Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([CH:22]=[CH2:23])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)ccc2N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 3-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.49 g, prepared from 3-amino-2-bromo-pyridine following procedures described in Example 6, Step A to Step C), tributylvinyl tin (0.36 g), tetrakis(triphenylphosphine)palladium (0.035 g) in toluene (20 ml) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to afford 3-amino-6-vinyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.32 g) as a yellow solid. MS (ES+) 443/445 (MH+); 1H NMR (400 MHz, CDCl3) 1.40 (s, 9H), 1.70 (m, 2H), 1.90 (m, 2H), 2.75 (m, 2H), 2.80 (m, 1H), 4.15 (m, 2H), 5.4 (d, 1H), 6.2 (d, 1H), 6.7 (dd, 1H), 7.15 (d, 1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.8 (m, 1H), 7.9 (s, 1H), 8.5 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][NH2:12])=O.[CH2:13]([O:15][C:16](=[O:21])[C:17](Cl)=[N:18][CH3:19])[CH3:14].Cl>ClCCl>[CH2:13]([O:15][C:16]([C:17]1[N:18]([CH3:19])[C:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:11][N:12]=1)=[O:21])[CH3:14]
Reactant: NNC(=O)Cc1ccccc1Cl
Reactant: CCOC(=O)C(Cl)=NC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1nnc(Cc2ccccc2Cl)n1C
Reaction time: 2 h

Procedure:
14.8 g (80 mmol) of o-chlorophenylacetic acid hydrazide are suspended in 230 ml of dichloromethane. At 5°, 12 g (80 mmol) of 2-chloro-2-(N-methylimino)acetic acid ethyl ester [Tetrahedron Lett. 30, 2827 (1979)] are added dropwise thereto. The whole is then stirred for 2 hours while cooling with ice and then overnight at room temperature. The reaction mixture is then poured onto ice, 50 ml of 2N hydrochloric acid are added thereto and the whole is extracted twice with dichloromethane. The combined dichloromethane phases are washed twice with water. All the acidic aqueous phases are combined, rendered alkaline with solid sodium carbonate and extracted three times by shaking with dichloromethane. These three organic phases are combined, washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 150 ml of xylene and stirred under reflux for 44 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and recrystallised from ether. 5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 87°-88° is obtained in a yield of 12.4 g (55% of the theoretical yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH:7]([C:8]1[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([OH:18])=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[Br:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 18 (1.0314 g, 3.22 mmol) in 7.3 mL CCl4 was added N-bromosuccinimide (0.5827 g) and a catalytic amount of benzoyl peroxide. The reaction was heated to 60° C. overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to an orange oil (0.8654 g, 2.17 mmol), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.[Pd](Cl)Cl.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.[Cu]I>[C:12]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9](=[O:11])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Cc1ccccc1C#Cc1ccccc1
Yield: 80.8 %

Procedure:
A solution of 28.3 g (112 mmole) of 2-bromophenyl-2-propanone, 14.7 ml (134 mmole) of phenylacetylene, 1.8 g (2.24 mmole) of bis(triphenylphosphine) palladium (II) chloride and 0.85 g (4.48 mmole) of copper (I) iodide in 250 ml of triethylamine under nitrogen was heated under reflux for 31/2hours. An additional 3.6 ml of phenylacetylene, 0.36 g of palladium complex and 0.1 g copper (I) iodide were added. The mixture was heated under reflux for 31/2 hours. An addtional 5.0 ml of phenylacetylene, 0.36 g of palladium complex and 0.17 g of copper (I) iodide were added. The mixture was heated under reflux for 2 hours. An additional 5.0 ml of phenylacetylene was added. The mixture was heated under reflux for 31/2 hours. The solvent was evaporated in vacuo and the residue taken up in ether. The ether was washed with water and brine, dried (K2CO3) and the solvent evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate:hexane, 9:1, as eluant. The solvent was evaporated from the major compound bearing fraction to afford 21.2 g (81% yeild) of 2-[(phenyl)ethynyl]phenyl-2-propanone as an oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([C:2]1[N:1]([CH2:6][C:7](=[O:8])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C(Cn1cccc1)c1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Product: O=C(Cn1cccc1C(=O)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To a chilled (0° C.) solution of the 2-(1H-pyrrol-1-yl)-1-[5-(trifluoromethyl)pyridin-2-yl]ethanone (100 mg, approx. 90% pure, 0.35 mmol) in dry CH2Cl2 (5 mL) was added trichloroacetyl chloride (90 μL, 0.80 mmol) under nitrogen. The mixture was allowed to warm to room temperature. After completion (44 hours, monitored by LCMS) the mixture was cooled to 0° C. and quenched with a saturated aqueous solution of NaHCO3 (5 mL). The aqueous layer was then extracted with CH2Cl2 (2×2 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to yield a residue that was purified by flash chromatography (Biotage, 12 g cartridge, gradient hexanes 1 CV, 0-60% EtOAc in hexanes 10 CV) to give 2,2,2-trichloro-1-(1-{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H-pyrrol-2-yl)ethanone as an orange oil (105 mg, yield: 75%). ESI-MI m/z [M+H]+ 398.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CS(O)(=O)=O.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.03 h
Yield: 93.9 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and they were vigorously stirred. To this mixture was added 0.32 ml (5 mmol) of methanesulfonic acid, and isobutene gas (98 mmol) was introduced thereto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 20 minutes. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction solution was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the solution was concentrated by distilling off toluene by using a rotary evaporator, to give 2.52 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 94% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:17]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CF)c1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
2-Fluoroacetophenone (2.0 mg, 14.5 mmol) was dissolved in DMF (50 mL), phenol (1.4 g, 14.5 mmol) and potassium carbonate (2.0 g, 14.5 mmol) were added thereto, and then the mixture was stirred at 120° C. for 7 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 85:15) to give the title compound (2.0 g, yield 65%).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH2:13][OH:14]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:4])[O:5][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:2]
Reactant: CCP(=O)(O)CCC#N
Reactant: OCCCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CCC#N)OCCCCO
Yield: 91.8 %

Procedure:
441 g (3.0 mol) of ethyl-2-cyanoethylphosphinic acid (produced as in Example 5) are at 80° C. dissolved in 400 ml of toluene and admixed with 315 g (3.5 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene and excess ethyl glycol is removed in vacuo to leave 604 g (92% of theory) of 4-hydroxybutyl ethyl(2-cyanoethyl)phosphinate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[NH:5][C:4]=2[N:3]=1.[CH:22]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23]1.[H-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[N:5]([CH2:26][CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:3]=1
Reactant: BrCC1CCC1
Reactant: C[C@H]1Nc2nc(Cl)ncc2N(c2cccc(C#N)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1CC1CCC1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirred solution of 3-[(7R)-2-chloro-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile (120 mg, 0.4 mmol) in anhydrous DMF (3 ml) was added cyclobutyl methyl bromide (119 mg, 0.8 mmol) at 0° C. under nitrogen. To the resulting solution was added sodium hydride (32 mg of 60% dispersion in oil, 0.8 mmol) at 0° C. The reaction was then allowed to warm up to rt in 20 min and then heated at 50° C. for 3 h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried (Na2SO4) and evaporated to give a crude residue, which was then purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to give desired product (Yield: 41%). 1HNMR (300 MHz, CDCl3) δ 1.50 (d, J=6.9 Hz, 3H), 1.78-1.94 (m, 4H), 1.96-2.21 (m, 2H), 2.68-2.87 (m, 1H), 3.17 (q, J=6.9 Hz, 1H), 4.22-4.36 (m, 2H), 7.10 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.66-7.78 (m, 1H) and 7.79-7.81 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[N+:24]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)=[CH:7][CH:6]=1)([O-:26])=[O:25]
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Temperature: 10 °C
Yield: 85.9 %

Procedure:
A solution of 2-benzyl-4-(4-pyridyl)thiazole (4.50 g, 0.018 mol) in chloroform (25 mL) was added dropwise to concentrated sulfuric acid (15 mL). The resulting mixture was cooled to 10° C. and fuming nitric acid (1.45 g, 0.97 mL) carefully added dropwise such that the reaction temperature did not exceed 40° C. The mixture was allowed to stir for thirty minutes, carefully neutralized with saturated sodium carbonate and the layers separated. The aqueous layer was reextracted with chloroform (2×25 mL) and the combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, and concentrated to afford a crude product (4.6 g). Several recrystallizations from hexane/ethyl acetate afforded pure 2-(p-nitrobenzyl)-4-(4-pyridyl)thiazole. mp. 140°-142° C.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17]([Cl:21])[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17]([Cl:21])[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:26][CH:27]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
A mixture of 0.50 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole, 0.50 g of 10% palladium/carbon and 40 mL of tetrahydrofuran was stirred at room temperature under hydrogen gas (1 atm.) for 6 hours. The mixture was filtered through Celite® under nitrogen, and the resulting solution was concentrated in vacuo. The crude product was extracted with hot chloroform. After cooling, the chloroform mixture was concentrated in vacuo, and the resulting solid was washed with hexane to afford 0.16 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ9.43 (s, 1H); 6.81 (A2B2, 4H); 5.21 (t, 1H); 5.10 (s, 2H); 4.33 (d, 2H); 2.47 (t, 2H); 1.44 (quint 2H); 1.23 (sext., 2H); 0.79 (t, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Product: CN1CCN(c2ncccc2C(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of N-methylpiperazine gives 1 g of the desired product :M+ =500.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16][CH2:17]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(F)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of 3-fluoro-4-methylbenzoic acid (13.23 g, 85.85 mmol) in EtOH (200 mL) at 0° C. was added SOCl2 (3 mL) dropwise. The reaction mixture was heated at 60° C. overnight, then cooled to room temperature, concentrated under reduced pressure and diluted with DCM. The organic layer was washed with 1N NaOH (100 mL×2), dried (MgSO4) and concentrated to give ethyl 3-fluoro-4-methylbenzoate (15.02 g, 96%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[C:20](Cl)(=[O:22])[CH3:21].CN(C=O)C.CC(C)([O-])C.[K+]>O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:20](=[O:22])[CH3:21])[C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.1 g of 3-acetoxy-4-chloro-10H-phenothiazine (see Example 4) was added acetyl chloride (7 ml), DMF (5 ml) and potassium tert-butoxide (0.42 g). The reaction mixture was stirred at ambient temperature for 1 hour and then, poured in water. The resulting precipitate was filtered and purified by chromatography on silica gel to give (1.08 g) 3-acetoxy-10-acetyl-4-chloro-10H-phenothiazine (m.p. 155° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>[Cu](I)I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2C)cc1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Product: COc1ccc(-c2cc(=O)n(-c3ccccn3)nc2C)cc1

Procedure:
5-(4-Methoxy-phenyl)-6-methyl-2-pyridin-2-yl-2H-pyridazin-3-one was prepared from 5-(4-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one and 2-bromopyridine in the presence of copper iodide using the procedure described in Example 98 Step 2; Mp 156-7° C.; MS m/z 294 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:31][C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Cn1cc(CCl)cn1
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting with 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 505 [M+H]+; 4.28 min (ret time).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:28]=1)[CH3:19]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CCOC(=O)c1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-ethoxycarbonyl-phenylboronic acid to give 3-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzoic acid ethyl ester. LC-MS m/e 359(MH+).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:35][C:36](=[O:45])[NH:37][CH:38]1[CH2:43][CH2:42][CH:41](O)[CH2:40][CH2:39]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([NH:37][CH:38]1[CH2:43][CH2:42][CH:41]([O:12][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:9]=2)[CH2:40][CH2:39]1)=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(NC1CCC(O)CC1)OCc1ccccc1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)OC3CCC(NC(=O)OCc4ccccc4)CC3)c2)cc1
Yield: 48.6 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.8 mmol) and (4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (0.69 g, 2.8 mmol) were used to afford 0.8 g of the required product. 1H NMR (DMSO-d6): δ 1.21 (4H, m), 1.32 (4H, m), 3.12 (1H, m), 3.32 (1H, m), 4.51 (2H, s), 5.21 (2H, s), 7.3 (10H, m), 7.89 (2H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CCCCC.S(O[CH2:33][CH2:34][C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)(=O)(=O)C>CN(C)C=O>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[CH2:34][CH2:33][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Reactant: CS(=O)(=O)OCCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CCc2ccco2)C(=O)C3)c1
Temperature: 0 °C

Procedure:
A solution of 5.0 g (18.5 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 100 ml of anhydrous dimethylformamide was added to a stirred suspension of 1.4 g (28 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 75 ml of anhydrous dimethylformamide heated at 50° under nitrogen. The mixture was heated at 90° for 2 hours, then cooled to 35°. A solution of 7.1 g (37 mmoles) of freshly prepared 2-furylethyl mesylate (prepared according ot the procedure of Crossland and Servis, J. Org. Chem., 35, 3195 (1970)) in 10 ml of anhydrous dimethylformamide was added and the reaction mixture heated at 90° overnight. It was the cooled and poured into ice-water, and extracted with ether. Evaporation of the ether gave an oil which was purified by column chromatography (Silicar CC-7, eluting with acetone-benzene). The major fraction was identified as N-(2-furylethyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline