Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Cu][C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14])#[N:17]
Reactant: COC(=O)c1ccc(Br)c(OC)c1C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC)c1C
Temperature: 150 °C
Yield: 67.6 %

Procedure:
To a sealed tube vessel was added methyl 4-bromo-2-methyl-3-(methyloxy)benzoate (280 mg, 1.08 mmol), copper (I) cyanide (97 mg, 1.08 mmol) and dimethylformamide (2 mL). The mixture was heated at 150° C. for 24 hours, then was cooled to room temperature and filtered through a pad of Celite. After washing the Celite with ethyl acetate, the combined filtrate was washed with 5% aqueous lithium chloride, and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10% ethyl acetate in hexane, purified fractions were pooled and concentrated to afford 150 mg, 0.73 mmol (68%) of methyl 4-cyano-2-methyl-3-(methyloxy)benzoate. 1H NMR (400 MHz, CDCl3): 7.61 (d, 1H), 7.47 (d, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.49 (s, 3H). MS (EI) for C11H11NO3: 206 (MH+).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]>CCOC(C)=O.CN(C=O)C.[Pd]>[C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Yield: 55.9 %

Procedure:
A solution of tert-butyl 1-(4-(4-((2-(1-carbamoylcyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (0.25 g, 0.44 mmol) in EtOAc (12 mL) and DMF (2.0 mL) was stirred with Pd/C 10% (0.15 g) under an atmosphere of hydrogen for 16 hours at ambient temperature. The reaction mixture was diluted with EtOAc, filtered through a plug of Celite and washed with EtOAc. The solvents were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf 0-100% EtOAc in cyclohexane) to give the title compound 70 as a colourless oil (0.14 g, 56%). LCMS-C: rt 5.88 min; m/z 570 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.CN(C)C=O>O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:30]=[CH:29][C:27]=1[O:28][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH:21]=[O:20]
Reactant: ClCc1csc(N2CCCCC2)n1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1csc(N2CCCCC2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine (1.00 g), potassium carbonate (0.64 g), vanillin (0.70 g) and N,N-dimethylformamide (30 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.34 g, 88%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[CH:3]=1.[I:21](O)(=O)(=O)=O.II>CO.ClCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[I:21]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(F)c2)n1
Agent: II
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Yield: 236.6 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoropicolinate (3.1 g, 10.38 mmol) was dissolved in methanol (40 mL). Periodic acid (0.946 g, 4.15 mmol) and iodine (2.371 g, 9.34 mmol) were added. The reaction mixture was heated at reflux overnight. The cooled reaction mixture was diluted with dichloromethane and washed with 1N sodium sulfite. The organic phase was washed with 1N sodium sulfite, washed with saturated sodium chloride, dried over magnesium sulfate, fitered, and concentrated onto celite. The product was purified by flash chromatography (SiO2, 100% dichloromethane) to provide the title compound 4.17 g, 9.82 mmol, 95% yield) as a pink solid: 1H NMR (400 MHz, DMSO-d6) d 3.88 (s, 3H), 6.80 (s, 2H), 7.65-7.77 (m, 2H), 7.77-7.84 (m, 1H); 19F NMR (376 MHz, DMSO-d6) d −140.15 , −115.85. ESIMS m/z 426 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [H][H]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Product: COc1ccc(C)c(N)c1
Yield: 72 %

Procedure:
A mixture of 10 gm. (60 mmol) of 3-nitro-4-methylanisole and 4 gm. of 10% Pd/C was stirred under 1 atm. of hydrogen for 30 hours, filtered, and evaporated in vacuo to give 3-amino-4-methylanisole as a residue which was dissolved in 250 ml. of tetrahydrofuran containing 13 gm. (60 mmol) of tert-butyl dicarbonate, refluxed for 3 hours, cooled, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient 5-10% Et2O /hexane to give 2 (R1=5-OMe), 10.3 gm., 72% yield, mp 72°-74° C.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([SH:14])[N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH3:3].[CH3:25]I>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([S:14][CH3:25])[N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)n2nc(S)nc2c1Cc1ccc([N+](=O)[O-])cc1
Reactant: CI
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C)n2nc(SC)nc2c1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of 7-n-propyl-5-methyl-2-mercapto-8-(4-nitrobenzyl)-1,2,4-triazolo[1,5-c]pyrimidine, prepared in Example 37, are dissolved in 50 ml of chloroform and 2.2 ml of triethylamine. 1.5 ml of methyl iodide are added and the mixture is stirred at room temperature for 2 hours and then left overnight. The mixture is then washed with dilute sodium hydroxide solution and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated under vacuum to give a residue which crystallise in an ether/pentane mixture to yield 4 g of 7-n-propyl-5-methyl-2-methylmercapto-8-(4-nitrobenzyl)-1,2,4triazolo[1,5-c]pyrimidine in the form of crystals of melting point 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]([N:9]([CH3:22])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([N:9]([CH3:22])[C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][S:27][C:25](=[O:28])[CH3:26])[CH2:14][CH2:15]2)=[O:8])=[CH:23][CH:24]=1
Reactant: CC([O-])=S
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C

Procedure:
To 1.72 g (4.58 mmol) trans-Methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl ester in 17 ml DMF, 0.78 g (6.86 mmol, 1.5 eq) potassium thioacetate were added and the mixture was heated to 100° C. for 10 min. The mixture was concentrated under vacuum and the residue was dissolved in saturated NaHCO3/Et2O(3×). The organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 1.69 g (quantitative) of trans-Thioacetic acid S-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl} ester, MS: 356 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][C@@H:13]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:31]([NH:38][C:39](=[O:40])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][C@@H:13]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(NC(=O)NCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (100 mg, 0.234 mmol) in THF (5 ml) was added dropwise benzylisocyanate (32 μl, 0.257 mmol). The reaction mixture was stirred at room temperature for 2 hours and the solvent was concentrated in vacuo. The residue was purified by silica gel (4.5 g) column chromatography eluting with chloroform/methanol (30:1) to give 1-[(R)-4-(6-(3-benzylureido)indol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (101 mg, 77%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 69.8 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.00 g; 4.3 mmol), the product from 12a (1.37 g; 4.3 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 1.03 g; 5.0 mmol), and pyridine (2.0 mL) in dichloromethane (40 mL) using Procedure E. The crude product was purified on a 100×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2), collecting 16×50 mL fractions. From evaporation of fractions 4-9 gave 1.6 g (71%) product was obtained (yellowish oil).
Reaction SMILES: [K].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][N:4]=1.ClC1C2C(=CC=C(Cl)C=2)C=C(C)N=1.[C:28]([N:32]1[CH2:36][CH:35]([CH2:37][OH:38])[O:34][CH:33]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:31])([CH3:30])[CH3:29]>C(O)(C)(C)C>[C:28]([N:32]1[CH2:36][CH:35]([CH2:37][O:38][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)[C:6]([CH3:14])=[CH:5][N:4]=2)[O:34][CH:33]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cnc(Cl)c2cc(Cl)ccc12
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Agent: Cc1cc2ccc(Cl)cc2c(Cl)n1
Agent: [K]
Solvent: CC(C)(C)O
Product: Cc1cnc(OCC2CN(C(C)(C)C)C(c3ccccc3)O2)c2cc(Cl)ccc12

Procedure:
0.74 g of Potassium is dissolved in 15 ml of absolute tert.-butanol and 4.0 g of 1,7-dichloro-4-methylisoquinoline [m.p. 90°-92°: preparable in manner analogous to that described in Helv. Chim. Acta 52 (1969) 1755-1762 for the preparation of 1,7-dichloro-3-methylisoquinoline] and 4.4 g of 3-tert.-butyl-5-hydroxymethyl-2-phenyloxazolidine are added. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness. The product is digested in water, extracted with ether, the ether phase dried and the ether distilled off. 1-(3-tert.-Butyl-2-phenyl-5-oxazolidinyl-methoxy)-7-chloro-4-methylisoquinoline is obtained as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.P(Br)(Br)(Br)=O.[CH3:29][Sn:30](Cl)([CH3:32])[CH3:31]>>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:30]([CH3:32])([CH3:31])[CH3:29])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Reactant: C[Sn](C)(C)Cl
Agent: O=P(Br)(Br)Br
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1

Procedure:
FIG. 38 depicts the synthesis of 1,8-bis(3,3′-(3,5-dimethylphenyl)-9,9′-diacridyl)naphthalene (32). Suzuki coupling of commercially available 3-bromoaniline, 25, and 3,5-dimethylboronic acid afforded 3-(3,5-dimethyl-phenyl)aniline, 26, in high yields. Treatment of 26 with 2-chlorobenzoic acid 27 gave N-3-(3,5-dimethylphenyl)anthranilic acid, 28, which was converted to 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, using phosphorous oxybromide. Lithiation of 29 at −78° C. followed by stannylation with trimethylstannyl chloride resulted in the formation of 3-(3,5-dimethylphenyl)-9-trimethylstannylacridine, 30, in high yields. Employing stannane 30 and 1,8-dibromonaphthalene 31 in a CuO-promoted Stille coupling yielded 1,8-bis(3,3′-(3,5-dimethylphenyl)-9,9′-diacridyl)naphthalene, 32. We were pleased to find that the anti-isomers of 32 can be separated on a WhelkO-1 column. The CD spectra of the enantiomers of 32 are shown in FIG. 39.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20]C(C#N)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([OH:26])(=[O:25])[CH3:24]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:21]=[CH:20][C:24]([C:23]([OH:26])=[O:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 38 %

Procedure:
4-(4-Benzylpiperazin-1-yl) benzonitrile (4.0 g, 15 mmol) was dissolved in glacial acetic acid (40 mL), 6 M hydrochloric acid (50 mL) was added and the reaction mixture was stirred at 100° C. for 17 h. The solvent was evaporated, the residue was suspended in water (10 mL) and the pH was adjusted to 3 by addition of 2 M sodium hydroxide (35 ml). The slurry was stirred at 50° C. for 2 h, cooled and the precipitate was filtered and dried in vacuo to give 4.1 g of a crude product. The solid was partitioned between methylene chloride (40 mL) and water (220 mL) with 2 M sodium hydroxide (8 mL). The aqueous phase was washed with methylene chloride (40 mL) and the pH was adjusted to 5 with 2 M hydrochloric acid. The aqueous phase was cooled, the precipitate was filtered and dried in vacuo to give 1.6 g (38% yield) of the title compound: mp 226° C. (dec); EIMS (70 eV) m/z (relative intensity) 296 (44, M+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]([OH:17])=[O:16])(=[O:4])=[O:3].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][S:2]([C:5]2[C:6]3[C:11](=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:4])=[O:3])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)O)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
5-Chlorosulfonyl-naphthalene-1-carboxylic acid 45 (2.00 g, 7.39 mmol) was dissolved in dichloromethane (30 mL). Triethylamine (2.24 g, 3.1 mL, 22.2 mmol) was added followed by 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 8.13 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (50 mL) and charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 46 (3.0 g, 93%) as a yellow foam. 1H NMR (300 MHz, d6-DMSO) δ 9.11 (d, 1H), 8.62 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.62 (m, 2H), 3.91 (d, 1H), 3.62 (m, 2H), 3.15 (m, 1H), 2.67 (m, 2H), 1.89 (m, 2H), 1.52 (m, 2H), 1.40 (s, 9H) LC/MS m/z 435 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>CC(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2-(4-Hydroxy-phenyl)-propionic acid (788 mg, 1 mmol) in CH3COOH (10 ml) is added to 60% Nitric acid (552 mg, 1.11 mmol) at room temperature. The reaction mixture is stirred for 1 h. The iced water (50 ml) added to the reaction mixture. The mixture is extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=2[C:7]=1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]2[CH3:17])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=1)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1>>[CH2:1]([C:3]1[O:4][C:5]2[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=2[C:7]=1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([CH2:18][N:30]3[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[N:14]2[CH3:17])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=1)[CH3:2]
Reactant: CCc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)(O)C1CCNCC1
Product: CCc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 2-(2-ethylbenzofuran-3-yl)-9-methyl-6-morpholino-9H-purine-8-carbaldehyde and 2-(piperidin-4-yl)propan-2-ol were reacted to give 430. [M+H]+ 519.6
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([O:44][C:45]2[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=[CH:49][C:50]=2[O:51][CH3:52])[CH2:43][CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:47]1[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:45]([O:44][CH:40]2[CH2:41][CH2:42][CH2:43]2)[CH:46]=1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC1CCC1
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CCC1
Yield: 64.7 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 0.40 g (1.1 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 0.49 g (1.6 mmol) of 2-(3-cyclobutoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(f) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 339 mg of the title compound was obtained as a pale yellowish solid. (Yield: 67%)
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CS(O[CH2:22][C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)(=O)=O>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][C:27]=3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1[nH]ccc1Cc1cccc(F)c1
Reactant: Cc1ccc(OC2C(C(=O)O)C2(C)C)cc1
Product: Cc1ccc(OC2C(C(=O)OCc3[nH]ccc3Cc3cccc(F)c3)C2(C)C)cc1

Procedure:
Following the procedure of Example 2, 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylic acid is reacted with 3-(3-fluorobenzyl)-pyrrolylmethyl methanesulfonate to yield 3-(3-fluorobenzyl)-pyrrolylmethyl 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4].[CH2:19](I)[CH3:20].[H-].[Na+]>C1COCC1>[CH2:19]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])=[C:6]1[CH3:16])[CH3:20]
Reactant: CCI
Reactant: COc1ccc2c(C(=O)C(F)(F)F)c(C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(6-methoxy-2-methyl-1H-indol-3-yl)-ethanone 71a (1.3 g, 5.05 mmole) in 20 ml anhydrous THF was added ethyl iodide (2.36 g, 15.15 mmole) and sodium hydride (404 mg, 60% in mineral oil, 10.1 mmole) with ice bath cooling. The mixture was warmed slowly to room temperature and stirred for an additional four hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under rot vap. The residue was purified by column chromatography (eluting with 20–30% EtOAc in hexanes) to give a brown oil (580 mg, 40% yield). 1H NMR (300 MHz, CDCl3) δ 7.91 (1H, d, J=8.9 Hz), 6.93 (1H, dd, J=2.3, 8.9 Hz), 6.82 (1H, d, J=2.3 Hz), 4.18 (2H, m), 3.88 (3H, s), 2.76 (3H, s), 1.40 (3H, m).