Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1O
Solvent: c1ccncc1
Product: C=CCc1cc(C(=O)OC)cc(C)c1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of methyl 4-hydroxy-3-allyl-5-methylbenzoate (157 mg) in pyridine (5 mL) was cooled in an ice-bath under a nitrogen atmosphere and treated with acetic anhydride (1 mL). The reaction was stirred in the ice-bath for one hour and was then warmed to room temperature for 4 hours. The solvent was then removed under reduced pressure and the residue was suspended in anhydrous toluene (5-10 mL) and evaporated to dryness. The crude product was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous ammonium chloride. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a brown oil. Yield=0.176 g (quantitative).
Reaction SMILES: Br[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(NC(C)C)(C)C.CCCCCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:37][Si:38]([CH3:40])([CH3:39])[C:41]#[C:42][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: C=C1c2ccccc2C=C(Br)c2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: C=C1c2ccccc2C=C(C#C[Si](C)(C)C)c2ccccc21
Yield: 47.9 %

Procedure:
To a stirred mixture of 4 (5.66 g, 20 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.7 g, 1 mmol), copper(II) acetate hydrate (0.18 g, 1 mmol) and triphenyl-phosphine (0.52 g, 2 mmol) in 40 mL of diisopropyl amine was added trimethylsilyl acetylene (2.16 g, 22 mmol) and heated to reflux. On refluxing for an hour the mixture turns dark and solidifies. The reaction mixture was diluted with 50 mL of hexane and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel with hexane/methylene chloride (9:1 by volume) as eluant to yield 2.88 g (50 percent) of trimethyl[2-(5-methylene-5H-dibenzo[a,d]cyclohepten-10-yl)ethynyl)silane, 5, as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:23]=[N:22][NH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:24][N:25](COCC[Si](C)(C)C)[C:26]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]3)=[C:11]2[N:10]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:23]=[N:22][NH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[C:12]2[NH:24][N:25]=[C:26]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:32][CH2:33]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]n4)ccc32)c1NC1CCN(S(C)(=O)=O)CC1
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(-c4cn[nH]n4)ccc23)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 10.8 %

Procedure:
116 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine are introduced into 10 ml of DCM. After cooling to 0° C. using an ice bath, 1.1 ml of TFA are added and the mixture is stirred at RT for 5 h. It is concentrated under RP and the solid obtained is taken up in 60 ml of water, neutralized with 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (92.5/7.5 by vol.), to give 10 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow solid). 1H NMR: 1.62-1.75 (m, 2 H) 2.10 (m, 2 H) 2.82-2.97 (m, 5 H) 3.57 (m, 2 H) 3.74-3.86 (m, 1 H) 6.04 (d, J=8.0 Hz, 1 H) 7.35 (t, J=8.0 Hz, 2 H) 7.63-7.75 (m, 1H) 8.13 (broad s, 1 H) 8.39 (broad d, J=8.6 Hz, 1 H) 8.45 (broad m, 1 H) 8.49 (d, J=8.6 Hz, 1 H) 12.77 (s, 1 H) 15.23 (broad m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methylbenzoic acid (20 g, 146.90 mmol, 1.00 equiv) in thionyl chloride (60 g). The mixture was stirred for 2 h at 80° C. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (200 mL). This was followed by the addition of triethylamine (29.7 g, 293.51 mmol, 2.00 equiv) dropwise with stirring at 0° C. To this was added aniline (13.6 g, 146.04 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring overnight at room temperature. The resulting mixture was washed with 3×100 mL of hydrogen chloride (5%) and 2×100 mL NaOH (5%). The mixture was washed with 3×100 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 19.37 g (62%) of 4-methyl-N-phenylbenzamide as a white solid. MS (ESI) m/z 212 ([M+H]+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:16]=1[CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][C:27]=2[F:40])=[C:21]([CH2:41][CH2:42][CH3:43])[N:20]2[N:44]=[CH:45][N:46]=[C:19]12>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:16]=1[CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:3][C:4](=[O:7])[O:5][N:39]=3)=[CH:28][C:27]=2[F:40])=[C:21]([CH2:41][CH2:42][CH3:43])[N:20]2[N:44]=[CH:45][N:46]=[C:19]12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(Cc2ccc(OC)cc2OC)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(Cc2ccc(OC)cc2OC)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.7 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2,4-dimethoxybenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.18 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[N:4]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxylate (150 mg, 0.42 mmol) from Example 5 in methanol (5 mL) was added 5N sodium hydroxide (0.42 mL, 2.1 mmol). The reaction was stirred at rt for 72 h and was then diluted with water and acidified with 2N hydrochloric acid. The mixture was extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title product as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]=1[O:20][CH3:21].[H-].[Na+].O1CCCC1.I[CH2:30][CH2:31][CH2:32][C:33]1[C:38]([O:39][CH2:40][O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=[C:35]([O:45][CH2:46][O:47][CH3:48])[C:34]=1[O:49][CH3:50]>CN(C)C=O.C(OCC)C>[CH3:50][O:49][C:34]1[C:35]([O:45][CH2:46][O:47][CH3:48])=[CH:36][C:37]([O:43][CH3:44])=[C:38]([O:39][CH2:40][O:41][CH3:42])[C:33]=1[CH2:32][CH2:31][CH2:30][O:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]=1[O:20][CH3:21]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCI)c1OC
Reactant: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1cc(OC)c(OCOC)c(CCCOCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Temperature: 50 °C

Procedure:
374 Milligrams of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was dissolved in 3 ml of dimethylformamide, under ice-cooling conditions, 80 mg of sodium hydride (60% dispersion) was added thereto, then 2 ml of tetrahydrofuran solution containing 527 mg of 1-(3-iodopropyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was added. The reaction mixture was heated at 50° C. in an oil bath. 6 Hours later, ice water and 100 ml of diethyl ether were added to the reaction mixture. The ether layer was washed twice with 50 ml of water, then washed twice with 50 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. This solution was concentrated under reduced pressure, and the residue obtained was purified by means of a silica gel column chromatography (diameter 3 cm×length 15 cm, eluent: 40% ethyl acetate-n-hexane mixed solvent, adsorbent: "Wakogel C-200") to obtain 484 mg of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethyl 3 -[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propyl ether.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:20][O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=1)[C:4]([CH3:3])=[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(C)n(-c2ncnc3ccccc23)c2ccc(OC)cc12
Reaction time: 0.25 h

Procedure:
A stirred suspension of sodium hydride (0.24g.) in dry dimethylformamide (20ml.; dried with calcium hydride) was treated at 5°-10° C. with a solution of ethyl 2-methyl-5-methoxyindol-3-ylacetate (2.3g.) in dry dimethylformamide (10ml.). The mixture was stirred at 25°-30° C. for 15 minutes, and the solution obtained was treated with a freshly prepared solution of 4-chloroquinazoline (1.65g.) in dry dimethylformamide (10ml.). The mixture was stirred at 30°-40° C, for 4 hours, and then poured into water (500ml.). The mixture was extracted with ethyl acetate (4 × 100ml.) and the extracts washed successively with water (2 × 100ml.) and brine (100ml.), and then dried (sodium sulphate). Evaporation of solvent gave an oil which was purified by chromatography on silica gel (250g.) using an increasing gradient of ether in petroleum ether (b.p. 40°-60° C.) (the polarity increased by incremental addition of 10% v/v ether) to give ethyl 5-methoxy-2-methyl-1-(quinazolin-4-yl)indol-3-ylacetate, m.p. 121°-123° C.
Reaction SMILES: C[NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:9]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:18]CCCCC>>[CH:9]1([N:15]([CH3:18])[C:16]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CNC1CCCCC1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCCC
Product: CN(C(=O)NC1CCCCC1)C1CCCCC1

Procedure:
A solution of 19.12 g of N-methyl-N-cyclohexylamine (0.169 mol) in 160 ml of hexane is admixed dropwise with 18.38 g of cyclohexyl isocyanate (0.147 mol) and then the cloudy mixture is heated at reflux for 2 hours, then evaporated to dryness to give 35 g of crude N,N′-dicyclohexyl-N-methylurea. A suspension of 17 g of this crude product (71.33 mmol) in 65 ml of dry toluene is admixed with 12 g of POCl3 (78 mmol) over 1 hour, and then, after a number of hours at 20° C., 15.5 g of N-butyl-N-methylamine (0.178 mmol) are added over 2 hours, and then, after a further 2 hours at 20° C., 50 ml of water are added. 49 g of 35% sodium hydroxide solution are then added while cooling, after which the two-phase mixture is extracted with diisopropyl ether. Following drying and evaporation to dryness, the oil obtained, 26.5 g, is distilled at 180° C. under 1 mbar to give 21.25 g of the expected guanidine (97% yield).
Reaction SMILES: CC[O:3][C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:16].[ClH:21].P(Cl)(Cl)(Cl)=O>P(Cl)(Cl)Cl>[Cl:21][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:6][C:4]([Cl:16])=[O:3]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cl
Solvent: ClP(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)C=C(Cl)c1ccccc1
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of 60 g (0.312 mol) ethyl benzoyl acetate in 96 ml (150 g) of phosphorous trichloride is added dropwise to 150 g (0.72 mol) of phosphorous pentachloride under nitrogen. The suspension that forms is cautiously brought to reflux temperature (HCl evolution observed) and is refluxed and stirred for 2-21/2 hrs. The solution that forms is stripped of phosphorous trichloride and phosphorous oxychloride at atmospheric pressure (76°-82° C.). The pot residue is distilled at 97°-108° C./0.75 mm to give 54 g (86% yield) of product as an isomeric mixture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.Cl.O.[CH3:27]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:27])=[O:12])=[CH:7]2
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (4.7 g) in a mixture of methanol (30 mL) and toluene (90 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (7.4 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and 2M trimethylsilyldiazomethane diethyl ether solution (3.7 mL) was added dropwise to the mixture. After stirring at 0° C. for 30 min, 1M hydrochloric acid (2 mL) was added to the mixture to quench the reaction. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual yellow oil was solidified with ethyl acetate-diethyl ether. The resulting solid was washed with diethyl ether to give the title compound (3.6 g, 74%) as a pale orange solid. MS 363 (MH+).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([OH:20])=O)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[N:6][C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[NH2:2].[NH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[CH3:35]N(C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F>O.CN(C)C=O>[CH3:35][N:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[N:11]=[CH:10][N:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=5)[N:6]=4)[C:13]=3[CH:14]=2)=[O:20])[CH2:30][CH2:31]1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: NC1CCNCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(C(=O)O)cc32)nc1-c1cccc(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.060 g (0.15 mmole) of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazole-5-carboxylic acid (I.10a), 0.06 mL of 4-aminopiperidine, 0.070 g (0.18 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 4 mL of dimethylformamide was stirred at room temperature for 16 hours. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 20 mL of 1 M hydrochloric acid. The combined aqueous extracts were made basic with potassium carbonate, and the resulting solid collected by filtration, washed with water, and air-dried to give 0.038 g of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazole-5-carboxylic acid (1-methyl-piperidin-4-yl)-amide (I.10) as a light yellow solid. MH+/Z=495
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([S:21][C:22]([F:23])([F:25])[F:24])=[CH:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Yield: 80.9 %

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (4.0 g) in dry tetrahydrofuran (20 ml) was treated with tert-butyl nitrite (5.76 g) at room temperature. The mixture was then heated under reflux for 3 hours and evaporated in vacuo to give a yellow solid. Purification by chromatography eluting with petroleum ether/dichloromethane (2:1) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylthiopyrazole (3.12 g), m.p. 126.5°-128° C., in the form of a white solid. By proceeding in a similar manner but replacing the 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole by the following phenylpyrazoles, there was obtained:
Reaction SMILES: C1C(=O)[N:5](Br)[C:3](=O)C1.[Cl:9][C:10]1[C:11]([O:17][CH3:18])=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[C-]#N.[K+]>C(Cl)(Cl)(Cl)Cl.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:10]1[C:11]([O:17][CH3:18])=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][C:3]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)cccc1CC#N
Reaction time: 16 h
Yield: 81.1 %

Procedure:
39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide are added to 31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CCl4. It is refluxed over 16 hours, allowed to cool and filtered. Solvent is removed from the filtrate, and the filtrate is dissolved in 214 ml of N,N-dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of potassium cyanide is added at 0° C. and stirred over 16 hours. The reaction mixture is diluted with water and extracted several times with tert-butyl-methyl ether. The organic phase is washed several times with saturated sodium chloride solution and dried on sodium sulfate. The solvent is removed in a vacuum and after chromatographic purification on silica gel (hexane/ethyl acetate 20%), 29.7 g of product is obtained.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][Si:10]([CH3:54])([CH3:53])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:16]1[N:21]2[N:22]=[CH:23][CH:24]=[C:20]2[N:19]=[C:18]([CH:25]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][CH2:26]2)[CH:17]=1>C(#N)C>[CH3:52][Si:49]([CH3:50])([CH3:51])[CH2:48][CH2:47][O:46][CH2:45][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:53])[CH3:54])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([I:1])=[C:20]2[N:19]=[C:18]([CH:25]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]([C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])[CH2:27][CH2:26]2)[CH:17]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CN1C(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
N-Iodosuccinimide (1.26 g, 5.61 mmol, dissolved in 25 ml acetonitrile) was added into a solution of di-tert-butyl 5-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate (3.8 g, 5.61 mmol) in acetonitrile (26 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (3.16 g, 70% yield) at clear oil. LC-MS: 804 [M+H].
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.CCO.C([O-])(O)=O.[Na+]>CC(O)=O.[Fe]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc(N)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
A mixture of tert-butyl 4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (21) (5.20 g, 12.7 mmol) and iron mesh (4.30 g, 76 mmol) was suspended in AcOH and EtOH (1:2, 120 mL) and was heated to 60° C. and stirred rapidly until the reaction was judged to be complete by LC-MS. The mixture was cooled to RT, poured carefully onto saturated aq NaHCO3 solution (1000 mL) and extracted with EtOAc (500 mL×2). The combined organic layers were washed with saturated aq NaHCO3 solution (1000 mL), water (1000 mL), brine (1000 mL) and dried. The solution was filtered and evaporated in vacuo to give the title compound (22) as a yellow oil (5.00 g, 95%): m/z 380 (M+H)+ (ES+).