtained N-ethyl-4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester having a melting point of 165°-167° C. (recrystallization from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.CCN=C=NCCC[N:21]([CH3:23])C.Cl.C(N(CC)CC)C.N[O:33][CH3:34].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:21]([O:33][CH3:34])[CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CON
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A mixture of 4-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g), DMAP (12.2 g), triethylamine (28 mL), and NH2OMe.HCl (12 g) in CH2Cl2 (300 mL) was stirred at room temperature for 16 h. The reaction was quenched with water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by silica gel flash chromatography eluting with 33% hexanes in ethyl acetate gave the title compound (19.5 g) as a solid.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>N1C=CC=CC=1>[NH2:2][C:1]1[S:29][C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)sc1N
Yield: 25 %

Procedure:
To a solution of the ethyl 2-cyano-2-(2,6-difluorobenzamido)acetate (1 eq) in pyridine (0.1 M) was added Lawesson's reagent (1.5 eq.). The mixture was stirred at reflux under Ar for 18 hours. Solvents were removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the ethyl 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylate in 25% yield. LC/MS (m/z): 284.9 (MH+), Rt: 0.76 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:28][CH:27]=1)=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)C(C)C
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 4-methyl-3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](Cl)=[O:14])(=O)=O)=CC=1.[OH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:23][CH:22]=1.CN(C)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[N+:11](=[CH:12][C:13]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:37])=[CH:23][CH:22]=1)=[O:14])=[N-:10]
Reactant: O=C(Nc1ccc(/C=C/CO)cc1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)Cl)cc1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Glyoxylic acid chloride p-toluenesulfonylhydrazone (1.66 g, 6.35 mmol) was added to a suspension of benzyl 4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (1.0 g, 3.53 mmol) in dichloromethane (25 mL). The mixture was cooled to 0° C. and treated with N,N-dimethylaniline (0.8 mL, 6.35 mmol). After 0.5 h, triethylamine (2.5 mL, 17.6 mmol) was added and the mixture stirred 2 h at 0° C. and warmed to room temperature. The reaction mixture was then concentrated and water was added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine and dried (MgSO4), filtered and concentrated. Purification by silica gel column chromatography (gradient 0-25% EtOAc-hexane) provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](CC(O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:25](OCC)(=[O:27])[CH3:26]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:26][CH2:25][OH:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(t-butoxycarbonylamino)-benzeneacetic acid (2.9 g, 11.4 mmoles) is dissolved in 10 ml of anhydrous THF at 0° C. and added to a suspension of LiAlH4 (0.52 g, 13.6 mmoles) in 30 ml of THF. The reaction mixture is agitated at ambient temperature for 1.5 hours. 50 ml of ethyl acetate then 20 ml of 2 N soda are added to the medium. The expected product is extracted from the organic phase, which is then washed with 3 times 15 ml of water. The organic phase is dried and the solvent evaporated off under reduced pressure. Then the reaction product is purified on silica gel in a dichloromethane/methanol mixture (95/5). 1.1 g (40%) is thus obtained in the form of a colourless oil.