Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[N:7](C)[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].P(OC)(OC)(O[CH3:18])=O.CS(O)(=O)=O>>[F:1][CH:2]([F:14])[C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:6]([CH3:18])[N:7]=1
Reactant: COP(=O)(OC)OC
Reactant: CCOC(=O)c1cnn(C)c1C(F)F
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 170 °C
Reaction time: 7 h
Yield: 79.4 %

Procedure:
To 20.4 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) was added 14.4 g of trimethyl phosphate and 0.82 g of methane sulfonic acid. The mixture was heated to 170° C. and stirred for 7 hours. The solution was cooled and distilled to recover recycled trimethyl phosphate and 2.0 g of starting ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. The remaining solution was added to 50 g of cold water. The solution was allowed to stir for 30 min. The precipitating solid was filtered and dried to give 16.2 g of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([P:6]([CH3:13])(=[O:12])[O:7]CC(C)C)[CH3:5]>Cl>[NH2:1][CH2:2][CH2:3][CH:4]([P:6]([CH3:13])(=[O:7])[OH:12])[CH3:5]
Reactant: CC(C)COP(C)(=O)C(C)CCN
Agent: Cl
Product: CC(CCN)P(C)(=O)O
Temperature: 25 °C

Procedure:
A solution of 21.5 g of isobutyl P-(4-aminobut-2-yl)-P-methyl-phosphinate in 80 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 10 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated twice with 100 ml of water. The crude material is dissolved in water, washed with chloroform, and the aqueous layer treated with activated charcoal. The aqueous solution is filtered hot, evaporated to dryness, the crude product is dissolved in 50 ml of methanol and treated with 1-2 ml of propylene oxide. The hygroscopic solid is filtered and triturated with acetone. After drying, P-(4-aminobut-2-yl)-P-methyl-phosphinic acid is obtained as a hygroscopic solid, m.p. 68°-75°, 3P-NMR spectrum: δ=+46.5 ppm (D2O).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)([C:8](O)=[O:9])[CH2:3]1.[ClH:19]>C1COCC1.O1CCOCC1>[ClH:19].[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:8][OH:9])([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:3]1
Reactant: NC1CCCC(Oc2cccc(F)c2)(C(=O)O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCCC(CO)(Oc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 3-amino-1-(3-fluorophenoxy)cyclohexanecarboxylic acid (0.2 mmol, 50.6 mg) in THF was added a solution of borane dimethylsulfide complex in THF (1 mmol, 2 M, 0.5 mL). The reaction mixture was stirred at room temperature for overnight. A solution of HCl in dioxane was added dropwise. The product, HCl salt of (3-amino-1-(3-fluorophenoxy)cyclohexyl)methanol, was obtained after removal of solvent.
Reaction SMILES: [Br-:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:1].[CH2:2]([P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Decane bromide (7.0 g) and 10 g of triphenylphosphine were stirred at 120° C. under a nitrogen atmosphere for 8 hours. The mixture was recrystallized from acetone-ether to give 14.4 g of colorless, crystalline decyltriphenylphosphonium bromide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.CC([O-])=O.[K+].C(#N)C>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>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[O:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3o2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[2,3-d]pyrimidine (1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.7 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M KOAc aqueous solution (3 eq) and an equal volume of acetonitrile (3 eq) was heated to 140° C. in a sealed microwave reactor for 12 min. Upon completion, the reaction mixture was concentrated and crude mixture was purified by reverse phase HPLC to yield 34 mg of 165. MS (Q1) 476 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](Cl)=[O:19])[CH3:16]>N1C=CC=CC=1>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18]([N:12]1[CH:13]=[N:14][C:10]([S:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11]1)=[O:19])[CH3:16]
Reactant: Cc1cccc(C)c1Sc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(Sc2c(C)cccc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2,6-Dimethylphenylthio)-1,2,4-triazole (2 g) is dissolved in pyridine (50 ml) and diethyl carbamoyl chloride (1.4 g) is added dropwise to the solution. The mixture is stirred first at room temperature for 1 h, then at 70° C. for 2 h. Thereafter, pyridine is distilled off. The residue is extracted with chloroform and dried with magnesium sulfate to obtain the crude product of 1-(diethylcarbamoyl)-3-(2,6-dimethylphenylthio)-1,2,4-triazole. After cooling to 0° C., m-chloroperbenzoic acid (4 g) is added and the mixture is stirred at room temperature for 4 h. The resulting product is washed with a 10% aqueous solution of potassium carbonate and dried with magnesium sulfate. After distilling off the solvent, the residue is recrystallized with n-hexane/ethyl acetate; m.p. 111°-112° C.; yield, 2.4 g (72%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][CH2:34][OH:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[F-].[K+].[CH3:38][CH2:39]N(CC)CC>CN(C=O)C.CO>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:38]#[CH:39])[CH:3]=[CH:4][C:5]=3[O:32][CH2:33][CH2:34][OH:35])[C:21]2=[CH:20][CH:19]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2OCCO)N1
Reactant: CCN(CC)CC
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.11 mmol) prepared in example 181b in DMF (2 mL), Et3N (0.3 mL), PdCl2(Ph3P)2 (Aldrich, 15 mg) were added and the mixture was purged with nitrogen and sealed. The vessel was heated on a microwave reactor for 25 min. and the mixture was poured into water. The mixture was extracted with EtOAc. The extracts were combined and dried with sodium sulfate and dried to give a brown oil, which was purified by chromatography on an ISCO machine (30-100% EtOAc/Hexanes) to give a foam. 45 mg. The foam was then dissolved in methanol (4 mL) and KF (Aldrich, 53 mg) was added. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partioned between EtOAc/water. The organic layer was dried and concentrated and the residue was purified by chromatography on ISCO machine (30-100% EtOAc/Hexane) to give an off-white solid. 25 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][N:15]=[CH:16]3)(=[O:10])=[O:9])[CH2:4][CH2:3]1>Cl.CO.O=[Pt]=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][NH:15][CH2:16]3)(=[O:9])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2cccc3c2CCNC3)CC1
Reaction time: 3.5 h
Yield: 124.1 %

Procedure:
5-(4-Methyl-piperazine-1-sulfonyl)-isoquinoline 10a (0.99 g, 3.41 mmol) was dissolved in a solution 2% of HCl in methanol (100 mL) under nitrogen. PtO2 (250 mg) was added under nitrogen and the mixture was hydrogenated in a Parr apparatus at 45 psi for 3.5 h. The catalyst was removed by filtration, rinsed with MeOH, and the filtrate was concentrated in vacuo to give 1.25 g of 5-(4-methyl-piperazine-1-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline 11a as a pale yellow foam. The crude hydrochloride salt of the product was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:11]=[C:10]([F:12])[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1>CO.O>[F:12][C:10]1[CH:11]=[C:4]([CH2:3][CH:2]=[O:1])[CH:5]=[C:6]([F:13])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)cc(CC(O)CO)cc1F
Solvent: O
Solvent: CO
Product: N#Cc1c(F)cc(CC=O)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,3-dihydroxypropyl)-2,6-difluorobenzonitrile (500 mg, 2.4 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0° C. by ice bath, then NaIO4 (754 mg, 3.5 mmol) was added and the mixture was stirred at 0° C. for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 2,6-difluoro-4-(2-oxoethyl)benzonitrile. MS m/z: 182 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3ccc(F)cc3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccc(F)cc1)Oc1ccc(Br)cc12
Temperature: 120 °C
Yield: 51 %

Procedure:
A suspension of 6-bromo-2-(4-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.77 mmol) and Lawesson's Reagent (310 mg, 0.77 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 min with microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(4-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (160 mg, 50%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[CH:40]=[N:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[CH:40]=[N:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=4)=[CH:37][N:36]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1
Yield: 8.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((4-(piperidin-1-yl)-2-((5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)carbamoyl)phenyl)carbamoyl)benzylthio)propanoate (140 mg, 0.19 mmol, 1.00 equiv) in dichloromethane (2 mL). This was followed by dropwise addition of 2,2,2-trifluoroacetic acid (1 mL) with stirring. The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 11 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.47 (s, 1H), 11.01 (s, 1H), 9.47 (s, 1H), 9.23 (s, 1H), 8.44 (d, J=4.5 Hz, 2H), 8.10 (d, J=9 Hz, 1H), 7.80 (m, 4H), 7.51 (m, 3H), 7.36 (m, 1H), 3.83 (s, 2H), 3.41 (s, 4H), 2.60 (d, 2H), 1.60 (m, 6H). MS (ES, m/z): 644 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:10]=2[S:9]1(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:25]1.O.O.O.O.[Na+].[NH4+].[Cl-]>C1COCC1.O>[OH:25][C:17]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:9](=[O:23])(=[O:22])[C:10]=2[CH:18]=1
Reactant: [O-]B1OO1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2S1(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(O)cc2S1(=O)=O

Procedure:
A suspension of 4.7 g (13.69 mmol) of the product of Step G of Example 1 in a mixture of 90 ml of THF and 90 ml of water is stirred at ambient temperature in the presence of 5.27 g (34 mmol) of sodium perborate tetrahydrate overnight. The reaction mixture is diluted by adding saturated aqueous NH4Cl solution and is then extracted with CH2Cl2. The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated using a rotary evaporator. The residue from evaporation is taken up and triturated in heptane in the presence of a few drops of isopropyl ether; a precipitate is formed which is filtered off to yield the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl.[H][H]>CO.O=[Pt]=O>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)c1cncc(C)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCC(C)C1

Procedure:
To methyl 5-methylnicotinate (2 g), PtO2 (100 mg) was added. The reaction flask was put under vacuum, and 125 N HCl in methanol (15 mL) was added. The reaction was put under 40 psi hydrogen gas and shaked overnight. The reaction mixture was filtered through celite and concentrated under vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[N:10]=[C:11]([S:12][CH3:13])[C:3]=12.[CH3:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][NH:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1>C(#N)C>[CH3:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][N:29]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]3[N:9]([C:14]4[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[N:10]=[C:11]([S:12][CH3:13])[C:3]=23)[CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(Cl)c12
Reactant: Cc1ccc(CNCCCO)cc1
Solvent: CC#N
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccc(C)cc3)c12
Yield: 88.7 %

Procedure:
A mixture of 4-chloro-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (788 mg, 2 mmol) and 3-(p-methylbenzyl)amino-1-propanol (716 mg, 4 mmol) in 10 ml of acetonitrile was heated at reflux for 4 hours. The mixture was cooled, quenched with water and dilute hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine, separated, dried and concentrated to give 953 mg of the title compound as an off-white glass form. The material was purified through silica gel column chromatography using chloroform as eluent to give the title compound as a white glass form. 1H NMR (CDCl3): 1.79 (m, 2H), 2.38 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H), 3.56 (t, 2H), 3.86 (t, 2H), 5.12 (s, 2H), 7.20 (s, 4H), 7.51 (s,2H) ppm. 13C NMR (CDCl3): 16.20, 21.13, 25.53, 29.64, 43.51, 53.88, 58.24, 127.78, 128.77, 129.33, 133.51, 136.18, 137.41, 142.93, 159.13, 164.89 ppm. IR(KBr): 3350, 2935, 1540 cm−1. Anal. calc. for C24H24N5OSCl3: C, 53.69; H, 4.50; N, 13.04; found: C, 53.33, H, 4.44, N, 12.84.
Reaction SMILES: [Br-].[CH:2](=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5].C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:19]1([CH2:6][CH2:4][CH2:3][CH2:9][CH2:8][CH2:7][O:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[CH:2]=[O:10])[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1O
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCCCCc1ccccc1
Temperature: 100 °C

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil. A mixture of the bromide (8.00 mmol), salicylaldehyde (8.19 mmol) and potassium carbonate (9.33 mmol) in dimethylformamide (10 ml) was heated to 100° C. and maintained at that temperature for one hour. The cooled reaction mixture was taken up in hexane (50 ml) and washed with 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation yielded a colorless oil which was purified by flash chromatography over silica gel with 5% ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]([O:7][CH2:8][C@@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C

Procedure:
The crude compound of Example 3E (0.96 g) was dissolved in 19 mL of dichloromethane and cooled to 0° C.; 3.1 g of pyridinium dichromate was added, followed by 22 mg of pyridinium p-toluenesulfonate. The resultant mixture was stirred for 1.5 hours at 0° C.; an additional 1.3 g of pyridinium dichromate and 20 mg of pyridinium p-toluenesulfonate were added, and the mixture was allowed to warm to ambient temperature overnight. The mixture was diluted with ether and filtered through a pad of diatomaceous earth with an ether wash. The filtrate was washed with 1 N aqueous HCl, and then filtered through a plug of silica gel. The crude product was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 8% to 15% ethyl acetate in hexanes. Fractions containing the titled compound were combined and concentrated in vacuo (0.77 g, 96%, 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:36][CH2:35][C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:38])[CH3:37]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(=O)(=O)NC(C)(C)CO)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-propyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.27) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 542.3 [(M+H)+]; mp 207-208° C.
Reaction SMILES: BrC1C2C=NC=CC=2N(CCCS(C)(=O)=O)C=1C[N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:30][CH2:29]2)[C:20]1=[O:31].[Cl:32][C:33]1[N:38]=[C:37]2[CH:39]=[C:40]([CH2:47]O)[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][F:46])[C:36]2=[CH:35][CH:34]=1>>[Cl:32][C:33]1[N:38]=[C:37]2[CH:39]=[C:40]([CH2:47][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:29][CH2:30]4)[C:20]3=[O:31])[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][F:46])[C:36]2=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(Br)c2cnccc21
Reactant: OCc1cc2nc(Cl)ccc2n1CCCCF
Product: O=c1n(Cc2cc3nc(Cl)ccc3n2CCCCF)c2cnccc2n1C1CC1

Procedure:
3-((5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P42 was synthesized following the procedure reported for the synthesis of 3-((3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P17, using (5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol 11 instead of (3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol 12. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-0.96 (m, 2H) 1.03-1.12 (m, 2H) 1.47-1.72 (m, 4H) 2.98 (tt, J=6.93, 3.61 Hz, 1H) 4.18-4.53 (m, 4H) 5.34 (s, 2H) 6.69 (s, 1H) 7.18 (d, J=8.53 Hz, 1H) 7.28 (d, J=5.02 Hz, 1H) 8.01 (d, J=8.53 Hz, 1H) 8.25 (d, J=5.27 Hz, 1H) 8.39 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[O:22][N:21]=4)=[C:9]3[C:8]2=[O:28])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].O>FC(F)(F)C(O)=O>[N:1]([C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[O:22][N:21]=4)=[C:9]3[C:8]2=[O:28])=[CH:4][CH:3]=1)=[N+:35]=[N-:36]
Reactant: Nc1ccc(Cn2c(=O)c3c(-c4noc(C5CC5)n4)ncn3c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(Cn2c(=O)c3c(-c4noc(C5CC5)n4)ncn3c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(4-aminobenzyl)-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline (0.1 g, 0.25 mmol) in trifluoroacetic acid (3 ml) at 0° C. was added sodium nitrite (0.1 g, 1.4 mmol). After 5 min. sodium azide (0.16 g, 2.5 mmol) was added. Stirring was continued for 1 h. Then water (20 ml) was added, and the mixture was extracted twice with dichloromethane (20 ml). The combined extracts were dried over sodium sulphate and evaporated to give the title compound as a pale yellow solid, m.p. 183°-184° C. (dec.). Chromatographic purification (SiO2)/CH2Cl2 -acetone 4:1) gave crystals with m.p. 194°-197° C. (dec.).