Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(C)=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To 80 mL of methyl ethyl ketone, 9.05 g (50 mmol) of 4-hydroxybiphenyl, 10.20 g (60 mmol) of 6-bromo-1-hexanol, and 20.7 g (150 mmol) of potassium carbonate were added. This solution was refluxed for 24 hours and then cooled to room temperature. This solution was diluted with 200 mL of methylene chloride and rinsed with water three times. The organic phase was then separated and dried over magnesium sulfate, and the solvent was distilled off. The residue was dissolved in toluene and purified by recrystallization to provide 10.25 g of 6-(4-phenylphenoxy)hexane-1-ol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[C:34]([Zn]C#N)#[N:35].O>CN(C=O)C.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>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([C:34]#[N:35])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:14])=[CH:5]2
Reactant: N#C[Zn]C#N
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ((S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (1.5 g, 3.1 mmol, 1.0 eq) and tetrakis(triphenylphosphine)palladium (181 mg, 0.16 mmol, 0.05 eq) in DMF (50 mL) at RT, dicyanozinc (476 mg, 4.06 mmol, 1.3 eq) was added and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonitrile 29.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4]>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
A solution of 3-(methoxycarbonyl)benzoic acid (1.05 g, 5.83 mmol) in THF (25 mL) was cooled to 0° C., and treated with the dropwise addition of 2.0 M borane-methylsulfide complex in THF (14.57 mL, 29.1 mmol) at a rate which did not allow the temperature to exceed 5° C. The mixture was stirred at 0° C. for 15 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction was cooled to 0° C. and quenched with the addition of small pieces of ice, causing vigorous gas evolution. When gas evolution had ceased, the mixture was diluted with brine and extracted 3× with ethyl acetate. The combined organic phases were washed 3× with dilute bleach to remove residual methyl sulfide, 3× with saturated sodium carbonate to remove any unreacted acid, 1× with water, and 1× with brine, then dried over sodium sulfate and concentrated in vacuo to yield the title compound (845 mg, 5.09 mmol, 87% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
Placed 2-bromopyridine (0.833 g, 5.27 mmol) in THF (25 mL) and cooled to −78° C. Butyllithium (2.11 mL, 5.27 mmol) was slowly added and stirred for 5 minutes. Dissolved tert-butyl 4-formylpiperidine-1-carboxylate (0.500 g, 2.34 mmol) in THF (3 mL) and added slowly to the above solution then stirred at −78° C. for 30 minutes. Added ammonium chloride and extracted with CH2Cl2. Concentrated and purified by silica gel to give the title compound (0.229 g, 33.4% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([C:11]3[S:12][C:13]4[C:18]([N:19]=3)=[CH:17][CH:16]=[C:15]([C:20]3([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:21][CH2:22]3)[N:14]=4)=[C:2]([F:1])[CH:3]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(NC1CC1)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (93 mg, 0.238 mmol) and cyclopropanamine (20 μl, 0.286 mmol). MS (ESI) m/z: Calculated: 429.1; Observed: 430.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>O1CCCC1>[OH:20][C:17]1([CH2:1][C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1
Reactant: Cc1ccc(O)cn1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1ccc(CC2(O)CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred suspension of 6-methylpyridin-3-ol (5.01 g, 45.9 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium solution (1.6 M in n-hexane, 63 mL, 101 mmol) dropwise at −20° C. After addition, the mixture was allowed to warm to room temperature and stirred at the same temperature for 1 h. Then the mixture was cooled to −78° C., and tetrahydro-4H-pyran-4-one (5.06 g, 50.5 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with acetic acid (11.6 mL) and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with acetone/n-hexane (1:1 to 2:1) to give 7.87 g (82%) of the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20](=O)([O:23]C)[O:21][CH3:22]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:19])[CH2:18][C:20]([O:21][CH3:22])=[O:23])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirring suspension of NaH (3.7 g, 154.2 mmol) in DMF (25 mL) was added 1-[4-(benzyloxy)phenyl]ethanone (7 g, 31 mmol) at −5° C. and stirred for 30 min, then dim ethyl carbonate (13.5 g, 150 mmol, dissolved in DMF) was added at −5° C. slowly (exothermic) and warmed slowly to RT, stirred at RT for overnight. Reaction mass was quenched with ice cold water and extracted with ethyl acetate, organic layer was washed with water and brine dried over Na2SO4. The organic layer was concentrated to give the product (7 g, Yield: 92%): 1H NMR (300 MHz, CDCl3): δ 7.84-7.87 (d, 2H), 7.28-7.35 (m, 5H), 6.94-6.96 (d, 2H), 5.07 (s, 2H), 3.89 (s, 2H), 3.68 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:19])=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: OCCCCO
Reactant: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Product: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(OCCCCO)c1ccc(Cl)cc1
Yield: 47.2 %

Procedure:
The named compound was synthesised from 3-(4-chloro-phenyl)-2-[1-(4-chloro-phenyl)-ethyl]-3-hydroxy-2,3-dihydro-isoindol-1-one (498 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure B and obtained as a clear oil (304 mg, 64%). 1H NMR (300 MHz, CDCl3): 7.87-7.84 (m, 1H, C(O)═C═CH), 7.53-7.46 (m, 2H, Ar—H), 7.07-7.00 (m, 9H, Ar—H), 4.41 (q, J=7.2 Hz, 1H, N—CH), 3.70 (m, 2H, HO—CH2), 3.31-3.24 and 3.02-2.95 (m, 2H, OCH2), 1.86 (d, J=7.2 Hz, 3H, CH3), 1.76-1.66 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3): 168.32, 145.27, 141.48, 137.77, 134.80, 133.15, 133.06, 132.84, 130.20, 129.67, 128.74, 128.41, 123.72, 123.27, 95.45, 63.36, 62.88, 52.49, 29.96, 26.48, 20.08. m/z (ES): 470 [M+H]+. Anal.: calc. for C26H25Cl2NO3+0.3 H2O: C, 65.62; H, 5.43; N, 2.94. Found: C, 65.58; H, 5.77; N, 2.45.
Reaction SMILES: Br[C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([SnH](CCCC)CCCC)CCC.[CH2:22]([O:29][C:30]([NH:32][C:33](=[CH2:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH2:22]([O:29][C:30]([NH:32][CH:33]([CH2:38][C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(Br)CCCCC1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)C(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-1-methylcyclohexane (7.200 g, 3.0 equiv), tributyltin hydride (8 mL, 2.2 equiv), methyl 2-(benzyloxycarbonylamino)acrylate (3.120 g, 13.26 mmol, 1.0 equiv), and 2,2′-azobisisobutyronitrile (0.370 g, 0.17 equiv) in benzene (30 mL) was heated at 100° C. for 6 h. After the reaction mixture was evaporated under reduced pressure, the crude methyl 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoate was used directly in the next step without further purification. MS ESI +ve m/z 356 (M+Na).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CI>C1COCC1>[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]([CH3:1])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
THF (5 ml) was taken in a RBF, diisopropyl amine (0.19 ml, 1.29 mmol) was added and cooled to −78° C. under nitrogen atmosphere. Then n-BuLi (0.8 ml, 1.29 mmol) was added and stirred at same temperature for 30 mins. At this stage methyl 2-(quinolin-6-yl)acetate (0.2 g, 0.99 mmol) was added and stirred at −78° C. for 30 mins. Then methyl iodide (0.17 g, 1.2 mmol) was added and stirred at −78° C. for 30 mins and then slowly brought to rt. At rt the reaction mixture was allowed to stir overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer dried on anhydrous Na2SO4 and EtOAc removed using a rotary evaporator to obtain the crude product, which was purified by column chromatography on 60-120 mesh silica gel and EA and Petether (25:75) as eluent. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.89-8.86 (m, 1H), 8.13 (d, J 7.8, 1H), 8.07 (d, J 8.7, 1H), 7.76-7.64 (m, 2H), 7.42-7.37 (m, 1H), 3.92 (q, J 7.2, 1H), 3.68 (s, 3H), 1.60 (d, J 7.2, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=O)[CH3:2].[ClH:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:4]1[N:3]([CH2:1][CH3:2])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: Cl
Reactant: CCn1c(=O)[nH]c2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c(Cl)nc2ccccc21
Yield: 77 %

Procedure:
1-Ethyl-2-benzimidazolinone (100 g, 0.62 mol) was dissolved in phosphorus oxychloride (475 mL) with stirring and heated to reflux temperature. Hydrogen chloride gas was passed into the refluxing solution for 4 h. Excess phosphorous oxychloride was removed on a rotary evaporator at 70° C. The residue was poured into a stirred mixture of aqueous potassium carbonate solution and methylene chloride. The mixture was basified with 50% sodium hydroxide solution and the methylene chloride layer was separated, dried (Na2SO4), concentrated, and distilled to obtain 86 g (77%) of oil, bp 110°-115° C./2-0.3 mmHg, which crystallized on standing; mp 50°-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCBr
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCOc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Yield: 85 %

Procedure:
25.8 g (0.119 mol) of the 3-bromo-4-hydroxybenzoic acid prepared in Step I was dissolved in 615 ml ethanol and 42.6 g (0.238 mol) of heptyl bromide was added to the solution. Aqueous potassium hydroxide (13.5 g of potassium hydroxide in 62 ml of water) was added with heating and the above solution was refluxed for ten hours. 125 ml of 10% aqueous potassium hydroxide was added and the solution was refluxed for two more hours. The reaction solution was allowed to stand to cool to room temperature, and excess 5 N hydrochloric acid solution was added commencing crystallization. The crystals were fractionated through filtration by suction, washed with water, dried and recrystallized with ethanol to yield 31.9 g of purified 3-bromo-4-n-heptyloxybenzoic acid. The yield was calculated to be 85.5%.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14](C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[O:1]([CH:8]([CH3:12])[CH2:9][C:10]([O:15][CH2:14][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(CCO)Oc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCOC(=O)CC(C)Oc1ccccc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 3.15 g of the crude alcohol 27 (prepared in 30-(3)) in 80 ml of acetone is added 10 ml of 8N Jones' reagent at 20° C. to 30° C. dropwise. The mixture is stirred for additional 10 minutes, and 3 ml of isopropyl alcohol is added thereto. The resulting mixture is stirred for 10 minutes and acetone is evaporated under reduced pressure. Water is added to the residue, and the residue is extracted with ethyl acetate twice. The organic layer is washed with water and then extracted with 1N aqueous solution of sodium hydroxide. The aqueous layer is acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate again. The ethyl acetate extract is washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is dissolved in 50 ml of ether and an ethereal solution of diazoethane is added at 0° C. until the orange color persists. The reaction mixture is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (50 of silica gel, ethyl acetate-n-hexane=1:19) to give 2.35 g of the desired ethyl ester 28 as an oil in 67.0% yield from the compound 26.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O>[CH2:21]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12])[CH:20]=[CH2:19]
Reactant: O=Cc1c(O)ccc2c1OCO2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1C=O)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-hydroxy-1,3-benzodioxole-4-carbaldehyde (0.166 g, 1.00 mmol) and K2CO3 (1.00 mmol) in dry N,N-dimethylformamide (2 ml) was added allylbromide (1.00 mmol) under argon. The mixture was stirred at room temperature for 18 h until the starting material was consumed (monitored by TLC). Then the mixture was poured onto ice-water (15 ml). The aqueous phase was filtered off, the precipitated product was washed with water and n-heptane and dried to give analytically pure crystals.
Reaction SMILES: [NH:1]1[CH:5]([C:6](O)=O)[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][C:11]1[CH:16]=C[CH:14]=[CH:13][C:12]=1[O:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>C(Cl)Cl.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:6]([CH:5]2[NH:1][C:2](=[O:9])[CH2:3][CH2:4]2)=[CH:10][C:11]=1[CH3:16]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: COc1ccccc1C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CCC(=O)N2)cc1C
Temperature: 100 °C
Yield: 55.9 %

Procedure:
2-Pyrrolidone-5-carboxylic acid (2.0 g, 15.5 mmol) and 2-methylanisole (2.1 mL, 17.0 mmol) were added to a mixture of 1.0 g (3.52 mmol) of phosphorous pentoxide and 6.7 mL methanesulfonic acid. The mixture was heated at 100° C. for 2 hr, cooled down to rt, and poured into a mixture of H2O and CH2Cl2. The aqueous layer was separated, and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, washed with sat'd NaHCO3, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 4:1 v/v EtOAc/hexanes as the eluant afforded 1.78 g (56%) of the title compound: 1H NMR δ 1.88-1.97 (m, 1H), 2.21 (s, 3H), 2.35-2.54 (m, 3H), 3.81 (s, 3H), 4.66 (t, J=7.1, 1H), 6.53 (br. s, 1H), 6.79 (d, J=8.6, 1H), 7.05-7.09 (m, 2H).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>Cl[Ni]Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CCOP(OCC)OCC
Agent: Cl[Ni]Cl
Product: CCOP(=O)(OCC)C1=Cc2ccccc2C1

Procedure:
To 91.0 g (0.467 mol) of 2-bromo-1H-indene and 3.02 g (0.023 mol) of NiCl2 in 250 ml flask equipped with a distillation head, 85.0 ml (82.4 g, 0.496 mol) of (EtO)3P were added. This black mixture was heated in the oil bath at 185–190° C. for 3 hours. During this procedure, argon gas was bubbled through the mixture to eliminate ethyl bromide formed. The crude product was distilled in vacuum (171–175° C./1 mm). Yield 102.4 g (87%) of colorless oil of diethyl 1H-inden-2-ylphosphonate, 9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:15])[C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=4)[CH:20]=3)=[CH:6][CH:7]=2)=[CH:39][CH:38]=1)[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4cccc(C(F)(F)F)c4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](O)(=[O:30])/[C:24](=[C:26](\[CH:28]=O)/[Cl:27])/[Cl:25]>C(O)(=O)C>[Cl:25][C:24]1[C:23](=[O:30])[N:21]([C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:14]=3)[CH:20]=[CH:19][N:18]=2)[N:22]=[CH:28][C:26]=1[Cl:27]
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Solvent: CC(=O)O
Product: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 125 °C
Yield: 43.6 %

Procedure:
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (5 g) in acetic acid (80 mL) was added 2.8 g of Mucochloric acid. The mixture was heated at 125° C. for 4 h. The solvent was concentrated and the crude was poured into water (500 mL). The suspension was neutralised by addition of solid potassium carbonate until pH 7. The aqueous phase was extracted with ethyl acetate (3×200 mL). The organic phases were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (1-0 to 1-1), afforded the title compound as a solid (3.11 g, 44%). Mp 238–240° C., 1H NMR (DMSO-d6) 10.3 (1H, s, NH), 8.84 (1H, d, 5 Hz), 8.76 (1H, d, 5 Hz), 8.42 (1H, s), 8.38 (1H, s), 8.28 (1H, 2 Hz, 5 Hz), 8.04 (1H, t, 2 Hz), 7.74 (1H, dd), 7.62 (1H, d, 5 Hz), 7.32 (1H, t, 8 Hz), 7.02 (1H, dd, 2 Hz, 8 Hz). 13CNMR DMSO-d6) 160.3, 160.2, 159.9, 155.5, 153.5, 150.2, 146.6, 141.7, 136.7, 136.6, 134.0, 132.9, 130.1, 121.9, 121.1, 118.7, 118.2, 117.3, 109.3.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[N:16]([CH3:30])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[C:1]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:29])=[CH:25][CH:26]=4)[N:16]([CH3:30])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 535 mg (1.0 mmol) of 3-methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide in 10 mL ethanol was mixed with 5 mL of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then the mixture was diluted with 10 mL water, the alcohol was distilled off, the aqueous phase was washed with 20 mL ethyl acetate and acidified with concentrated hydrochloric acid, whereupon the desired compound was precipitated in the form of white crystals. Yield: 375 mg (74% of theory), C26H26N6O3 (470.54); Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia=90:5:5); mass spectrum: (M+H)+=471.