Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[C:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([OH:26])=[O:25]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[O:11]=[C:5]1[NH:6][C:7]2[C:3](/[C:4]/1=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[C:2]([C:30]1[CH:31]=[CH:32][C:27]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH:10]=[CH:9][CH:8]=2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3ccc(C(=O)O)cc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 112.2 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (151 μL, 0.303 mmol), (Ph3P)2PdCl2 (3 mg, 0.004 mmol) (Aldrich), and 4-carboxyphenylboronic acid (18 mg, 0.108 mmol) (Lancaster) in 4.5 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 40% ethyl acetate-hexanes then 50% ethyl acetate-hexanes with 1% glacial acetic acid elution) to yield pure (Z)-4-[2,3-Dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-benzoic acid (yield: 33 mg, 91%) as an orange solid (mp 315-317° C.).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12].B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cccc(C(C)=O)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cccc(O)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.7 %

Procedure:
A solution of 2',3'-dimethoxyacetophenone (4.85 g, 26.9 mmol) in dichloromethane (100 ml) was added at -70° C. with a 1M boron tribromide solution in dichloromethane (68 ml). The mixture was left to cool, keeping stirring for 2.5 hours at room temperature, then added with methanol (70 ml), left under stirring for 1 h, thereafter evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml), washed with 2% NaHCO3 (1×30 ml), dried and the solvent was evaporated off, to obtain a crude which was purified by crystallization in methanol, thereby obtaining 3.10 g of the title compound as a yellow solid (76% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@:5]([CH3:10])([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.[Cr](Cl)(O)(=O)=O.N1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[O:6][C@@:5]([CH3:10])([CH2:7][CH:8]=[O:9])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@](C)(CCO)O1
Agent: O=[Cr](=O)(O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)OC[C@](C)(CC=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
4.33 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-ethanol dissolved in 7 ml of absolute methylene chloride were added dropwise to a suspension of 7.59 g of pyridine chlorochromate in 30 ml of absolute methylene chloride. The reaction mixture was stirred at room temperature for 3 hours. By addition of 75 ml of ether, the chromium salt was precipitated and separated by filtration over 120 g of Kieselgel. After removal of the solvent on a rotary evaporator and distillation of the residue at 90°-100°/10 mmHg, there were obtained 3.00 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-acetaldehyde. [α]D20 =-35.5° (c=1.50; n-hexane).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH3:26][NH2:27]>CCO>[CH3:26][NH:27][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (26 mg, 0.078 mmol) and methylamine (1 mL, 2M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-10% EtOAc/CH2Cl2+1% AcOH) to give 18 mg of the title compound as a white solid. MS: (+) m/z 335.02 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CO
Solvent: ClCCCl
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (5.0 g, 17.7 mmol) and dimethylpiperidin-4-ylamine (2.7 g, 21.2 mmol) in DCE (100 mL) was stirred at room temperature for 4 hours then triacetoxyborohydride (5.6 g, 26.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (2×70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was precipitated from IMS to give [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]dimethylamine as a white solid (4.45 g, 64%). LCMS (Method B): RT 0.37 min and 1.85 min; [M+H]+ 396
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14](=[O:16])[CH3:15])[CH3:2].[Br-:17].[Br-:18].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:17][CH:15]([Br:18])[C:14]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[O:3][CH2:1][CH3:2])=[O:16]
Reactant: [Br-]
Reactant: CCOc1ccc2ccccc2c1C(C)=O
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1C(=O)C(Br)Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 1-(2-ethoxy-naphthalen-1-yl)-ethanone (26 g) in tetrahydrofuran (200 mL) at 0° C. was added phenyl trimethylammonium tribromide (50 g). The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 4.5 hours. The mixture was washed with water (200 mL) and the aqueous phase was extracted with diethyl ether. The combined organics were washed with water (200 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford a dark green sticky solid. The sticky solid was triturated with diethyl ether (100 mL) and filtered to give 2,2-dibromo-1-(2-ethoxy-naphthalen-1-yl)-ethanone (12.6 g, 35%) as an off-white solid. The filtrate was evaporated to a dark green oil and purified by column chromatography, elution with 40% to 60% dichloromethane in cyclohexane, affording 2-bromo-1-(2-ethoxy-naphthalen-1-yl)-ethanone (15.8 g, 44%) as an off-white solid. 1H NMR (CDCl3): 1.45 (3H, m), 4.2 (2H, m), 4.5 (2H, m), 7.2 (1H, m), 7.4 (1H, m), 7.5 (1H, m), 7.8 (2H, m), 7.9 (1H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].C(O)=[O:11].C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C.O>[OH:11][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: O=CO
Reactant: Cc1oc(=O)oc1CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1oc(=O)oc1CO
Temperature: 12.5 °C
Reaction time: 5.5 h

Procedure:
To a solution of 4-chloromethyl-5methyl-1,3-dioxol-2-one (50 g) in acetonitrile (500 ml), formic acid (45 g) was added at 20-25° C. and the reaction mass cool to 10-15° C. followed by addition of triethylamine (95 g). Reaction mass was heated to 60-65° C. and stirred at the same temperature for about 5-6 hrs. Reaction mass was cooled to 15-20° C., filtered and washed by acetonitrile. Filtrate was taken and acetonitrile was distilled out under vacuum to concentrate the solution. Reaction mass was cooled to 25-30° C. and ethyl acetate and water was added, followed by stirring for about 15-20 minutes at 25-30° C. Aqueous layer extracted with ethyl acetate and combined organic layer were washed with brine solution. Organic layer was separated and evaporated completely under vacuum below 35-40° C. To the oily mass, methanol was added and heated to reflux temperature. A solution of HCl in isopropyl alcohol was added and the resulting solution was refluxed for about 60-75 mins. Reaction mass was cooled to 30-35° C. Distilled out the solvent completely to obtain title compound as oily mass. (Yield: 34.6 g; 79%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18](O)=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([N:32]([CH3:33])[CH3:31])=[O:19])=[N:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxylic acid (88 mg, 0.20 mmol) obtained in Example 3 in methylene chloride (2 ml), dimethylamine hydrochloride (18 mg, 0.22 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 4-methylmorpholine (0.048 ml, 0.44 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol) were added at room temperature. After stirring for 6 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane, and collected by filtration to obtain the title compound (83 mg, 0.18 mmol, 89%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 85 °C
Yield: 90.7 %

Procedure:
A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (1.5 g, 5.36 mmol) in dry toluene (12 ml) was added dropwise to 4-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran, 6.96 ml, 6.96 mmol) at 0° C. The reaction mixture was heated to 85° C. for 3 hours, poured onto ice, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified over flash silica chromatography eluting with petroleum ether to ethyl acetate/petroleum ether (5:95) to afford the desired product (1.91 g, 91% yield). LC/MS: (PS-A2) Rt 3.78 [M+H]− 391.93.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].CCN(CC)CC>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (121 mg, 0.28 mmol), isobutyryl chloride (30 mg, 0.29 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (1 mL) was allowed to stir at r.t. for 2 h then concentrated in vacuo. The resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-6%) followed by triturating with Et2O affording 824 as a white solid (86 mg, 61%). LCMS (method I): RT 3.42 min, [M+H]+ 503.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.30-7.22 (2 H, m), 4.50-4.20 (4 H, brd s), 4.41 (1 H, t, J=8.45 Hz), 4.32-4.21 (1 H, m), 3.98 (1 H, dd, J=8.63, 5.41 Hz), 3.90-3.80 (5 H, m), 3.76 (3 H, s), 3.34 (2 H, q, J=7.49 Hz), 3.28-3.25 (1 H, m), 3.16-3.11 (2 H, m), 2.47-2.46 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.12 (6 H, dd, J=6.82, 2.82 Hz)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Cl:8][C:7]1[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17][CH:18]2[CH3:22])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC1CN(Cc2ccccc2)CCN1c1nccnc1Cl
Temperature: 115 °C
Reaction time: 17 h
Yield: 28 %

Procedure:
A mixture of 2,3-dichloropyrazine (0.332 g, 2.23 mmol), 1-benzyl-3-methylpiperazine* (0.423 g, 2.23 mmol), and K2CO3 (0.339 g, 2.45 mmol) in acetonitrile (2.5 mL) was stirred at 115° C. for 17 h in a sealed tube. The reaction mixture was diluted with ether, filtered, and concentrated. The brownish oily residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 0.19 g (28%) of the title product as a viscous oil that was sufficiently pure for the next step.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH3:13].O>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O:5][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCP(=O)(O)CCCO
Reactant: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCCO
Yield: 83.9 %

Procedure:
456 g (3 mol) of ethyl-3-hydroxypropylphosphinic acid (produced as in Example 10) are at 85° C. dissolved in 400 ml of toluene and admixed with 888 g (12 mol) of butanol. At a reaction temperature of about 100° C., the water formed is removed by azeotropic distillation to obtain 524 g (84% of theory) of butyl ethyl(3-hydroxy-propyl)phosphinate purified by distillation at reduced pressure.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:33])[CH2:23][NH:24][C:25](=[O:32])[CH2:26][O:27]S(C)(=O)=O)[CH3:21])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35].[CH3:36][O-].[Na+].O>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:33])[CH2:23][NH:24][C:25](=[O:32])[CH2:26][O:27][CH3:36])[CH3:21])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35]
Reactant: C[O-]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-(N-mesyloxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg) in methanol (2 ml) was added sodium methoxide (317 mg), and the mixture was stirred for 1 hour. Sodium methoxide (200 mg) was added thereto, and the mixture was stirred for 3 hours. To the reaction mixture was added water, and the mixture was extracted with methylene chloride 3 times. The extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(methoxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (60 mg).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34](=O)[CH2:35][CH2:36]/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH:34][CH2:35][CH2:36]/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC/C=C/CCC=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCC/C=C/CCC=CCc1ccccc1
Yield: 62.3 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.20 g, 7.15 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.5 mL, 7.15 mmol, 1.0 equiv.) and (E)-dec-4-enal (1.66 g, 10.7 mmol, 1.5 equiv.), 1.08 g (62%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [C:1]1([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:19][Mg]Br>>[C:1]1([C:11]2[N:12]=[CH:13][C:14]([CH:15]([OH:16])[CH3:19])=[CH:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2cccc3ccccc23)nc1
Product: CC(O)c1ccc(-c2cccc3ccccc23)nc1

Procedure:
Synthesized using compound 54b (231 mg, 0.99 mmol) and methylmagnesium bromide (1.98 mL, 1.98 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. White solid. Yield: 172 mg, 70%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.59 (d, J=6.1 Hz, 3H), 5.00 (m, 1H), 7.44-7.62 (m, 5H), 7.80-7.86 (m, 1H), 7.90-7.96 (m, 2H), 8.07 (d, J=7.9 Hz, 1H), 8.74 (s, 1H); (ESI): m/z=250.29 [M+H]+.
Reaction SMILES: O.[OH-].[Ba+2].[OH-].[Br:5][C:6]1[CH:11]=[CH:10][C:9](I)=[C:8]([CH3:13])[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)=[C:8]([CH3:13])[CH:7]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Br)ccc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 21 %

Procedure:
Barium hydroxide monohydrate (2.27 g, 2.0 equiv), 4-bromo-1-iodo-2-methylbenzene (0.94 mL, 1.1 equiv), 3-chlorophenyl boronic acid (0.94 g, 1.0 equiv), and palladium tetrakis(triphenylphosphine) (0.14 g, 0.02 equiv) were combined and stirred in dioxane (15 mL) and water (5 mL), heated at reflux for 2 hr and then allowed to cool to room temperature. The solution was concentrated and the residue dissolved in CH2Cl2, washed with water and brine and then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, hexane) to give 4-bromo-3′-chloro-2-methyl biphenyl (0.33 g, 21%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:47])([C:23]4[N:24]=[CH:25][N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:27]=4)[CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl.N1C=CC=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:47])([C:23]4[N:24]=[CH:25][NH:26][CH:27]=4)[CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)C(O)(c1ccc(-c2cccc(C(=O)NC3CC3)c2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1ccc(-c2cccc(C(=O)NC3CC3)c2)cc1)c1c[nH]cn1
Yield: 29 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-cyclopropyl-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide (2.13 g) and pyridine hydrochloride (650 mg), the title compound (375 mg) was obtained as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH2:36]1[CH2:42][O:41][CH2:40][CH2:39][NH:38][CH2:37]1.Cl>>[CH:32]([N:29]1[CH2:28][CH2:27][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][C:19]([C:21]([N:38]4[CH2:37][CH2:36][CH2:42][O:41][CH2:40][CH2:39]4)=[O:23])=[CH:20][C:15]=3[N:14]=2)=[O:35])[CH2:31][CH2:30]1)([CH3:34])[CH3:33]
Reactant: C1CNCCOC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)N4CCCOCC4)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-([1,4]oxazepane-4-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 147.8 mg (0.296 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 44.8 mg (0.326 mmol) homomorpholine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([S:33]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(S(=O)(=O)C2CC2)C3)cc1

Procedure:
Compound ec was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with cyclopropylsulfonyl chloride. LC-MS: m/z=+501 (M+H)+.