Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])(=[O:8])=[O:9])=[CH:11][CH:12]=1
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)CCNS(=O)(=O)c1ccc(N)cc1

Procedure:
To a solution of N-(2-diethylamino-ethyl)-4-nitro-benzenesulfonamide (200 mg, 0.664 mmol) and ammonium formate (377 mg, 5.980 mmol) in EtOH/EtOAc (1/1: 8 mL) under nitrogen was added Pd/C 10% (35.3 mg, 0.033 mmol). The mixture is refluxed overnight until completion of the reaction. After filtration through a celite plug, the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].[I-].[K+].O>CS(C)=O>[CH2:2]([C:7]1([CH2:7][CH2:6][CH2:14][CH3:13])[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:1][CH2:4][CH3:5]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=O)cc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 181.3 %

Procedure:
15.9 g of 2-acetylfluorene (11) (76.4 mmol), 18.9 g of potassium hydroxide (0.27 mol, purity: 80%), and 1.26 g of potassium iodide (7.6 mmol) were dissolved in 350 ml of anhydrous dimethylsulfoxide under nitrogen atmosphere, and a reaction temperature was maintained at 15° C. Then, 33 ml of n-bromobutane (0.3 mol) was slowly added thereto for 2 hours, followed by stirring at 15° C. for 1 hour. Thereafter 200 ml of distilled water was added to the reaction mixture and stirred for about 30 minutes, a product was extracted with 300 ml of dichloromethane, and the extracted organic layer was washed with 100 ml of distilled water three times. Then, the recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained product was purified using a silica gel column chromatography (developing solvent: dichloromethane:n-hexane=15:1), thereby obtaining 22.2 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone (12) (90.8%) as a light yellow liquid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:26]O>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:26])=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(=Cc2ccc(C(=O)O)cc2)C1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCN1C(=O)NC(=Cc2ccc(C(=O)OC)cc2)C1=O
Temperature: 40 °C

Procedure:
3-n-Butyl-5-(4-carboxybenzylidene) hydantoin (5.8 g; 0.02 mole) was added gradually to a stirred mixture of thionylchloride (1.5 ml; ca 0.02 mole) in methanol (100 ml.) prepared at -10° C. The mixture was gradually warmed to 40° C. and after 1 hour was boiled under reflux for 3 hours. After cooling and storage in the refrigerator, a white solid formed and was filtered off, washed with cold methanol and dried. This solid was recrystallised from ethyl acetate to give the title compound. Yield 3.2 g; m.p. 212° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH3:30])(=[O:4])[CH2:2][CH3:3].C(=O)(O)[O-:32].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][CH3:30])=[O:32])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCSCCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)CCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(3-propylthiopropoxy)quinoline (200 mg, 0.47 mmol) was dissolved in 5 ml methylene chloride. A solution of sodium bicarbonate (80 mg, 0.95 mmol) in 5 ml water was added. The mixture was cooled to 2°-4° C. A solution of 70% m-CPBA (115mg, 0.47 mmol) in 5 ml methylene chloride was added dropwise during 10 min. The temperature was allowed to rise and the mixture was stirred for 30 min at room temperature. The methylene chloride layer was separated and washed with water. The organic layer was then dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (methylene chloride: ethanol 95:5). 160 mg (77%) of the title compound was obtained.
Reaction SMILES: [O:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N:10]1[C:17]2[N:13]([N:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[CH:12]=[CH:11]1)[CH3:2].[F:24][S:25]([F:38])([F:37])([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[CH3:2][O:1][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([S:25]([F:38])([F:24])([F:35])([F:36])[F:37])[CH:27]=2)=[CH:5][C:4]=1[N:10]1[C:17]2[N:13]([N:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[CH:12]=[CH:11]1
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: COc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: COc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
45 mg (0.15 mmol) of the compound of Example 10A and 37 mg (0.15 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid were reacted and worked up analogously to the procedure of Example 16. This gave 72 mg (91% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([O:29][CH2:30][C:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([C:31]2([CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: O=S(=O)(Cl)C1(COCc2ccccc2)CC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCS2
Yield: 682 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with 1-benzyloxymethyl-cyclopropanesulfonyl chloride (137 mg, 0.52 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 0.21 g of the product (70% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c2c1CC(OC(C)=O)CC2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(OC(C)=O)CC2
Reaction time: 2.5 h
Yield: 81 %

Procedure:
A solution of acetic acid 8-acetylamino-5-bromo-1,2,3,4-tetrahydronaphthalen-2-yl ester (2.6 g, 8 mmol) in 40 mL of trifluoroacetic acid was cooled in an ice bath. Fuming nitric acid (2 mL) was added dropwise and the mixture was stirred for 2.5 h. The solvent was removed by rotoevaporation, and water was added to the residue which induced solidification. The solid was collected by filtration, washed with ether and dried to give the product (2.4 g) in 81% yield.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a three-necked, 500 mL, round-bottomed flask fitted with a nitrogen inlet, mechanical stirring apparatus, and septum was added D-allo-threonine (24.98 g, 210 mmol) followed by anhydrous DMSO (250 mL) and potassium carbonate (63.7 g, 460 mmol). This mixture was stirred under nitrogen at room temperature for a period of 30 min. To this mixture was then added 2-chloro-4-fluoro-3-methylbenzonitrile (35.51 g, 210 mmol) followed by heating of the reaction mixture to 70° C. in an oil bath for a period of 48 hs. The reaction was then allowed to cool to room temperature followed by subsequent cooling to 0° C. and a 5% citric acid/water solution (1.5 Liters) was slowly added followed by careful addition of solid citric acid until evolution of gas was no longer observed. This solution was then extracted with EtOAc (5×1 L). The combined organic extracts were then dried over Na2SO4 and decanted away from the drying agent. The solvent was then removed under reduced pressure using rotary evaporation to reveal a red oil that was purified by silica gel chromatography by first eluting with hexanes/EtOAc, 1/1 (2 L) followed by methanol/EtOAc 1/7 (5 L) to afford of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid as a light red oil/solid (27.05 g, 48%). 1H NMR (500 MHz, CD3OD, δ in ppm) 7.42 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H), 2.32 (s, 3H), 1.35 (d, J=6.6 Hz, 3H); 13C NMR (125.6 MHz, CD3OD) δ 174.2, 151.9, 137.16, 134.0, 122.6, 119.1, 110.1, 101.2, 69.1, 63.2, 20.0, 14.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12]([Cl:15])([Cl:14])[Cl:13].[OH-].[K+]>CN(C=O)C.CO>[Cl:13][C:12]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([Cl:15])[Cl:14]
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 3-nitrobenzaldehyde (200 g, 1.32 mol) and chloroform (238 ml, 2.97 mol) in 800 ml of DMF cooled to -9° C. under nitrogen was added dropwise a solution of potassium hydroxide (59.8 g, 0.92 mol) in 180 ml of methanol over a 2.7 hour period. The deep purple reaction mixture was aged for 2 hours at -8° C. before quenching over 40 minutes into 1.8 liter of lN HCl and 1.8 liter of toluene cooled to -5° C. The quench mixture was stirred and cooled for an additional 0.5 hour and then brought to ambient temperature. The toluene layer was separated and washed twice with 1.8 liter of water. After treatment with 35 g of Darco G-60 charcoal for 1 hour and filtration through Super-Cel, the organic layer was washed with 1.8 liter of aqueous 5% sodium bicarbonate solution and then 1.8 liter of water. After evaporation to 550 ml the desired product was crystallized by the addition of 450 ml of hexanes. The resulting slurry was cooled at 0° C. for 2 hours and the solid was collected by filtration and rinsed with hexanes. After drying, 320 g (90% yield) of TMBA was obtained; m.p. 91- 95° C; 1H NMR 3.75 (1H, d, J=1 Hz), 5.25 (1H, d, J=1 Hz), 7.20-8.45 (5H, m).
Reaction SMILES: C1C=CN=CC=1.[FH:7].[CH3:8][O:9][C:10]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]([CH3:17])=[C:14](N)[CH:15]=1.N([O-])=O.[Na+]>N1C=CC=CC=1>[F:7][C:14]1[CH:15]=[C:10]([O:9][CH3:8])[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]=1[CH3:17]
Reactant: F
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
Under nitrogen in a nalgene bottle, a stirring solution of pyridine (17.1 mL, 3.2 M, −70° C.) was treated dropwise with HF-pyridine (51.91 mL). Next, 5-methoxy-2-methyl-4-nitro-phenylamine (10.0 g, 54.9 mmol) was added followed by sodium nitrite (6.4 g, 92.76 mmol). The dry ice/acetone bath was removed and the reaction was allowed to warm to room temperature. The solution was then heated at 60° C. for 2 h (or until nitrogen evolution stops.) After cooling to room temperature, the nalgene bottle was placed in an ice bath and 375 mL of water was slowly added to the solution. The resulting orange precipitate was collected by suction filtration and washed with 250 mL of water. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided 1-fluoro-5-methoxy-2-methyl-4-nitro-benzene (7.69 g, 76%) as a light orange solid: mp 71–74° C.; Rf 0.56 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.82 (d, J=7.5 Hz, 1 H), 6.75 (d, J=10.5 Hz, 1 H), 3.93 (s, 3 H), 2.25 (d, J=2.1 Hz, 3 H); ESI-LC/MS m/z calcd for C8H8FNO3: 185.1; Found 186.0 (M+1)+. Anal. calcd for C8H8FNO3: C, 51.90; H, 4.36. Found C, 52.11; H, 4.47.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20](Cl)[C:21]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: NCc1ccccc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccccc3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein benzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][N:63]([CH2:71][C@@H:72]([C:81]2[CH:90]=[CH:89][C:88]([O:91][C:92]([O:94][C:95]([CH3:98])([CH3:97])[CH3:96])=[O:93])=[C:87]3[C:82]=2[CH:83]=[CH:84][C:85](=[O:99])[NH:86]3)[O:73][Si:74]([C:77]([CH3:80])([CH3:79])[CH3:78])([CH3:76])[CH3:75])[C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:48][CH:47]=1>>[C:95]([O:94][C:92]([O:91][C:88]1[CH:89]=[CH:90][C:81]([C@@H:72]([O:73][Si:74]([C:77]([CH3:80])([CH3:79])[CH3:78])([CH3:76])[CH3:75])[CH2:71][N:63]([CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][CH2:53][CH2:52][C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:11](=[O:12])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]4[CH:23]=[C:24]5[C:29](=[C:30]([CH3:32])[CH:31]=4)[N:28]=[CH:27][C:26]([C:33](=[O:34])[NH2:35])=[C:25]5[NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=4)(=[O:20])=[O:21])[CH:14]=3)=[CH:51][CH:50]=2)[C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[C:82]2[C:87]=1[NH:86][C:85](=[O:99])[CH:84]=[CH:83]2)=[O:93])([CH3:98])([CH3:97])[CH3:96]
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OC(=O)OC(C)(C)C)c7[nH]c(=O)ccc67)C(=O)OC(C)(C)C)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 108 in place of 8-aminooctanol. ES/MS calcd. for C68H87N6O13SSi+ 1255.6. Found m/z=1256 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=[CH:8]1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:18][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:16])([CH3:17])[CH3:1])[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 60 °C
Yield: 43.6 %

Procedure:
To a stirred solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5.0 g, 19.5 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.47 g, 19.5 mmol) and AIBN (160 mg, 5 mol %) at room temperature. The reaction mixture was heated at 60° C. for 3 h, cooled to room temperature, and filtered through a small pad of CELITE®. The filtrate was concentrated in vacuo to give light yellow colored residue which was dissolved in EtOAc and washed with 10% NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give crude compound. The crude material was purified by flash chromatography (gradient from 20 to 30% EtOAc/hexanes), to provide the title compound (2.85 g, 43%). 1H NMR (CDCl3) δ 7.76 (s, 1H), 5.30 (s, 2H), 3.90 (s, 3H), 3.55 (t, J=8.0 Hz, 2H), 0.92 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 335.0 (M+H)+.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: c1cc[nH]c1
Reactant: O=c1c(I)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc[nH]2)coc2ccccc12
Temperature: 0 °C
Yield: 56.7 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, pyrrol (134 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added and the mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by the silica gel column chromatography, and the purified product was recrystallized from benzene/hexane to give the titled compound (59.9 mg; yield=56.4%) as light ocher crystals. Melting point: 134°-135 ° C. 1H-NMR(CDCl3, δ ppm): 6.31 (s ,H3), 8.22 (dd, H5), 7.41-7.54 (m, H6), 7.70 (t, H7), 7.41-7.54 (m, H8), 7.32 (br. t, H2'), 6.44(br. t, H3'), 6.44(br. t, H4'), 7.32(br. t, H5').
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:22]([CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1)[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C(Cl)Cl>[CH:22]([CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=1)[C:26]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
To a solution of m-phenoxybenzyl alcohol (1.89 g) and pyridine (1 ml) in methylene chloride (6 ml) is added a methylene chloride (7 ml) solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride, prepared from the corresponding acid (2.46 g) as illustrated in Example 15. After stirring the reaction mixture overnight, it is washed with water, diluted hydrochloric acid solution, dilute potassium hydroxide solution, water and evaporated to an orange oil. Purification by silica gel chromatography gives the desired ester (2.76 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([Cl:14])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: NCc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(NCc3ccncc3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (200 mg, 0.87 mmol) and (pyridin-4-yl)methanamine (188 mg, 1.74 mmol), DIEA (302 μL, 1.74 mmol) were dissolved in dioxane (5 mL). The reaction mixture was stirred at 90° C. overnight and then cooled to room temperature. The solvent was removed under vacuum and the crude product was purified by silica column chromatography using hexane/ethyl acetate/7N NH3 in methanol (60:33:7) to obtain the yellow 5-((pyridin-4-yl)methylamino)-7-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 1H NMR (DMSO-d6) δ 9.45 (t, J=6 Hz, 1H), 8.49 (m, 3H), 7.32 (d, J=6H, 2H), 6.68 (s, 1H), 4.73 (d, J=6 Hz, 2H), 3.46 (s, 3H); ESI-MS m/z 302.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:17]1([CH:23]2[CH2:24][CH2:25][N:26]([CH:14]3[C:15]4[C:10](=[N:9][C:8]5[C:3]([C:2]=4[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:11][CH2:12][CH2:13]3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCC(c2ccccc2)CC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 hours in 300 ml of toluene that contained 4-phenylpiperidine (8.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was concentrated and the residue purified by flash chromatography (5% Et3N/toluene) to give, after concentration of theproduct-containing fractions and recrystallization from EtOAc/pentane, 3.22g of analytically pure product, m.p. 189°-190°.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[O:10]=[C:2]1[N:1]([C:22]([O:24][CH3:25])=[O:23])[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of methyl (S)-(+)-2-pyrrolidone-5-carboxylate (4.80 grams, 33.5 mmol) in tetrahydrofuran (90 mL) was added a solution of lithium bis(trimethylsilyl)amide (1 M solution in hexanes, 40.0 mL, 40.0 mmol) dropwise via syringe over 15 minutes; then methyl chloroformate (2.90 mL, 36.9 mmol) was added dropwise via syringe over 5 minutes. The resulting slurry was stirred at −78° C. for 1 hour after which the reaction was quenched with 1 M HCl (50 mL). The mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and 1 M HCl (200 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound. MS (DCI/NH3) m/e 202 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 4.70 (dd, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.74-2.30 (m, 3H), 2.15-2.05 (m, 1H).