Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCC2)CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (53%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20][NH:21][C:22]1[C:23](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([N:21]([CH3:20])[C:22]1[C:23](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1NC
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1ccccc1N(C)C(=O)C1CCCN1Cc1ccccc1

Procedure:
A mixture of 21 g. of N-benzylproline and 300 ml. of benzene is stirred and 12 g. of thionyl chloride is added dropwise. The reaction mixture is heated on the steam bath for 2 hours, and 18 g. of ethyl N-methylanthranilate are added. The mixture is heated at reflux temperature for 6 hours, washed with dilute sodium hydroxide and concentrated. The residue is purified by partition chromatography and ethyl N-(N-benzyl-2-pyrrolidinylcarbonyl)-N-methylanthranilate is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH:13]=[CH2:14])=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[C:4]([CH3:15])=[N:3]1.C(O)(=O)C.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CO>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:13][CH2:14][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[C:4]([CH3:15])=[N:3]1
Reactant: C1CCNC1
Reactant: C=Cc1nc2c(cc1C#N)c(C)nn2C
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nn(C)c2nc(CCN3CCCC3)c(C#N)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1,3-dimethyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2.20 g, 11.1 mmol) in methanol (110 mL) was treated with acetic acid (635 μL, 11.1 mmol) and pyrrolidine (4.59 mL, 55.5 mmol). The mixture was stirred at room temperature for 3 hours and the solvent removed under reduced pressure. The residue was suspended in water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give 1,3-dimethyl-6-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile as a tan solid.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([O:22]C)=[C:20]([NH:24][C:25]2[C:30](=[O:31])[N:29]3[C:32]4([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[NH:33][C:34](=[O:35])[C:28]3=[C:27]([CH3:41])[CH:26]=2)[N:19]=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.ClCCl.B(Br)(Br)Br>O>[NH2:8][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:24][C:25]2[C:30](=[O:31])[N:29]3[C:32]4([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[NH:33][C:34](=[O:35])[C:28]3=[C:27]([CH3:41])[CH:26]=2)[C:21]=1[OH:22]
Reactant: COc1c(Nc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)ncnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc(N)c2O)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with tert-butyl N-tert-butoxycarbonyl-N-(5-methoxy-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate (3, 0.40 g, 0.70 mmol) and dichloromethane (20 mL) was added and mixture was cooled to −20° C. boron tribromide (0.87 g, 3.50 mmol) was then added to the mixture drop wise. The reaction mass was stirred at room temperature overnight. After completion, water was added to the reaction mixture and quenched with saturated aqueous solution of sodium bicarbonate till pH 8. Yellow solid was precipitated out, filtered and washed with water (20 mL) followed by diethyl ether then finally dried under high vacuum to afford 6′-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 202) as yellow solid. Yield: 0.085 g, 34%; MS (ESI) m/z 357.16 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.15 (brs, 1H), 8.50 (s, 1H), 8.40 (m, 1H), 8.08 (s, 1H), 6.65 (brs, 2H), 3.00-2.94 (m, 2H), 2.44 (s, 3H), 1.73-1.62 (m, 5H), 1.46-1.43 (m, 2H), 1.24-1.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]=[C:11]([NH2:18])[CH:10]=1.[Cl:19][CH2:20][C:21](=O)[CH2:22]Cl>C(O)C>[Cl:19][CH2:20][C:21]1[N:18]=[C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]2[CH:22]=1
Reactant: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CCl)cn12

Procedure:
3 g (9.99 mmol) of 6-(2,4-dichlorophenyl)-2-(ethylsulphanyl)pyrimidine-4-amine (Example 3A) are added to a solution of 1.395 g (10.99 mmol) of 1,3-dichloropropan-2-one in 33 ml of dry ethanol, and the mixture is then heated under reflux conditions for 20 h. The solvent is substantially removed and the residue is purified by preparative HPLC. 1.5 g (37% of theory) of the product are obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[CH2:13][C:12]2=[O:28])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[CH2:13][C:12]2=[O:28])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(NC(C)=O)cc3)C2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(N)cc3)C2)cc1
Yield: 97.1 %

Procedure:
Methyl 4-[1-(4-acetylaminophenyl)-2-pyrrolidon-4-yl]methoxybenzoate (1.70 g) is dissolved in methanol (30 ml) and thereto is added conc. sulfuric acid (0.24 ml). The mixture is stirred under refluxing for 23 hours. Subsequently, the reaction solution is concentrated under reduced pressure, and water and the neutralization amount of sodium hydrogen carbonate are added to the resulting residue. The precipitated crystal is collected by filtration and washed with water to give the desired product (1.47 g), m.p. 136°-138° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[F:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([C:13]2[N:12]([C:25]3[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[N:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CN(Cc1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
tert-Butyl({5-[(4-fluorophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methyl)methylcarbamate (132 mg) was dissolved in ethyl acetate (2 ml) and 2-propanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and ethyl acetate to give the title compound as colorless crystals (yield 83 mg, yield 73%). melting point 211-214° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([CH:22]=O)=[CH:16]2)=[CH:12][CH:11]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[CH:16]=[C:17]([CH2:22][N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:18]=[CH:19][C:20]2=[O:21])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Reactant: CNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
According to Scheme 7 Method A: A solution of N-methylbenzenamine (1 eq, 0.40 mmol, 0.04 mL) and 1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde (1 eq, 0.40 mmol, 0.10 g) in CH2Cl2 (8 mL) was stirred for 10 min. at room temperature then AcOH (1 eq, 0.40 mmol, 0.02 mL) and NaBH(OAc)3 (1.5 eq, 0.60 mmol, 0.10 g) were added. The reaction mixture was stirred 3 hours at room temperature, was quenched with water and the aqueous phase was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 95/5 followed by crystallization in pentane/diisopropyl ether to afford 1-(4-chlorobenzyl)-5-((methyl(phenyl)amino)methyl)pyridin-2(1H)-one (0.12 mmol, 0.04 g, 29%) as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]([O:16][C@@H:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:18][C:19](OC)=[O:20])([CH3:15])[CH3:14].[Cl-].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:11][O:12][C:13]([O:16][C@@H:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:18][CH:19]=[O:20])([CH3:15])[CH3:14]
Reactant: CCCCCCCCCCC[C@@H](CC(=O)OC)OC(C)(C)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCC[C@@H](CC=O)OC(C)(C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (10.7 mL, 60 mmol) dissolved in toluene (30 mL) was precooled to -80° C. and added during 1 h at a temperature of -80° C. to a solution of the crude methyl (S)-3-(2-methoxyprop-2-oxy)tetradecanoate (IX, 13.20 g, 40 mmol) in toluene (100 mL), obtained according to the foregoing described procedure. After complete addition the mixture was stirred for an additional 30 min, diluted with methanol (10 mL), and allowed to warm up to room temperature. A saturated aqueous solution of sodium chloride was added and the precipitate removed by filtration over a pad of fine sand. The filter cake was washed with ethyl acetate (5×15 mL). Filtrate and washings were combined. The aqueous phase was separated and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with water (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residual colorless oil (13.7 g, containing still traces of toluene) was used in the next step without further purification. [α]25D +4.89 (c=0.5 in hexane); 1H NMR (DMSO-D6) δ 0.86 (t, J=7 Hz, 3H), 1.24-1.69 (m, 26H), 3.08 (s, 3H), 4.17-4.21 (m, 1H), 9.67 (t, J=2 Hz, 1H), 13C NMR (DMSO-D6) δ 13.85, 22.05, 24.49, 24.87, 24.96, 28.68, 28.94, 28.97, 29.00, 29.04, 31.28, 35.56, 48.50, 48.93, 66.25, 100.48, 202.80. Anal. Calcd for C18H36O4 : C, 71.95; H, 12.08. Found: C, 72.05; H, 12.28.
Reaction SMILES: [CH2:1]([C:8]1([O:12][C:13]([NH:15][C@@H:16]([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]([O:19]C)=O)=[O:14])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:28]1([P:34](=[CH:47][C:48]#[N:49])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:48]([C:47](=[P:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:17]([C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])#[N:49]
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)OC
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
To 2.44 g (7.32 mmol) of methyl(2S)-2-({[(1-benzylcyclobutyl)oxy]carbonyl}amino)hexanoate in 24 mL of tetrahydrofuran:water (1:1) was added 429.9 mg (10.24 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolver in 36 mL of dichloromethane, then 44.7 mg (365.9 μmol) of 4-dimethylaminopyridine was added. To this solution was added 2.31 g (7.68 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 1.55 g (8.05 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 17 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 3.25 g (74%) of 1-benzylcyclobutyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.25 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.66 (m, 3H), 7.64-7.54 (m, 12H), 7.20-7.14 (m, 5H), 7.03 (d, J=8 Hz, 1H), 4.55-4.50 (m, 1H), 3.21 (m, 2H), 2.24-2.16 (m, 2H), 2.14-2.06 (m, 2H), 1.80-1.70 (m, 2H), 1.70-1.60 (m, 1H), 1.60-1.46 (m, 1H), 1.42-1.24 (m, 4H), 0.89 (t, J=7 Hz, 3H); ES-LCMS m/z 603 (M+H).
Reaction SMILES: [BrH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1>C1(C)C=CC=CC=1>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([Br:1])[C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Br
Reactant: COC(=O)C(O)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reaction time: 3 h

Procedure:
Hydrobromic acid (20 ml of 62% w/v solution in water) was added to methyl 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetate (from step (b), 11 g, 52 mmol) in toluene (200 ml). After stirring for 3 hours the aqueous layer was removed and the organic layer was evaporated in vacuo. The residue was flash chromatographed, eluting with dichloromethane, and then crystallised with diisopropylether and hexane.
Reaction SMILES: ClCCl.C([O:11][CH2:12][C:13]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1)=[O:14])C1C=CC=CC=1>[Pd].CO>[OH:11][CH2:12][C:13]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1)=[O:14]
Reactant: O=C(COCc1ccccc1)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(CO)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Reaction time: 8 h
Yield: 46 %

Procedure:
Dichloromethane was added to 5 ml of a whitish methanol solution containing the 2-benzyloxy-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide prepared in Example 60, until the solution became transparent. Thereafter, 10 mg of 10% Pd—C was added thereto, and the obtained mixture was then stirred under a hydrogen atmosphere for 8 hours. Thereafter, the reaction solution was filtrated with celite, and the filtrate was then concentrated, so as to obtain 7.8 mg (46%) of 2-hydroxy-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide in the form of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C1S(=O)(=O)CCC1>[OH:1][C:2]1[C:11]([N+:18]([O-:19])=[O:17])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]=O
Reactant: Oc1ccc2ccncc2c1
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1c(O)ccc2ccncc12

Procedure:
To a 300 ml round bottom flask is added 14.5 g (0.1 mole) of 7-hydroxyisoquinoline and 100 ml of warmed tetramethylene sulfone. The brown slurry is stirred and to it is added portionwise 18.6 g (0.14 mole) of nitronium tetrafluoroborate with cooling (ice bath). The reaction is stirred for 3 hours. The reaction is then quenched with 100 ml of methanol, evaporated to dryness and triturated twice with ether to precipitate a dark solid (19.0 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:34][C@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@H:26]2[OH:35])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(2-Formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=2)=[N:11][CH:12]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:25][CH2:22][CH2:12][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:20]=[CH2:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](C)CCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCCCOc1ccc(-c2ncc(CCCC[C@@H](C)CC)cn2)cc1
Temperature: 0 °C
Yield: 242.2 %

Procedure:
A mixture of 0.66 g of 9-decen-1-yl-p-tosylate, 0.5 g of (S)-4-(5-[5-methylheptyl]-2-pyrimidinyl)phenol and 0.97 g of potassium carbonate and 50 ml of absolute butanone was heated under reflux overnight. The cooled reaction mixture was subsequently poured into ice-water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 500 ml of water, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with toluene and subsequent bulb-tube distillation gave 0.9 g of (S)-5-(5-methylheptyl)-2-(4-[9 -decenyloxy]phenyl)pyrimidine; m.p. (C-SC *) 19° C., phase transition (SC *-Ch) 32.5° C., cl.p. (Ch-I) 43° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:8]([F:15])=[N:9][CH:10]=[C:11]([CH3:14])[C:12]=1I)=[O:6].[C:25](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>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.O1CCOCC1>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:8]([F:15])=[N:9][CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:25])=[O:6]
Reactant: COc1cc(C)c(C(=O)c2c(F)ncc(C)c2I)c(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C)c(C(=O)c2c(F)ncc(C)c2C)c(OC)c1OC
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1.50 g (3.37 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-fluoro-4-iodo-5-methylpyridine obtained in Step (c), 1.40 g (10.1 mmol) of potassium carbonate, 0.39 g (0.34 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of dioxane and 0.42 g (1.67 mmol) of 50% trimethylboroxin were mixed, followed by reflux with heating for 6 hours. After cooling to room temperature, filtration on the pad of celite and washing with ethyl acetate and tetrahydrofuran were carried out, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 0.79 g (yield: 70%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-fluoro-4,5-dimethylpyridine (Compound No. 19).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH:31]C(OCC3C=CC=CC=3)=O)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(N)C(C)(C)C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of compound 23 (2.4 g, 4.1 mmol) and 10% Pd-on-carbon (wet, 500 mg) in MeOH/EtOAc (1:1, 100 mL) was pressurized to 50 PSI H2 and shaken for 3 h using a Parr apparatus. The reaction mixture was filtered through a pad of celite and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to give 33 as a white solid (1.84 g, 100%). The crude product was used without further purification. Mass spectrum, m/z [454.2] (M+H)+.