Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:13]4[S:18][C:17]([CH:19]([CH3:23])C(O)=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.Cl.CNC.[CH3:41][N:42]([CH:44]=[O:45])[CH3:43]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:13]4[S:18][C:17]([CH2:19][CH2:23][C:44]([N:42]([CH3:43])[CH3:41])=[O:45])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN(C)C=O
Reactant: CC(C(=O)O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionic acid (145 mg) in DMF (5 mL) at room temperature was added carbonyliimidazole (115 mg). The reaction mixture was then stirred at room temperature for 1 h. Then, triethylamine (0.15 mL) and dimethylamine hydrochloride (58 mg) were added and the solution was stirred at room temperature for 16 h. The reaction was then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (3×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 148 as a white solid (96 mg). NMR: DMSO: 2.68-2.84 (2 H, m, CH2), 2.86 (3 H, s, Me), 3.02 (3 H, s, Me), 3.18 (2 H, t, J 7.22, CH2), 3.79-3.84 (4 H, m, CH2), 3.98-4.02 (4 H, m, CH2), 7.40 (1 H, s, Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+ 437.22
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=1)(C)(C)C.Cl[CH2:22]Cl>FC(F)(F)C(O)=O>[Br:15][C:13]1[CH:12]=[C:11]([C:16]([O:18][CH2:19][CH3:22])=[O:17])[CH:10]=[C:9]([CH:14]=1)[O:8][CH2:7][C:6]([OH:5])=[O:20]
Reactant: COC(=O)c1cc(Br)cc(OCC(=O)OC(C)(C)C)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(Br)cc(OCC(=O)O)c1
Reaction time: 2 h

Procedure:
A solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-acetic acid tert-butyl ester (12.8 g) in a mixture of dichloromethane (100 ml) and trifluoroacetic acid (100 ml) was stored at room temperature for 2 h. The solution was concentrated under reduced pressure. The residual solid was suspended in toluene and the solvent removed under reduced pressure to give the title compound as a brown solid (10.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[NH:6]1)=[O:4].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:6]1[S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
(2R,5S)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.33 g, 1.5 mmol) was dissolved in 1,2-dichloroethane (2 mL) and Et3N (1.0 mL, 7.4 mmol, 5 eq) was added followed by 4-chlorobenzenesulfonyl chloride (0.78 g, 3.7 mmol, 2.5 eq). The mixture was heated at 100° C. for 16 hr. Solvent was removed under vacuum and the residue was dissolved in EtOAc (10 mL), washed with 10% NaHCO3 and brine, dried (Na2SO4) and concentrated under vacuum. Chromatography on silica gel (5–10% EtOAc/hexanes) yielded 0.45 g (75%) of pure (2R,5S)-1-(4-chloro-benzenesulfonyl)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester as yellowish solid. 1H NMR (CDCl3, 300 MHz) δ 7.67 (2H, d), 7.42 (2H, d), 7.24 (3H, m), 6.98 (1H, m), 4.95 (1H, t), 4.82 (1H, q), 3.94 (3H, s), 2.45–2.25 (3H, m), 2.05 (1H, m).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:27])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClCCl>CO>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:2])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)([CH3:15])[C:13](=[O:27])[NH:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1[N+](=O)[O-]
Yield: 64.6 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 4,6-dichloro-2-[2-(4-methoxy-3-nitro-phenyl)-propionylamino]-benzoic acid methyl ester (0.20 g, 0.47 mmol) and LiHMDS (1.40 mmol, 1M THF solution). After normal workup, the objective compound (120 mg, 71%) was obtained as yellow solid by a flash column chromatography (dichloromethane:methanol=30:1): 1H NMR (200 MHz, DMSO-d6) δ 1.60 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.05 (d, J=2.0 Hz, 1H, ArH), 7.29-7.37 (m, 2H, ArH), 7.61 (d, J=2.0 Hz, 1H, ArH); m.p. 255-256° C.; MS(EI) m/e 394 [M+], 207, 132, 119; HRMS m/e cacld. for C17H12N2O5Cl2 394.0123, found 394.0114.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:12]1>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:11][CH:12]=2)(=[O:21])=[O:22])=[O:25])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1csc2ccccc12
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2csc3ccccc23)n1
Yield: 73.9 %

Procedure:
To 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 25 ml acetonitrile was added 2.4 g of benzothiophene-3-sulfonyl isocyanate with stirring. After stirring overnight at ambient temperature the mixture was filtered and the precipitate was washed with butyl chloride to yield 2.8 g of a white solid, m.p. 187°-188°. It showed absorption peaks by Nuclear Magnetic Resonance (60 MC) at 2.25 and 3.9 (methyl and methoxy in triazine), at 7-8 (benzo hydrogens) and 8.3 δ (thiophene hydrogen) consistent for the desired product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=3)[CH2:1]2)=[CH:15][CH:14]=1
Reactant: ClC/C=C/c1ccc(Cl)cc1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)CCN(C/C=C/c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 62.4 %

Procedure:
A mixture of 2 g of 1,2,3,4-tetrahydro-6-isoquinolinol and 2.5 g of (E)-1-chloro-4-[3-chloro-1-propenyl]-benzene, 2 g of potassium carbonate and 50 ml of DMF was stirred for 36 hours at 25° C. and then the DMF was evaporated off under reduced pressure. The residue was taken up in a mixture of methylene chloride and water and filtration was carried out to obtain 2.5 g of the desired product melting at 233-234° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CC(N(C)C)=O.ClCCl>[CH:19]1([NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:3]=2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6pyrrolidinyl-3-pyridinecarboxylate (Example C-2, 500 mg, 1.83 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 1 day. The reaction mixture was diluted with dichloromethane (40 mL), washed with water and dried on sodium sulfate. Flash chromatography on a silica gel column using dichloromethane/hexane (3:2) as eluent provided 270 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:21][CH3:22]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC)c1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (prepared according to M. I. Dawson et al WO 2003048101; 0.5 g, 2.04 mmol), potassium carbonate (0.84 g, 6.12 mmol) and iodoethane (0.2 mL, 2.45 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under vacuum to an oil. The oil was purified by column chromatography using EtOAc/hexane (0-50%) as eluent to give the product (0.35 g, 62%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1c(F)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound, 2-Bromo-6-fluorobenzonitrile, the procedure for the preparation of which may be found in Hynes, John B. et. al., J. Hetercycl. Chem. 1988, 25, 1173-7, (2.0 g, 10.0 mmol) and phenylboronic acid (3.66 g, 30 mmol) were added to a mixture of toluene (80 mL), methanol (20 mL), and 2 M aqueous sodium carbonate (20 mL). This mixture was refluxed while stirring under argon for 15 min. The resulting mixture was cooled to room temperature and tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1 mmol) was added. The. resulting mixture was then refluxed for 12 hours while stirring under argon. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (2×), brine (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0-10% methylene chloride in hexane. Recrystallization from methylene chloride hexane gave the title product as a white crystalline solid. mp 78-79° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)NC(C)C
Product: CC(C)N(C(=O)CSc1nc(-c2ccc(F)cc2)cs1)C(C)C

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 75.1 mg (0.74 mmol) of diisopropylamine. Yield: 57 mg.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:28]5[CH2:29][O:30][CH2:31][CH2:32][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CC1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (85 mg, 75%), MS (ISP) m/z=457.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCO
Agent: [Pt]
Solvent: CCO
Product: Nc1cnc2ccccc2c1NCCO

Procedure:
2-[(3-Nitro4-quinolinyl)amino]ethanol (6 g) was combined with ethanol (200 mL) and platinum on carbon catalyst. The mixture was hydrogenated on a Parr apparatus. This procedure was repeated four additional times using a total of 30 g of starting material. The mixtures from all five hydrogenations were combined and then filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide crude 2-[(3-amino-4-quinolinyl)amino]ethanol.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[O:25]([C:2]1[C:3]2[N:10]([CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(Cn1ccc2ncnc(Cl)c21)OCC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(Cn1ccc2ncnc(Oc3ccccc3)c21)OCC
Temperature: 140 °C
Yield: 94.7 %

Procedure:
A mixture of 4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1 g), phenol (420 mg), potassium carbonate (617 mg) and 1-methyl-2-pyrrolidone (6.74 mL) was stirred with heating at 140° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→40/60) to give the title compound (1.15 g) as a yellow oil.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:26])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1cc(-n2cnc3ccccc32)nc(N[C@@H](C)c2ccccc2)n1
Yield: 48.9 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (30 mg) and 2-methylphenyboronic acid (18 mg) in 10:1 toluene:EtOH was added 1M Na2CO3 (0.215 mL) and Pd(PPh3)4 (5 mg). The resulting mixture was heated and maintained at reflux for 9 h, then cooled and filtered through MgSO4. The filtrate was concentrated under reduced pressure and purified by preparative thin layer chromatography (1:50 EtOAc:CH2Cl2) to give 17 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.58 (br s, 1H); 7.85-7.3 (m, 13H); 6.9 (s, 1H); 5.9 (br s, 1H); 5.25 (br s, 1H); 2.45 (br s, 3H); 1.7 (d, J=7.1 Hz, 3H). Mass spectrum (CI) 406.3 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: C1COCCN1
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 55 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using morpholine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 132 mg, 55%) which was obtained as an off-white solid. MS: m/e=419.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCCC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 96.8 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 4-aminobutyric acid (0.134 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.35 g (98%) 142 as very pale yellow powder: mp=176-178° C.; Rf0.82 (A): Rf0.83 (B): Rf0.71 (D): IR (cm−1): 3000-3300 (OH), 3122 (C═CH), 1775 (C═O), 1707 (bs, C═O), 1617 (C═C), 1545 (N═O), 1446 (C═C), 1399 (C—O), 1349 (N═O), 1167 (C—O), 722 (C═CH); MS m/z (rel intensity) 291 (100), 191(8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=1
Reactant: CC(C)N
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3F)nnn2C)nc1
Yield: 85 %

Procedure:
As described for example 19b, 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (94 mg, 85%) which was obtained as a white solid. MS: m/e=370.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CN1C(=O)CCC1.CCOC(C)=O>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:14]=1
Reactant: NCc1ccncc1
Reactant: N#Cc1cccnc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1NCc1ccncc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 15.5 %

Procedure:
To a stirred solution of 2-chloro-nicotinonitrile (Aldrich, 10.4 g, 75.06 mmol) in dry NMP (40 ml) was added 4-(aminomethyl)pyridin (15.2 ml, 150.26 mmol). The reaction mixture was heated to 130° C., and stirred at this temperature for 20 hours. The mixture was cooled to room temperature and diluted with EtOAc (500 ml) and washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The remaining red-brown solid material was recrystallised from ethanol affording the title compound (7.73 g) as an off-white solid. The filtrate was evaporated under reduced pressure, redissolved in 2% methanol/EtOAc (v/v) and filtrated through a pad of silica gel. The filtrate was evaporated under reduced pressure and the residue was recrystallised from ethanol and gave an additional amount of the title compound (2.44 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([S:26]C(C)(C)C)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47]Cl)([O-:40])=[O:39]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([S:26][S:47][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N+:38]([O-:40])=[O:39])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SC(C)(C)C)c(Cl)cc3n2COCCOC)c1
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(SSc4ccccc4[N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1-[5-tert-butylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (3.00 g, 6.42 mmol) and DCM (32 mL) was added potassium carbonate (1.78 g, 12.9 mmol). The reaction mixture was treated with 2-nitrobenzenesulfenyl chloride (3.05 g, 16.1 mmol) and stirred at 23° C. for 16 h. The resulting residue was concentrated and purified by FCC (5-30% EtOAc/hexanes) to provide the titled compound (2.99 g, 82% crude yield) as a 2:1 ratio of regioisomers. This compound was used without further purification in subsequent reactions. MS (ESI/CI): mass calcd. for C23H22ClN5O6S2, 563.1; m/z found, 564.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.85-8.82 (m, 2H), 8.17 (s, 2H), 7.75 (s, 0.66H), 7.72 (s, 1.34H), 7.68 (s, 1.34H), 7.64 (s, 0.66H), 7.45-7.42 (m, 4H), 7.31-7.26 (m, 4H), 6.09 (d, J=2.1 Hz, 4H), 4.36 (q, J=7.1 Hz, 4H), 3.67-3.62 (m, 4H), 3.49-3.42 (m, 4H), 3.31 (d, J=1.9, 6H), 1.38 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][C:17](=[O:19])/[C:16](/[CH3:20])=[CH:15]/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
The carboxylic acid thus obtained (610 mg, 2.2 mmol) was dissolved in 10 mL of methanol and 3 drops of con. H2SO4 was added. The resulting solution was heated to reflux for 20 hr, cooled to room temperature, and partitioned between sat. NaHCO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to an oil. Silica gel chromatography (4:1, hexanes:ethyl acetate) afforded (E)-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-prop-2-en-oate as a colorless solid (610 mg, 96%). 1H-NMR (300 MHz): d 2.15 (d, 3, J=1.2), 3.81 (s, 3), 3.88 (s, 3), 7.63 (s, 1). Anal. Calcd for C17H22O4 : C, 70.32; H, 7.64. Found: C, 70.44; H, 7.72.