Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:38])(=[O:37])[NH:32]C(C)(C)C)=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:37])(=[O:38])[NH2:32])=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.2 %

Procedure:
A solution of 122 mg (0.221 mmole) of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one in 2.2 ml of anhydrous trifluoroacetic acid (TFA) containing 2 drops of anisole was stirred at room temperature under N2 for 2 days. The TFA was removed under a gentle stream of N2 followed by co-evaporation in vacuo 2× with toluene. The residue was chromatographed on a silica gel column (gradient elution with 0.5-2% MeOH in CH2Cl2). Concentration of the combined product fractions gave 98 mg (89%) of the title compound as a white solid, mp 140°-142° C.; satisfactory purity by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 497 (M+1)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH2:13].O=O>CO.[Pd](Cl)Cl.[Ti]>[CH3:1][C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O
Reactant: C=CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Ti]
Agent: O=O
Solvent: CO
Product: CCCCCCCCCCC(C)=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-dodecanone is prepared from 1-dodecene according to the process of the present invention as follows: A catalyst solution is prepared by dissolving .04 moles of palladium chloride in a mixture of 137 grams of methanol, 252 grams of polypropylene glycol having an average molecular weight of 430, and 15 grams of water. The catalyst solution is then charged to a 2 liter titanium autoclave where the catalyst solution is heated to a temperature of 60°C; while being stirred at 1,000 r.p.m. with the reactor being pressurized to 100 p.s.i.g. with oxygen. Using a piston pump, 600 grams of 1-dodecene is introduced to the autoclave over a period of 21/2 hours. During this period of addition, the reaction temperature is maintained at 60°C by cooling, with the reaction pressure of 100 p.s.i.g. being maintained by repressuration with oxygen. Stirring is continued for about 1/2 hour after the addition of 1-dodecene is completed.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1.C>CO.[Pd]>[CH3:15][N:7]1[C:6]2[N:5]=[CH:4][CH:3]=[CH:2][C:11]=2[C:10](=[O:12])[N:9]([CH3:13])[C:8]1=[O:14]
Reactant: Cn1c(=O)c2c(Cl)ccnc2n(C)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)c2cccnc2n(C)c1=O
Yield: 83.3 %

Procedure:
0.34 g of Compound 1 was dissolved in 100 ml of methanol and reduced in the presence of Pd-C. Activated charcoal powder was added, and the solution was heated and filtered. The filtrate was distilled under reduced pressure and ethanol was added thereto. The resulting crude crystals were separated from the solution by the filtration and recrystallized from ethanol to give 0.24 g of 1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 2).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:25]=[N:24][NH:23][CH:22]=2)=[O:20])[CH2:13][CH2:12]1
Reactant: O=C(NCC1CCN(C(=O)OCc2ccccc2)CC1)c1cn[nH]c1
Agent: [Pd]
Solvent: CCO
Product: O=C(NCC1CCNCC1)c1cn[nH]c1

Procedure:
4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 34) (600 mg, 1.75 mmol), 10% palladium on Carbon (150 mg) and ethanol (15 mL) were combined in a Parr® jar and hydrogenated at 50 psi for 24 h. The reaction mixture was filtered through Celite® and the filtrate was evaporated in vacuo to give the product as a white foam.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4]>CO.[Ni]>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: CNS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-methyl-4-nitrobenzenesulfonamide (Step 5) (4.8 g, 22.2 mmol) in methanol (100 ml) in a Parr bottle was added Raney-nickel in methanol. The reaction mixture was flushed with nitrogen and hydrogen several times and maintained under hydrogen at delivery pressure of 5 psi. After stirring at 25° C. for approximately 20 hr, the reaction was vented and purged with nitrogen. The contents of the reaction were filtered and concentrated to remove the solvent. The 4-[(N-methylamino)sulfonyl]aniline obtained as a white solid (4.1 g, 100%) was used in the next step without further purification: mp (DSC) 138° C. Anal Calc'd. for C7H10N2O2S 0.25 H2O: C, 44.08; H, 5.55; N, 14.69. Found: C, 43.83; H, 5.39; N, 14.81.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[N:30][CH:31]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[N:30][CH:31]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.34 mL, 1.03 mmol) was added to a THF solution (1.1 mL) of ethyl 3-(5-(2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)-4,5-difluorophenyl)picolinamido)propanoate (115 mg, 0.21 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via HPLC to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.Cl[CH2:15][C:16]#[N:17]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[C:12]2[C:5](=[CH:4][CH:3]=1)[NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH:11][CH2:15][C:16]#[N:17]
Reactant: N#CCCl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Solvent: C1CCOC1
Product: N#CCNCCc1c[nH]c2ccc(Cl)cc12

Procedure:
Using the procedure of Step A of Example 22, 21.4 g of 5-chlorotryptamine, 7.7 ml of chloroacetonitrile and 18.1 ml of 1,5-diaza[5,4,0]undec-5-ene in 210 ml of tetrahydrofuran were reacted to obtain 19.3 g of the expected product melting at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[N:8]=[C:7]1[NH2:20].C(#N)C.NN.C(OC(=O)C)C>CO.[Fe](Cl)(Cl)Cl>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]=[C:7]([NH2:20])[N:6]([CH2:5][C:4]3[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=3[O:2][CH3:1])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1Cn1cc(-c2cccc([N+](=O)[O-])c2)nc1N
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: COc1ccccc1Cn1cc(-c2cccc(N)c2)nc1N
Reaction time: 2 h

Procedure:
51.1 A mixture of 2.5 g 1-(2-methoxybenzyl)-4-(3-nitrophenyl)-1H-imidazole-2-ylamine (7.7 mmol, Example 45), 2.5 g activated carbon, 30 mg iron(III) chloride (in the form of the hexahydrate) in 100 mL methanol, and 20 mL acetonitrile was heated at reflux, slowly combined with 50 mL hydrazine, and then stirred for an additional 2 hr under reflux. The batch was filtered, concentrated, taken up in acetic ethyl ester, extracted with water, and the organic phase was dried (Na2SO4) and concentrated. The residue thus obtained was mixed with acetic ethyl ester, suctioned off, and dried (2 g target product).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: Brc1nccs1
Solvent: CN(C)C=O
Product: c1ccc(COc2ccccc2-c2nccs2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
o-Benzyloxyphenol (7.5 g, 37.5 mmol) in dry DMF (60 mL) was treated with Me4N+OH-.5H2O (37.5 mmol, 6.8 g) followed by 2-bromothiazole (6.15 g, 37.5 mmol). The stirred solution was heated to about 100° C. under N2 (g) for 16 hours. The mixture was cooled in ice and crystalline, H2O-soluble Me4N+Br- was removed by filtration. The filtrate was concentrated in vacuo and partitioned between Et2O (100 mL) and H2O (60 mL). The organic phase was washed with 1N NaOH (3×) and brine, dried over Na2SO4 and concentrated in vacuo to afford 4.9 g of crude 2-(2-benzyloxyphenyl)thiazole (GCMS m/z 283 (M+)). This material was directly deprotected by treatment with 33% HBr in HOAc (35 mL) for 2 hours at about 20° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[C:7]([CH3:13])[CH:6]=[CH:5]2.C1(C)C=CC(S([Cl:23])(=O)=O)=CC=1>ClC(Cl)C>[Cl:23][CH2:13][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2cc(F)ccc2[n+]1[O-]
Solvent: CC(Cl)Cl
Product: Fc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
6-Fluoro-2-methylquinoline N-oxide (2.70 g, 15.25 mmol) was added to a stirring solution of p-toluenesulfonyl chloride (2.9 g, 15.21 mmol) in dichloroethane (100 mL). The reaction mixture was heated to 100° C. overnight under N2, cooled and concentrated, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4 and evaporated under reduced pressure to afford a solid. The crude solid was purified by flash chromatography (15:1 hexane/ethyl acetate) to afford 1.59 g (63%) of pure product as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
Ethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 139, but using ethyl 5-bromopentanoate 1H NMR (CDCl3): δ 8.64 (s, 1H), 8.27 (s, 1H), 8.02 (d, 1H), 7.66 (s, 1H), 7.32 (d, 1H), 6.91 (d, 1H), 6.66 (s, 1H), 6.63 (d, 1H), 4.13 (q, 2H), 3.93 (t, 2H), 3.14 (t, 2H), 2.99 (t, 2H), 2.54 (s, 3H), 2.38 (t, 2H), 2.25 (s, 3H), 1.79-1.83 (m, 4H), 1.26 (t, 3H). LRMS [M+H]=472.3
Reaction SMILES: [S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH2:13].C(=O)([O-])[O-].[K+].[K+].Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCCC1>[S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH:13][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1ccncc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 25.4 %

Procedure:
To a mixture of 8H-Indeno[1,2-d]thiazol-2-ylamine 1b (Prepared in Example 1, Step 2, 640 mg; 3.4 mmol) and potassium carbonate (5.40 g; 39.1 mmol) in dry tetrahydrofuran (20 mL) under nitrogen was added isonicotinoyl chloride hydrochloride (959 mg; 5.10 mmol). The slurry was then heated to reflux for 18 hr. At this point, potassium carbonate (5.40 g; 39.1 mmol) and isonicotinoyl chloride hydrochloride (959 mg; 5.10 mmol) were added and reflux continued for 22 hr., then allowed to cool to room temperature. The solvent was removed in vacuo and the residue diluted with water and extracted with methylene chloride. The insoluble material was filtered off and washed methylene chloride and water and finally triturated with diethyl ether to provide 253 mg of N-(8H-Indeno[1,2-d]thiazol-2-yl)-isonicotinamide 8. EI-HRMS m/e calcd for C16H11N3OS (M+) 293.0623, found 293.0621.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[C:1]([C:6]1[N:7]([CH3:21])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: CCOC(=O)Cc1c(C(=O)OCC)n(C)c2ccccc12

Procedure:
Ethyl 2-Carboethoxy-3-indoleacetate (1 gm) in acetonitrile (50 ml) was combined with potassium carbonate (2 gm) and dimethyl sulfate (0.38 ml). The mixture was heated to reflux for 20 hours, filtered warm, and the solvent removed on the rotary evaporator. The residue was suspended in ether (150 ml) and the mixture washed with 5% hydrochloric acid (3×50 ml), 5% sodium bicarbonate (3×50 ml) and water (3×50 ml). The ether solution was dried over magnesium sulfate and the solvent removed on a rotary evaporator to provide the product.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:44][O:45][CH3:46].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH:1]1(/[C:7](=[N:44]/[O:45][CH3:46])/[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:21][CH:22]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C2CCCCC2)c2nc(C)nn12
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OC)C2CCCCC2)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of 4-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g), (aminooxy)methane hydrochloride (0.74 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.067 g, 26%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH2:1]([C:16]1([OH:19])[CH2:17][CH2:18][C:13]2([O:20][CH2:10][CH2:11][O:12]2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A 0° C. solution of 2M benzylmagnesium chloride in THF (20 mL) was treated with a solution of 1,4-cyclohexanedione mono-ethylene ketal (6.24 g, 40 mmol) in THF (50 mL), warmed to room temperature, stirred overnight, quenched with saturated NH4Cl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide the desired product (8.08 g, 81%). MS (CI) m/e 231(M−18)+, 249 (M+H)+, 266.2 (M+18 )+.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[S:10](Cl)(Cl)=[O:11].O>C(OCC)C>[CH2:1]([C:3]1([CH2:8][CH3:9])[CH2:6][O:7][S:10](=[O:11])[O:5][CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(CC)(CO)CO
Solvent: CCOCC
Solvent: O
Product: CCC1(CC)COS(=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Step A A mixture of 2,2-diethyl-propane-1,3-diol (Aldrich) (5.5 g, 40 mmol) in anhydrous ethyl ether (100 mL) at 0° C. was added thionyl chloride (10.6 g, 90 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-diethyl-[1,3,2]dioxathiane 2-oxide as a colorless oil (7 g, 98%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.C1(S([N:21]2[C:25]3[N:26]=[CH:27][N:28]=[C:29]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[C:24]=3[C:23]([CH3:36])=[CH:22]2)(=O)=O)C=CC=CC=1.[C:37]([O:41][C:42]([NH:44][CH2:45][C@H:46]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)[C:47](O)=[O:48])=[O:43])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>C(Cl)Cl.C([O-])(O)=O.[Na+].CO>[C:37]([O:41][C:42](=[O:43])[NH:44][CH2:45][C@H:46]([CH2:50][C:51]1[CH:52]=[CH:53][C:54]([Cl:57])=[CH:55][CH:56]=1)[C:47]([N:33]1[CH2:32][CH2:31][N:30]([C:29]2[C:24]3[C:23]([CH3:36])=[CH:22][NH:21][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:35][CH2:34]1)=[O:48])([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIPEA (120 μL, 0.70 mmol) was added to a suspension of 7-Benzenesulfonyl-5-methyl-4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (50 mg, 0.12 mmol) and (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (40 mg, 0.13 mmol) in DCM (10 mL) at room temperature. Then, HBTU (48 mg, 0.13 mmol) was added and the reaction stirred at room temperature overnight. MeOH (5 mL) and 3M LiOH (1.2 mL) were added and the mixture stirred and heated at 50° C. for 2 hours. The mixture was diluted with saturated aqueous NaHCO3 (10 mL), extracted into DCM, dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by column chromatography on silica (50% EtOAc/hexanes) to give (S)-{2-(4-Chlorobenzyl)-3-[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-3-oxo-propyl}-carbamic acid tert-butyl ester. LCMS (APCI+) m/z 253 [M+H]+; Rt: 2.85 min. This was taken up into MeOH (10 mL) and treated with anhydrous HCl (4M in dioxane, 20 mL.) The solution was stirred at room temperature overnight and concentrated in vacuo to give (S)-2-Aminomethyl-3-(4-chlorophenyl)-1-[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride (21 mg, 37%.) LCMS (APCI+) m/z 413 [M+H]+; Rt: 1.82 min.
Reaction SMILES: C(=O)C=CC1C=CC=CC=1.NC1C=CC(CC(O)=O)=CC=1.[As](=O)(O)(O)O.P(=O)(O)(O)O.[OH-].[Na+].[C:34](=[O:37])([O-])[O-:35].[Na+].[Na+].[C:40]1([C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH2:56][C:57](O)=O)[CH:52]=3)[N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(O)C.O.CO.CCCCC>[CH3:57][CH:56]([C:51]1[CH:52]=[C:53]2[C:48](=[CH:49][CH:50]=1)[N:47]=[C:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:55]=[CH:54]2)[C:34]([OH:35])=[O:37]
Reactant: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1
Reactant: O=C([O-])[O-]
Agent: Nc1ccc(CC(=O)O)cc1
Agent: O=CC=Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CCCCC
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2nc(-c3ccccc3)ccc2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
45 ml of cinnamaldehyde are added dropwise to a mixture of 38 g of p-aminophenylacetic acid, 71 g of arsenic acid and 300 ml of phosphoric acid. The reaction mixture is stirred for 2 hours at 120°C, 50 ml of polyphosphoric acid are then added and the whole is again stirred for 16 hours at 110°-120°C. The reaction mixture is cooled to 0°C and adjusted to a pH of 5-6 first with 2 N sodium hydroxide solution and then with solid sodium carbonate. This suspension is extracted with ethyl acetate and the organic phases are then extracted 6 times with 50 ml of 1 N hydrochloric acid at a time. The hydrochloric extracts are combined and a few pinches of sodium nitrite are added. The solution is left to stand for 15 minutes at room temperature and is then adjusted to pH 5.6, using a pH-meter, by adding sodium carbonate. This solution is extracted with ethyl acetate and the organic layers are washed with water, dried over sodium sulphate and evaporated. The residue obtained is crude 2-phenyl-6-quinolineacetic acid. Melting point 176°-179°C (from methanol-pentane). α-Methyl-2-phenyl-6-quinolineacetic acid of melting point 161°-162°C (from ethanol-water) is obtained analogously.
Reaction SMILES: BrCCCCCO[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.CNC.O>C(O)C>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[C:11]1[CH:20]=[CH:21][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCBr)cc1
Agent: CNC
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
A solution of 3.0 g of 4-[(5-bromopentyl)oxy]benzophenone in 30 ml of ethanol was heated to 90° in a pressure tube for 1.5 hours with 16 ml of a 33 percent solution of dimethylamine in ethanol. After cooling the mixture was poured into water and extracted three times with ethyl acetate. The organic phases, dried over sodium sulphate, were evaporated and the residue was chromatographed on neutral aluminium oxide (activity grade III) with hexane:ethyl acetate 7:3). There were obtained 2.69 g (97%) of 4- (5-(dimethylamino)pentyl)oxy]benzophenone as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[C:7]([O:14]C)[CH:8]=[CH:9][C:10]=2[O:12]C)[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].[F:19][C:20]1[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]2[C:21]=1[C:22](=[O:33])O[C:24]2=[O:32]>>[F:31][C:26]1[C:25]2[C:24](=[O:32])[C:9]3[C:8](=[C:7]([OH:14])[C:6]4[C:11]([C:10]=3[OH:12])=[C:2]([F:1])[C:3]([F:18])=[C:4]([F:17])[C:5]=4[F:16])[C:22](=[O:33])[C:21]=2[C:20]([F:19])=[C:28]([F:29])[C:27]=1[F:30]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: COc1ccc(OC)c2c(F)c(F)c(F)c(F)c12
Product: O=C1c2c(F)c(F)c(F)c(F)c2C(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O

Procedure:
{1-1} First, 1,2,3,4,7,8,9,10-octafluoro-6,11-tetrahydroxynaphthacene-5,12-dione (7) was synthesized from 1,2,3,4-tetrafluoro-5,8-dimethoxynaphthalene (6) and 4,5,6,7-tetrafluoroisobenzofuran-1,3-dione (2).