Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[N:16][N:17]([CH:18]([CH3:20])[CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:23]Br>C(O)(=O)C>[Br:23][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:22]=[CH:21][C:14]2[N:15]=[N:16][N:17]([CH:18]([CH3:19])[CH3:20])[C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(C)n1nnc2ccc(C(=O)Cc3ccc(F)cc3)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)n1nnc2ccc(C(=O)C(Br)c3ccc(F)cc3)cc21
Temperature: 50 °C

Procedure:
To a stirred solution of 191 mg of 2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone in 2 mL of acetic acid was added 0.64 mL of bromine (1 M in acetic acid). The mixture was heated at 50° C. for 3 hours. The reaction mixture was cooled to 22° C. and concentrated to dryness. The residue was taken-up into ethyl acetate and washed with saturated aqueous sodium bicarbonate, brine; the organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated to give 222 mg of 2-bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone as a light yellow oil. This material was used without further purification.
Reaction SMILES: C[Al](C)C.Cl.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH:10]1[C:11]2[CH2:9][C:8]3[C:12](=[CH:10][CH:11]=[CH:6][CH:7]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Product: c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C

Procedure:
About 2 g (0.01 mmol) of 1-carboxylic acid fluorene was suspended in 50 ml of toluene. Then 4.6 ml AlMe3 was added to the solution and the reaction mixture was refluxed for 10 hours. Upon heating, the reaction mixture formed a homogeneous solution. The reaction mixture was cooled to room temperature and then poured into ice cooled diluted aqueous HCl. The organic layer was separated, washed with H2O, and dried over Na2SO4. Then the solvent was removed in vacuo. The colorless residue was extracted with pentane, the solution filtered over silica, and the solvent removed in vacuo. The yield of 1-tert-butyl fluorene, formula 6, was quantitative.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CC[N:17](CC)CC.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:17])=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2cnco2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol) and Et3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to 0° C. and ClCOOi-Bu (745 mg, 5.46 mmol) was added dropwise. After the addition was over, the reaction mixture was stirred for additional 5 min and then aq NH4OH (0.63 mL of 28% solution, 10.46 mmol) was added. After overnight stirring, the solvent was evaporated, the residue was taken up in water and basified to pH 9. The precipitated solid was filtered, washed with water and dried over P2O5 in a vacuum desiccator to provide 500 mg (48%) of the 4-(5-oxazolyl)-benzamide: 1HNMR (DMSO-d6) δ 8.50 (s, 1H), 8.20–7.80 (m, 5H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH2:34][O:35][CH3:36])(=[O:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>ClCCl.O1CCOCC1>[CH3:36][O:35][CH2:34][CH2:33][S:30]([N:27]1[CH2:26][CH2:25][N:24]([C:21]2[CH:20]=[CH:19][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[CH:23][CH:22]=2)[CH2:29][CH2:28]1)(=[O:32])=[O:31]
Reactant: COCCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCS(=O)(=O)N1CCN(c2ccc(N3CCNc4ccccc43)cc2)CC1
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
0.35 g of 4-{4-[4-(2-methoxyethanesulphonyl)piperazin-1-yl]phenyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in 7 ml of dichloromethane. 2.5 ml of a 4N solution of HCl in dioxane are slowly added at 0° C. The mixture is stirred for 5 minutes under cold conditions and then the mixture is allowed to return to ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h and is then diluted with dichloromethane. A saturated aqueous sodium hydrogencarbonate solution is added until a pH=7-8 is reached. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered through a sintered glass filter and concentrated under reduced pressure. 0.246 g of 1-{4-[4-(2-methoxyethanesulphonyl)piperazin-1-yl]phenyl}-1,2,3,4-tetrahydroquinoxaline is obtained in the form of an oil.
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[CH3:12][O-].[K+].CI>CO>[CH3:12][O:4][C:3](=[O:5])[CH:2]([O:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[Cl:1]
Reactant: C[O-]
Reactant: O=C(O)C(Cl)Oc1cccs1
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(Cl)Oc1cccs1
Yield: 86.5 %

Procedure:
A mixture of 1.93 g of the product of Step A, 25 ml of methanol, 0.75 g of potassium methylate and 25 ml of methyl iodide was refluxed for 24 hours and was then evaporated to dryness. The residue was taken up in ether and the ether phase was washed with dilute sodium bicarbonate, dried, treated with activated carbon and was filtered. The filtrate was evaporated to dryness to obtain 1.79 g of methyl-2-chloro-thienyloxy-acetate.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].[Cl-].[NH4+]>C1COCC1>[Br:18][C:19]1[CH:20]=[C:21]([C:22](=[O:23])[CH2:16][C:15](=[O:17])/[CH:14]=[CH:13]/[O:12][CH3:11])[CH:25]=[CH:26][CH:27]=1
Reactant: COC=CC(C)=O
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO/C=C/C(=O)CC(=O)c1cccc(Br)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 1 ltr flask is cooled a solution of lithium hexamethyldisilazide (65 ml, 1.5 M) in THF (250 ml) to 75 ° C. During a period of 1 h is added 4-methoxy-but-3-en-2-one (7 ml). The mixture is stirred for 1 h at −70° C. A solution of 3-bromobenzoylchloride (6 g) in THF (250 ml) is added to the above mixture during 1 h at −70° C. The resulting mixture is slowly heated to ambient temperature and stirred for 1 h. Subsequently, the mixture is added to a cold aqueous solution of ammonium chloride and the resulting suspension is extracted with ethyl acetate. The organic phase is extracted twice with an aqueous solution of ammonium chloride, dried over sodium sulfate and evaporated. The crude oily product is transferred to the next step without any further purification.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH2:13]([N:15]([CH2:18][CH2:19]Cl)[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH2:17][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: CCN(CC)CCCl
Reactant: Sc1ncnc2ccccc12
Agent: Cl
Product: CCN(CC)CCSc1ncnc2ccccc12
Yield: 59.9 %

Procedure:
The title compound(4.82 g) was prepared from 4-mercaptoquinazoline(5.0 g) and N,N-diethylaminoethylchloride hydrochloride(5.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1)#[N:2].Br[C:14]1[CH:19]=[C:18]([C:20]2([CH3:31])[CH2:25][O:24][C:23]([CH2:28][F:29])([CH2:26][F:27])[C:22]([NH2:30])=[N:21]2)[C:17]([F:32])=[CH:16][N:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:30][C:22]1[C:23]([CH2:26][F:27])([CH2:28][F:29])[O:24][CH2:25][C:20]([C:18]2[C:17]([F:32])=[CH:16][N:15]=[C:14]([NH:11][C:9]([C:6]3[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:10])[CH:19]=2)([CH3:31])[N:21]=1
Reactant: Cc1cc(C#N)cnc1C(N)=O
Reactant: CC1(c2cc(Br)ncc2F)COC(CF)(CF)C(N)=N1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C#N)cnc1C(=O)Nc1cc(C2(C)COC(CF)(CF)C(N)=N2)c(F)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (see Intermediates Amide 1, 96 mg, 0.596 mmol), 5-(2-bromo-5-fluoro-pyridin-4-yl)-2,2-bis-fluoromethyl-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (210 mg, 0.596 mmol), Xantphos (31.1 mg, 0.054 mmol) and Cs2CO3 (272 mg, 0.835 mmol) in dioxane (6 ml) was degassed with argon, Pd2(dba)3 (16.38 mg, 0.018 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. More Pd2(dba)3 (8.19 mg, 0.009 mmol) and Xantphos (15.60 mg, 0.027 mmol) was added and stirring was continued at 60° C. for 4 h. The reaction mixture was filtered through celite and the celite pad rinsed with DCM. The combined filtrates were concentrated and the resulting crude title compound was purified by NP-HPLC (Alltech Grom Saphir65 Si 10 μm column, 150×30 mm, gradient n-heptane:EtOAc:MeOH 68:30:2 to 0:65:35), then by RP-HPLC (Waters SunFire C18 column, 5 μM, 30×100 mm, gradient 10 to 30% ACN+0.1% TFA) and obtained as a free base after filtration over an SCX cartridge.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[N:12]2)=[C:7]([I:24])[N:6]=1)=[O:4].C1CCN2C(=NCCC2)CC1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.S([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[N:12]2)=[C:7]([I:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1O
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a dimethylformamide suspension (80 ml) of the above Compound 7 (8.76 g, 20 mmol) were added DBU (4.48 ml, 30 mmol) and benzylbromide (3.56 ml, 30 mmol), and the solution was stirred for 5 hours at room temperature. The reaction solution was added with 0.5M citric acid aqueous solution and 10% sodium hydrogen sulfite aqueous solution, and extracted twice with ethyl acetate. The organic phase was washed with water, saturated sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by distilling off the solvent was subjected to silica gel chromatography. The precipitated crystals were collected by filtering, and washed with diisopropyl ether, to give 8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylic acid methyl ester 8 (7.64 g) in 72% yield.
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C@@:27]23[C@:22]([CH3:30])([CH2:23][CH2:24][CH2:25][CH2:26]2)[C@@H:21]2[C@H:5]([C@H:6]4[C@:18]([CH3:31])([CH2:19][CH2:20]2)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]4)[CH2:4][CH:3]3[O:2]1.C(OCC)(=[O:34])C>N1C=CC=CC=1>[CH2:1]1[CH2:29][O:28][C:3]2([C@@H:27]3[C@:22]([CH3:30])([CH2:23][CH2:24][C:25](=[O:34])[CH2:26]3)[C@@H:21]3[C@H:5]([C@H:6]4[C@:18]([CH3:31])([CH2:19][CH2:20]3)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]4)[CH2:4]2)[O:2]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4OCCO[C@@]45CCCC[C@]5(C)[C@H]3CC[C@]12C
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4(OCCO4)[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
A solution of 6-ethylenedioxy-5α-cholestan-3β-(3, 12.5 g) in pyridine was added to ice-cold pyridine-CrO3 complex prepared by adding CrO3 (182 g) to ice-cold pyridine (182 ml). An additional amount of pyridine (90 ml) was utilized for complete transfer. The mixture was allowed to come to room temperature and stirred for 10 hr. It was then brought to a volume of 500 ml with ethyl acetate and filtered through a column packed with Celite (a diatomaceous silica product marketed by Johns-Manville Co.) (50 g, 4 cm diameter) slurried in ethyl acetate. Material eluted with a total of 750 ml of ethyl acetate was collected, and filtered through a 6 cm column packed with alumina (100 g) slurried in ethyl acetate. After elution with 1200 ml of ethyl acetate and evaporation of the solvent, a greenish solid was recovered. This was applied to a 2×23.5 cm (50 g alumina, AG-7 minus 200 mesh) column and eluted with ethyl acetate. The first 150 ml of eluant gave 12.3 g (98%) of pure 6,6-ethylenedioxy-5α-cholestan-3-one (4). An analytical sample recrystallized from MeOH was obtained as white crystals: m.p. 115°-116°; nmr (CDCl3) δ 2.35 (m, C-2 and C-4 protons), 3.9 (m, ketal); ir (KBr) 1710 cm+1 (C=O); mass spectrum: m/e 444 (M+, 19%, C29H48O3 : C, 78.33; H, 10.88; obs: C, 78.37; H, 10.93.
Reaction SMILES: [C:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]>Cl.C(O)C.[Pt](=O)=O>[NH2:2][CH2:1][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CCCCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1(CN)CCCCC1
Reaction time: 20 h
Yield: 32.4 %

Procedure:
Platinum (IV) oxide (1.72 g) was added to a solution of ethyl 1-cyanocyclohexanecarboxylate (17.15 g, 94.6 mmol) in concentrated hydrochloric acid (20 mL) and ethanol (200 mL), and the mixture was placed under hydrogen pressure on a Parr apparatus and shaken for 20 hours. The solvent was removed under reduced pressure, and the residue was diluted with water. The resulting mixture was adjusted to pH 7 with the addition of solid sodium carbonate and then extracted several times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 5.67 g of ethyl 1-(aminomethyl)cyclohexanecarboxylate as a colorless oil. A portion of the water was removed from the aqueous layer, and dichloromethane was added. The mixture was stirred overnight at ambient temperature, and the organic fraction was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.69 g of ethyl 1-(aminomethyl)cyclohexanecarboxylate hydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][CH2:28][C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ncc(CN)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (400 mg, 1.41 mmol) and (2-methylpyrimidin-5-yl)methanamine (400 mg, 3.25 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]2[S:7][C:8](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]2[S:7][C:8]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: CCOC(=O)/C=C/c1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1

Procedure:
A solution containing 0.8 mmol of the product obtained in Example 9 in 20 ml of methanol, and 0.2 g of 10% Pd/C is maintained at 40° C. for 24 hours under a stream of hydrogen. Filtration and concentration under reduced pressure and chromatography over silica gel (cyclohexane/ethyl acetate: 80/20) enable the expected product to be isolated.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.IC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[C:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][C:1]#[N:2])#[N:13]
Reactant: N#Cc1cccc(CBr)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: N#CCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102 %

Procedure:
To a solution of 9.8 g (200 mmole) of sodium cyanide and 1.61 g (5 mmole) of tetrabutylammonium bromide in 50 ml of water was added a solution of 19.61 g (100 mmole) of α-bromo-m-tolunitrile in 150 ml of dichloromethane. The mixture was stirred at room temperature for 24 hours. To this mixture was added 6.2 ml (100 mmole) of iodomethane. The mixture was stirred at room temperature for 3 hours. The layers were separated and the organic layer was dried over magnesium sulfate and was filtered. The filtrate was evaporated and the residue was triturated with petroleum ether and the insoluble material was collected to give 14.5 g of a white solid, mp-66-9° C.; 100% yield: 1H-NMR (300 MHz, CDCl3) δ (TMS) 3.80-3.90(s, 2H), 7.49-7.72(m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([O:19][CH3:20])[C:12]=1[O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:10].N1CCCCC1>O>[Cl:30][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:19][CH3:20])[C:12]=1[O:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OCCc2ccccc2)c1OC
Solvent: C1CCNCC1
Solvent: O
Product: COc1c(O)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1OCCc1ccccc1
Temperature: 90 °C

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-2-phenethyloxy-phenyl)-ethanone obtained from example 112 (89.3 mg, 0.1 mmol) was treated with piperidine (0.8 mL) and water (0.32 mL). The yellow suspension was heated to 90° C. for 54 hours. The solvent was evaporated in vacuo. The crude mixture was treated with NH4Cl (sat., 1 mL) and the organic products were extracted with EtOAc (3×2 mL). The combined organic phases was dried over Na2SO4 and evaporated in vacuo. Purification by flash chromatography using a gradient of EtOAc in toluene as eluent provided 2-(3,5-dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone as a white solid. Yield 8.6 mg (20%). 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone (5.5 mg, 0.013 mmol) was dissolved in DMSO (0.45 mL) and treated with K2CO3 (0.019 mL of a 1M aq. solution) followed by ethyliodide (0.019 mL of a 1M solution in DMSO). The reaction mixture was left at rt for 48 hours and purified by standard HPLC purification. 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-ethoxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone was obtained as a colourless solid. Yield 3.2 mg (36%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:27]N(C=O)C.CO>C(Cl)Cl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([O:18][CH3:27])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (440 mg) and thionyl chloride (0.131 ml) in methylene chloride (8 ml) was added DMF (0.14 ml) and the solution was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature before the addition of methanol (5 ml) and stirring continued for 2.5 hours. The reaction mixture was concentrated and then dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (2×), brine, dried (magnesium sulfate) and concentrated to yield the crude methyl 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoate as a brown solid (419 mg); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 3.87 (s, 3H), 6.65 (d, 1H), 7.11 (d, 1H), 7.23 (d, 1H), 7.57-7.62 (m, 3H), 7.80 (s, 1H), 7.97 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M+Na+ 332.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[CH:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1cc(C(F)(F)F)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (70 mg), [4-(trifluoromethyl)thiophen-2-yl]methanol (50 mg) and triphenylphosphine (144 mg) in tetrahydrofuran (3 ml) was added bis(2-methoxyethyl)azodicarboxylate (129 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (15 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21]C(=O)OC(C)(C)C)=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:10]=1[NH:9][C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of tert-butyl (2-(tetrahydro-2H-pyran-4-carboxamido)-4-(thiophen-2-yl)phenyl)carbamate in dichloromethane (20 mL) was added trifluoroacetic acid (7 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. the solvents were then removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The product was extracted with EtOAc, washed with water and brine, dried, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOH/CH2Cl2) to afford N-(2-amino-5-(thiophen-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide as a beige solid (1.1 g, 86% yield). ESI+ MS: m/z 303 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.12 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.03 (dd, J=5.5; 3.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.05 (s, 1H), 3.91 (dd, J=11.0; 2.0 Hz, 2H), 3.36 (dt, J=11.0; 2.0 Hz, 2H), 2.68-2.62 (m, 1H), 1.80-1.64 (m, 4H).