Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:27])[CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]2)=[O:15])[C:11]([CH2:34][OH:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:37]>C1C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:27])[CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]([O:26][CH3:37])=[O:25])[CH2:21][CH2:22]2)=[O:15])[C:11]([CH2:34][OH:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CC(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CN1CCC(N(C)C(=O)N2CC(c3cc(F)ccc3F)=CC2(CO)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
To 30 mg (0.06 mmol) of amino acid 17-1 in 1:1 PhH/MeOH was added 120 μL (0.24 mmol) of TMS-diazomethane. After stirring for 2 h, the reaction was concentrated by rotary evaporation and the residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 17-2 as a colorless film. Data for 17-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.45 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.7 (s, 3H), 3.2 (m, 2H), 3.05 (m, 2H), 2.9 (s, 3H), 2.3 (m, 2H), 2.0-1.8 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C27H31F2N3O4: 500.2356. Found: 500.2331.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[NH:12][C:11]=2[N:10]=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:25][CH3:26])[C:11]=2[N:10]=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2nc(Cl)n(Cc3ccccc3)c2c(=O)n1CCCO
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 318 %

Procedure:
To a solution of 7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.449 mmol) in DMF (5 mL) was added iodoethane (0.16 g, 0.13 mmol), followed by potassium carbonate (0.4 g, 2.90 mmol). The mixture was stirred at 40° C. for 4 h. The reaction was cooled and diluted with ethyl acetate. The organic phase was washed with water and brine; then it was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 92.3% yield) as yellow oil. LCMS retention time 1.296 min; LCMS MH+ 363.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[C:14]1[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([C:15]1[CH:16]=[C:17]([CH:19]=[O:20])[S:18][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 1-dodecyne (23.9 g), 5-bromo-2-thiophenecarboxaldhyde (25.0 g) and triethylamine (39.7 g) in dry tetrahydrofuran (75 ml) was degasseal and stirred at room temperature under a nitrogen atmosphere. Two mole percent of bis(triphenylphosphine)palladium(II)chloride (1.8 g) followed by one mole percent of copper(I)iodide (0.25 g) was added. The mixture was degassed and stirred at room temperature under nitrogen for three days. The precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated, and the residue was flash chromatographed (silica, 7:3-Hexane:dichloromethane). The appropriate fractions were collected and evaporated. The residue was dried at 50° C. under vacuum for three hrs to give 35.5 g (98%) of product.
Reaction SMILES: NC1C(O[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=2[O:24][CH3:25])=CC=C2C=1C=C(C)N2.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[CH:37]=[CH:36][C:35]=1[S:46](Cl)(=[O:48])=[O:47]>C(OCC)(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[CH:37]=[CH:36][C:35]=1[S:46]([NH:27][C:28]1[C:29]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=2[O:24][CH3:25])=[CH:30][CH:31]=[C:32]2[C:31]=1[CH:30]=[C:29]([CH3:28])[NH:27]2)(=[O:48])=[O:47]
Reactant: COC(=O)Cc1ccc(COc2ccc3[nH]c(C)cc3c2N)c(OC)c1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(OCC(F)(F)F)cc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Cc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(OCC(F)(F)F)cc2Cl)c(OC)c1
Reaction time: 2 h

Procedure:
Methyl 2-(4-((4-amino-2-methyl-1H-indol-5-yloxy)methyl)-3-methoxyphenyl)acetate 1.3 (30 mg, 0.088 mmol) in anhydrous pyridine (1 mol) was treated with 2-chloro-4-(2,2,2-trifluoroethoxy)benzene sulfonyl chloride (28.13 mg, 0.0968 mmol). After stirring 2 h, the reaction was diluted with ethyl acetate (5 mL) and washed with 1N HCl (2×), water (1×), saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was used immediately without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH2:12][CH2:13][OH:14])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][O:10][C:18]([CH3:20])([CH3:19])[N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CCCO)COC1(C)C

Procedure:
A solution of tert-butyl[(2S)-1,5-dihydroxypentan-2-yl]carbamate (9.45 g), 2,2-dimethoxypropane (48 mL) and p-toluenesulfonic acid monohydrate (0.41 g) in chloroform (100 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the solvent was distilled off under reduced pressure. Ethyl acetate was added thereto, and the resulting mixture was washed with water and brine, followed by drying over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=10:1-0:100) to afford tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.05 g).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.O>[Cl:26][C:24]1[CH:25]=[C:20]([C:14]2([C:16]([F:18])([F:19])[F:17])[CH:13]=[N:12][CH:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)ccc1C(=O)O
Yield: 77 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl-benzoic acid ethyl ester (Example 10.5) (2.8 g) in ethanol (40 ml) was added a solution of sodium hydroxide (0.51 g) in water (15 ml). The reaction mixture was stirred at reflux for 1 hour. After cooling to ambient temperature aqueous hydrochloric acid (1M) (20 ml), water (150 ml) and ethyl acetate (200 ml) was added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallised from diisopropyl ether to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl-benzoic acid (2.02 g) as a white solid. 1H-NMR (d6-DMSO, 400 MHz): 13.07 (s, 1H), 7.91-7.58 (m, 6H), 4.85 (d, 1H), 4.44 (d, 1H), 3.92-3.35 (m, 2H), 2.58 (s, 3H) ppm.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5][C:6]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>Cl>[CH3:1][C:2]1[NH:5][C:6]2[C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]=1
Reactant: CC(=O)O
Reactant: Nc1cccc(C(=O)O)c1N
Agent: Cl
Product: Cc1nc2cccc(C(=O)O)c2[nH]1
Yield: 72 %

Procedure:
Acetic acid (0.23 ml) was added to a solution of 2,3-diaminobenzoic acid (200 mg, 1.32 mmol) in hydrochloric acid (4M, 3.2 ml) and the mixture was refluxed for 1 hour. Solvents were evaporated and the residual solid was redissolved in boiling methanol (5 ml) iand decolorised with activated charcoal. Removal of the solvent furnished 2-methylbenzimidazole-4-carboxylic acid as an amorphous white solid (167.5 mg, 72%); δH (d6-DMSO) 2.9 (3H, s, imidazole-2-CH3), 7.6-7.8 (1H, t, Ar-5H) 8.1 (2H, d, Ar-4/6H); m/z (EI 176 (M+), 158, 130.
Reaction SMILES: [ClH:1].I.[CH3:3][N:4]([CH3:20])[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](SC)=[NH:17])[CH:14]=2)[NH:9][CH:8]=1.[C:21](O)(=O)[CH3:22].C([NH2:27])C>C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH3:3][N:4]([CH3:20])[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](=[NH:27])[NH:17][CH2:21][CH3:22])[CH:14]=2)[NH:9][CH:8]=1
Reactant: CC(=O)O
Reactant: CSC(=N)c1ccc2[nH]cc(CCN(C)C)c2c1
Reactant: CCN
Agent: Cl
Agent: I
Solvent: ClC(Cl)Cl
Product: CCNC(=N)c1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Stage (i) (1.0 g) was suspended in chloroform (25 ml) and acetic acid (0.5 ml) was added, followed by ethylamine (0.2 g) in chloroform (10 ml). The solution was stirred at room temperature for 3 h. The resulting suspension was collected, washed with diethyl ether (1 l) and dried in vacuo at 20° for 18 h to give a solid (0.5 g) which was recrystallised from methanol-ethyl acetate (1:3) to give the pure title compound as a solid (0.09 g), m.p. 261°-263°
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:14]=C(O)C=1)[C:12]#[N:13])C1C=CC=CC=1.B.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1.Cl.[C:25]([O-])(O)=O.[Na+]>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:19][C:23]=1[O:22][CH2:21][CH2:20][CH3:25])[C:12]#[N:13]
Reactant: N#Cc1cc(O)cc(OCc2ccccc2)c1
Reactant: O=C([O-])O
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: [Na+]
Product: CCCOc1ccc(C#N)cc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-benzyloxy-5-hydroxybenzonitrile (225 mg, 1 mmol) was dissolved in 2 mL THF. 2 mL of BH3-THF (1.5 M in THF and ether) was added dropwise, then the mixture was heated at reflux temperature for 3 hours. After cooling, the mixture was carefully poured to 3M HCl (ice cooled) and allowed to stir for 20 hours at room temperature. The mixture was neutralized with solid NaHCO3, thus the product precipitated as a white solid. The product was collected by filtration, washed with water, and dried (140 mg, 61%): MP 164–166° C. (dec); 1H NMR (DMSO-d6, 400 MHz) δ9.28 (br, 1H), 7.41 (d, 2H, J=6.9 Hz), 7.36 (dd, 2H, J=7.0 and 7.6 Hz), 7.30 (dd, 1H, J=7.0 and 6.6 Hz), 6.43 (s, 1H), 6.32 (s, 1H), 6.21 (dd, 1H, J=2.2 and 2.0 Hz), 4.99 (S, 2H), 3.57 (S, 2H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:4][CH:3]=2)=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Product: Clc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 49a was prepared from compound 15a and 2-chloro-5-pyridineboronic acid using the methods described in Example 1, Step G. Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H21ClN6O2: 473.1 [M+H]. found 473.2
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][OH:7])=[O:4].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][O:7][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])=[O:4]
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of tert-butyl (R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture was stirred for 4 h. The solvents were removed in vacuo. EtOAc (300 mL) was added and the solution was washed with sat'd aq NH4Cl (2×100 mL), sat'd aq NaHCO3 (100 mL) and brine (100 mL), dried, filtered and evaporated to give tert-butyl (R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)ethylcarbamate (40 g, yield 95%) as an oil that was used without further purification. 1H NMR (CDCl3, 400 MHZ): δ=0.02 (s, 6 H), 0.86 (s, 9 H), 1.45 (s, 9 H), 3.73 (s, 3 H), 3.82 (dd, J=14, 4.4 Hz, 1 H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 4.35 (m, 1 H), 5.34 (brs, 1 H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NCCC1C=CC(O)=C([OH:22])C=1>CN(C)C1C=CN=CC=1.O1CCCC1.CCCCCC.C1C=CC=CC=1>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCc1ccc(O)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
DHA is first converted to DHA anhydride in the presence of dicyclohexyl carbodiimide. This is then reacted with dopamine in the presence of 4-dimethylaminopyridine as the acid acceptor in tetrahydrofuran. In a typical experiment 300 mg of DHA (0.009 M) was dissolved in a mixture of 3 ml hexane and 4 ml benzene and stirred under nitrogen. Next, a solution of 0.00615 M of dicyclohexyl carbodiimide in 4 ml benzene (0.1267 g) was stirred together with the DHA for 3 hr at room temperature. A white precipitate of dicyclohexyl urea formed as the reaction proceeded. The dicyclohexyl urea was filtered off to give a clear solution of the anhydride in benzene. This was concentrated down to 2 ml in a rotary evaporator and diluted with 10 ml of tetrahydrofuran (dry). The freshly prepared anhydride was then added to a solution of dopamine hydrobromide (0.1053 g) (or 0.005 M) in the presence of 0.009 M of 4-diethylaminopyridine (0.098 g). The initially cloudy mixture after stirring for 30 min at room temperature gave a mixture of a clear liquid and a brown precipitate. At the end of the reaction, 0.2 ml of water was added to the mixture, and stirring was continued for an additional 30 min to completely hydrolyze any remaining unreacted anhydride. The liquid phase was isolated and evaporated to dryness to yield a brown viscous solid. This was then dissolved in 70% ethanol in water (25 ml), and the solution was then passed through a mixed-bed ion exchange resin containing a strong acidic resin based on polystyrene sulfonic acid and a strong basic resin based on quanternary amonium substituents such as tetramethyl amonimum hydroxide (RG501, Fisher Scientific, Cambridge, Mass.) using 90% ethanol in water as the eluent. This resin removes from the mixture unreacted dopamine, dimethylaminopyridine, as well as the liberated DHA molecule. The effluent from the column (a pale yellow solution) was then evaporated in a rotary evaporator to give a solid. The product was recrystallized from aqueous ethanol (yield =75%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:32]=1[CH2:33]Br)#[N:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:33][C:32]1[CH:35]=[C:36]([C:39]#[N:40])[CH:37]=[CH:38][C:31]=1[C:29]#[N:30])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C#N)c(CBr)c1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: N#Cc1ccc(C#N)c(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2,5 dicyanobenzylbromide as in the procedure of Example 43. MS (ESI) m/z 520.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O-]CC.[Na+].[N:14](OCCC(C)C)=O.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[OH:32]>C(O)C>[Cl:1][C:2]1[C:3]([N:9]=[N:14][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[OH:32])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)CCON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2ccccc2c1N=Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction flask was loaded with 3,5-dichloro-2-aminopyridine (40 g), ethanol (300 ml), and sodium ethoxide (14 g), followed by dropwise addition of isopentyl nitrite (28 g) to the flask in 30 minutes with stirring. After the dropwise addition was ended, heating was started and the mixture was stirred at 75 to 80° C. for four hours. The heating was stopped, and the reaction mixture was cooled to room temperature, followed by dropwise addition of 2-naphthol (17 g) dissolved in ethanol (50 ml) to the mixture in one hour. The resultant mixture was stirred at room temperature for one hour, heated, and stirred at 75 to 80° C. for three hours, followed by stopping the heating and then leaving the mixture to stand overnight. The reaction mixture was filtrated to remove insoluble components, and the filtrate was condensed by an evaporator. The residue was dissolved in ethyl acetate and, after being successively washed with an aqueous solution of sodium hydroxide and water, the ethyl acetate layer was condensed by an evaporator, followed by addition of methanol to the residue for crystallization. The resultant was filtrated and the crystals were dried to give intended crystals (10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:12]I.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].O>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:12][NH:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: NCCCO
Reactant: Clc1ccc(Cl)c(O[C@H](CCI)c2ccccc2)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: OCCCNCC[C@@H](Oc1cc(Cl)ccc1Cl)c1ccccc1
Reaction time: 24 h

Procedure:
The product of step (b) (0.2 g) and 3-amino-propanol (0.11 g) were dissolved in dimethylformamide (4 ml) and stirred for 24 h. The reaction was poured into water and extracted into ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate and evaporated to dryness and triturated with 1N HCl in ether to give the product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:33]([S:34]([NH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:12][CH:13]=2)=[N:5][N:4]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNS(=O)(=O)Cc3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) was mixed with α-toluenesulphonyl chloride (33 mg) in pyridine (6 ml) at 0° C. and the reaction stirred at room temperature for 72 hours. Further α-toluenesulphonyl chloride (66 mg) in pyridine (3 ml) was added and stirring continued for 18 hours. The reaction was diluted with DCM and washed with hydrochloric acid (2N, 4×5 ml) and then water (5 ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents 4′-(5-{[(benzylsulfonyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13]OS(C)(=O)=O)=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1.[CH3:32][NH:33][CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13][N:33]([CH3:34])[CH3:32])=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 77.1 %

Procedure:
Following the procedure of Example 7, 2-(3, 4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as slightly-yellow needles (yield: 77.1%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[CH:9]1([S:8][C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(SC2CCCC2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(SC3CCCC3)nc3c2CCC3)cc1
Yield: 108.8 %

Procedure:
Following general procedure B1, 4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.130 g, 0.51 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.137 g, 0.77 mmol) to afford crude product (0.220 g) as a colorless gum. MW=396.55. 1H NMR (CDCl3, 300 MHz) δ 7.27 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.74 (s, 1H), 5.62 (s, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.93-3.79 (m, 1H), 3.60 (s, 2H), 3.52-3.46 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.22-2.02 (m, 4H), 1.83-1.51 (m, 6H), 1.27 (t, J=7.0 Hz, 3H); APCI MS m/z 397 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[Br:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1CBr

Procedure:
To 100 mL round bottom flask charged with ester 101b (230 mg, 1.04 mmol), N-bromosuccinimide (214 mg, 1.2 mmol), benzoyl peroxide (25 mg, 0.1 mmol) in benzene (5 mL). After the mixture was stirred at reflux for 4 h, H2O (10 mL) was added. The aqueous phase was extracted with CH2Cl2 (2×10 mL), and the combined organic extracts were washed with brine (10 mL), dried with Na2SO4 and concentrated. The crude 101c (287 mg, 92%) was used without further purification.