Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]([CH3:21])[C:4](=[O:22])[O:3]1.[OH-:23].[Ba+2].[OH-]>O1CCCC1.O>[CH3:21][CH:5]([CH:6]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([OH:23])[CH3:1])[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)C1C(C)OC(=O)C(C)C1NCc1ccccc1
Reactant: [OH-]
Agent: [Ba+2]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl (2SR,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylate (3 mg) and barium hydroxide (7 mg) were dissolved in a mixture of tetrahydrofuran and water (2:1) and stirred vigorously at room temperature for 1 hour. The reaction mixture was treated as in Reference Example 17 to give (2RS,3RS,4SR,5SR)-2-methyl-3-benzylamino-4-ethoxycarbonyl-5-hydroxyhexanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[I:20]N1C(=O)CCC1=O.B(F)(F)F.[O-]S([O-])(=S)=O.[Na+].[Na+]>C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[C:16]([I:20])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCOC(=O)C1(c2nc3c(OC)ccc(I)n3n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under an argon atmosphere 1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester (4.1 g, 13.7 mmol) was mixed with N-iodosuccinimide (4.9 g, 21.9 mmol). BF3*2H2O (7.0 mL, 110 mmol) was added at 20° C. The dark suspension was stirred at rt for 24 h. NIS (2.5 g) and BF3*2H2O (2.0 mL) were added and the suspension was stirred for 24H. NIS (2.5 g) and BF3*2H2O (2.0 mL) were added and the suspension was stirred for another 24 h after which it was poured onto a 1:1 solution of saturated Na2S2O3 and saturated NaHCO3 (300 mL). The aqueous phase was extracted with DCM and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM-EtOAc as eluent. The title compound was obtained as a colourless solid (4.1 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CS(C)=O>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[CH:20]1[CH2:4][CH:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)/C=C/c1c(Cl)ccc2nn(C)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1c(Cl)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a suspension of sodium hydride (0.453 g, 10.4 mmol) in dimethyl sulfoxide (50.0 mL) was added a solution of trimethylsulfoxonium iodide (2.29 g, 10.4 mmol) in dimethyl sulfoxide (89 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(5-chloro-2-methyl-2H-indazol-4-yl)acrylate (4.20 g, 18.2 mmol) in dimethyl sulfoxide (50.0 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.10 g, yield 80%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[Cl:18][C:19]1[C:24]([C:25](O)=[O:26])=[C:23]([F:28])[C:22]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:21][CH:20]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[C:24]([C:25]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[O:26])=[C:23]([F:28])[C:22]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:21][CH:20]=1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(NCC(F)(F)F)ncnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NCC(F)(F)F)ncnc23)c1F
Yield: 12.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2,2,2-trifluoroethyl)quinazoline-4,8-diamine (Intermediate-65, 70 mg, 0.29 mmol), 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid (Intermediate-60, 118 mg, 0.43 mmol), thionyl chloride (1 mL), and DIPEA (148 mg, 1.15 mmol) in THF (2 mL) to afford 18 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.57 (s, 1H), 8.93 (t, 1H), 8.76-8.73 (d, J=7.2 Hz, 1H), 8.61 (s, 1H), 8.38 (t, 1H), 8.12-8.09 (d, J=9.3 Hz, 1H), 7.66-7.61 (t, J=7.8 Hz, 1H), 7.40-7.38 (m, 2H), 4.47 (m, 2H), 4.32 (d, J=4.8 Hz, 2H), 2.42 (m, 1H), 1.05-1.03 (d, J=6.9 Hz, 6H); MS [M+H]+: 498.31.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=1[CH3:10])([O-])=O.CO>[Pd].C1(C)C=CC=CC=1>[NH2:1][C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(N)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.7 %

Procedure:
To a stirred suspension of 5-nitro-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione (4.2 g, 20.084 mmol) in 1:1 mixture of methanol and toluene (200 ml) was added 10% Pd—C (1.2 g). The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. The mixture was then filtered over a celite bed and was thoroughly washed with methanol (200 ml). The filtrate was collected and evaporated to give viscous residue which was then purified by column chromatography to afford 4.1 g of the product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCCCC3)c2s1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
To a stirred solution of 100 mg (0.27 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 3 ml dioxane were added 0.2 g (0.54 mmol) tri-n-butyl-(1-cyclohex-1-enyl)-stannane, 5.0 mg (0.009 mmol) bis(dibenzylideneacetone)palladium and 10 mg (0.043 mmol) trifurylphosphine. The mixture was heated at 100° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1:4) afforded 16 mg (7-Cyclohex-1-enyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (18%) as an off white solid; F.p.: 164-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A mixture of 4-chlorophenol (5.61 g, 43.65 mmol), 2-bromoethanol (6.0 g, 48.0 mmol), sodium hydroxide (2.62 g, 65.47 mmol), and water (18 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath at 80° C. The solution was heated for 19 hours. Progress of the reaction was monitored by analytical HPLC with UV detection. The reaction mixture was partitioned using ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted once more with ethyl acetate (40 mL). The combined organic layer was washed with 1N NaOH (6×40 mL) and saturated aqueous NaCl (40 mL), dried (Na2SO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography using 30-100% ethyl acetate in hexanes to afford the title compound as a clear oil (5.67 g, 75% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (25 g, 0.123 mol) in methanol (250 ml) was added NaBH4 (7.02 g, 0.1847 mol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with 25 ml of water and solvent evaporated under reduced pressure. The compound was extracted with ethyl acetate, organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (25 g) as an oil. This was directly taken for next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:16]3[CH2:17][CH2:18][N:13]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH2:14][CH2:15]3)[C:7]=2[CH:8]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: c1cnc(N2CCNCC2)nc1
Product: Clc1ccc2scc(CN3CCN(c4ncccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 2-(1-piperazinyl)pyrimidine were processed as described in Example 2 to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ (2.62–2.9 (m, 4H), 3.75 (m, 6H), 6.6 (m, 1H), 7.38 (m, 2H), 7.85 (m, 2H), 8.31 (M, 2H). MS (DCI/NH3) m/z 345.0 (M+H)+; Anal. Calcd for C17H17ClN4S: C, 53.04; H, 4.74; N, 14.55. Found: C, 52.79; H, 4.41; N, 14.55.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=1
Reactant: CC(C)Oc1cc(F)ccc1B(O)O
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CC(C)Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 5 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [4-fluoro-2-(propan-2-yloxy)phenyl]boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)nc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 2-bromo-3-methoxy-6-nitropyridine (2.0 g, 8.6 mmol) in ethanol (20 mL) was added SnCl2-2H2O (3.9 g, 17 mmol) at room temperature. The reaction was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was poured into water (50 mL), basified to pH to 8 with saturated NaHCO3 and extracted with ethyl acetate (50×3 mL). The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford 6-bromo-5-methoxypyridin-2-amine (1.1 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.4, 1H), 6.43 (d, J=8.4, 1H), 4.27 (br s, 2H), 3.82 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:19]3[CH:18]([OH:20])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:22][C:23](=[O:45])[C@H:24]([CH2:43]O)[NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:1]1([C:7]2[C:19]3[CH:18]([O:20][CH2:43][C@@H:24]([C:23]([OH:45])=[O:22])[NH2:25])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1c2ccccc2-c2cccc(-c3ccccc3)c21
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COC1c2ccccc2-c2cccc(-c3ccccc3)c21)C(=O)O

Procedure:
from 1-phenyl-9H-fluoren-9-ol (prepared by NaBH4 reduction of 1-phenyl-9H-fluoren-9-one) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ; and
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:25])(=[O:24])[NH:10][C:11]3[C:20]2=[CH:19][C:18]([Cl:23])=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].CO.O>C1COCC1>[Cl:23][C:18]1[CH:19]=[C:20]2[C:11](=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[N:13]3)[NH:10][S:9](=[O:25])(=[O:24])[C:8]1[C:21]2=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 93.2 %

Procedure:
In a similar fashion using route 53 general procedure 121, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 523 (0.85 g, 2.2 mmol), LiOH (190 mg, 4.5 mmol), MeOH:H2O:THF (10 ml: 3 ml: 2 ml) gave the title compound (0.74 g, 89%) after washing with MeOH.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11](=[O:28])[CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:13])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11](=[O:28])[CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:20]=2)[CH3:13])=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
A solution of (3R and 3S)-1-[4-(3-hydroxypropyl)phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (1.57 g, 3.8 mmol) in dry dichloromethane (25 ml) was cooled to 0-50° C. and treated with triethylamine (1.1 ml, 7.9 mmol) followed by methanesulfonyl chloride (0.5 mL, 6.46 mmol) added dropwise over 2 minutes. After 45 minutes at 0-5° C., the reaction mixture was quenched by addition of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine and dried (anhydrous magnesium sulfate) and evaporated. Chromatography of the residual oil on silica gel (elution toluene-ethyl acetate, 9:1) gave 1.83 g (97%) of the title material as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:24])[CH2:9][C:10]([N:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Br:34]N1C(=O)CCC1=O>ClCCl>[Br:34][C@H:9]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:24])[C:10]([N:12]1[C@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][O:14][C:13]1=[O:23])=[O:11]
Reactant: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step B (2.87 g, 7.39 mmol) in dichloromethane (40 mL) was added diisopropylethylamine (1.93 mL, 11.1 mmol) and dibutylborontriflate (9.6 mL, 1M solution in dichloromethane, 9.60 mmol) at −78° C. The light yellow solution was stirred at −78° C. for 15 min, 0° C. for 1 h and recooled to −78° C. for 15 min. The above solution was transferred to a precooled suspension of N-bromosuccinimide (3.93 g, 22.2 mmol) in dichloromethane (40 mL) via cannula. The resultant mixture was stirred at −78° C. for 1 h and 0° C. for 3 h. The reaction was quenched by addition of 0.5N aqueous sodium bisulfite solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with saturated aqueous brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C([O-])(O)=O.[Na+].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:12](=[O:14])[CH3:13])=[N:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cc[nH]n1
Temperature: 25 °C
Yield: 49 %

Procedure:
1H-pyrazol-3-amine (ALDRICH, 11.32 g, 0.136 mol) was dissolved in 100 mL of distilled water. NaHCO3 (34 g, 0.408 mol) was slowly added. Acetic anhydride was then added dropwise and the resulting suspension was heated at reflux overnight. Then, the mixture was allowed to cool down to room temperature and the solid obtained was filtered off and characterized as the title compound (8.4 g, 0.067 mol, 49% yield). After concentration of the filtrate, a second precipitate was obtained (2.7 g, 0.021 mol, 16% yield), also characterized as the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.23 (br s, 1H), 10.30 (br s, 1H), 7.55 (br s, 1H), 6.45 (br s, 1H), 1.97 (s, 3H). [ES+MS] m/z 126 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:22])=[CH:17][CH2:16][C:15]([CH3:24])([CH3:23])[C:14]=3[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:26](=O)[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:26][CH3:27])[C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:22])=[CH:17][CH2:16][C:15]([CH3:24])([CH3:23])[C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2ccc3c(c2)C(C)(C)CC=C3C)cc1

Procedure:
Following General Procedure M, 4-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester (Compound 65, 38 mg, 0.11 mmol), was reacted to with acetaldehyde to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:24]1[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[F:18])[CH:12]=[CH:11]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)Nc1ccc2c(ccn2-c2ccc([N+](=O)[O-])cc2F)c1

Procedure:
The title compound can be synthesized from (1H-indol-5-yl)carbamic acid tert-butyl ester and 3,4-difluoronitrobenzene in the same manner as in Step A of Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:17]([CH2:18][CH2:19][OH:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.CN(C)C=O.[H-].[Na+].Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:17]([CH2:18][CH2:19][O:20][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(Nc2nc3cccnc3n2CCO)CC1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Nc2nc3cccnc3n2CCOc2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred mixture of 4.13 parts of 2-[(1-methyl-4-piperidinyl)amino]-3H-imidazo[4,5-b]pyridine-3-ethanol and 90 parts of N,N-dimethylformamide were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at room temperature, 1.7 parts of 2-chloropyrimidine were added. The whole was stirred for 1 hour at room temperature and the reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.7 parts (32.0%) of N-(1-methyl-4-piperdinyl)-3-[2-(2-pyrimidinyloxy)ethyl]-3H-imidazo[4,5-b]-pyridin-2-amine; mp. 158.1° C. (compound 168).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH:16]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=1)[NH2:17].CC(O)=O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:16]([C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1ccnc(-n2nc(-c3ccc(Cl)cc3)cc2O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a mixture of ethyl 3-(4-chlorophenyl)-3-oxopropanoate (500 mg, 2.2 mmol) and 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2, 296 mg, 2.2 mmol) in EtOH (15 mL) was added AcOH (2 mL) at r.t. The reaction mixture was stirred at 90° C. overnight. After the reaction was completed, the mixture was concentrated, washed with PE/EA (10 mL, V/V=1/1) to give the title compound (500 mg, 76%) as a brown solid and used as crude for next step.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:8][C:4]=2[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]([C@@H:37]3[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[NH:35][CH:36]=2)=[CH:28][CH:27]=1)#[CH:25].C(Cl)Cl>CN(C=O)C.[Cu]I>[C:18]([O:17][C:15]([N:10]1[CH2:11][C@@H:12]([CH3:14])[CH2:13][C@H:9]1[C:7]1[NH:6][C:5]2[CH:22]=[CH:23][C:2]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:33]=[C:34]([C@@H:37]5[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[NH:35][CH:36]=4)=[CH:28][CH:27]=3)=[CH:3][C:4]=2[N:8]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#Cc1ccc(-c2c[nH]c([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)n2)cc1
Reactant: C[C@H]1C[C@@H](c2nc3cc(I)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)nc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (68.5 mg, 0.16 mmol) in DMF (3 mL) are sequentially added tert-butyl (2S,4S)-2-[4-(4-ethynylphenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (47 mg, 0.13 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (5.4 mg, 0.0067 mmol). The mixture is degassed well under vacuum and to it is added TEA (37 uL, 0.27 mmol), followed by CuI (1.2 mg, 0.0067 mmol). Then the reaction mixture is stirred under nitrogen at rt overnight. After removal of the solvent, the crude is purified by flash column chromatography on silica gel using methanol/CH2Cl2 0-5% to obtain tert-butyl (2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (56 mg, 64%).