Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2ccc(F)c(C#N)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (45 mg, 0.081 mmol) in DCM (4 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (19 mg, 0.045 mmol, 55% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (s, 1H) 7.29-7.40 (m, 3H) 7.13-7.29 (m, 2H) 4.61 (s, 2H). LC-MS (ES+) m/z 423.12, [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:40])([CH3:39])[C:35](=O)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.FC(F)(F)C(O)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:39])([CH3:40])[C:35](=[N:43][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN1CCOCC1
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NN3CCOCC3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a solution of Compound (37) (573 mg, 1.00 mmol) in 60 ml of ethanol were added 306 mg (3.00 mmol) of N-aminomorpholine and 328 μl (3.51 mmol) of trifluoroacetic acid. The reaction was allowed to proceed for 72 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 100 g; n-hexane:ethyl acetate=7:3) to give 265 mg (40%) of Compound (60).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.CCOCC>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:6]=[N:7][C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:3][C:4]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)c1cc(N2CCOCC2)nnc1Nc1ccc(I)cc1F
Temperature: 135 °C

Procedure:
To mixture of 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (34 mg, 0.09 mmol) in DMF was added morpholine (37.7 mg, 0.43 mmol). The mixture was heated at 135° C. for 3.5 h. The mixture was diluted with ether and extracted with NaOH (1N). The aqueous layer was acidified by concentrated HCl. The desired product was precipitated and was collected by vacuum filtration. LC/MS [5.51 min; 445 (M+1)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]#[C:13][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]#[CH:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCC#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
To a solution of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (1.90 g, 7.7 mmol) in THF (24 mL) cooled in a ice bath at 0° C., was added dropwise 7.7 mL of tetrabutylammonium fluoride 1M in THF solution (7.70 mmol). The reaction mixture was stirred 15 min at 0° C., and warmed to room temperature for 2 h 30. The reaction was quenched with water and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 500 mg of 1-fluoro-4-(hexa-1,5-diynyl)benzene (Yield: 45%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.CC(O)=O>COCCO.[Pd]>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)s1
Agent: [Pd]
Solvent: COCCO
Solvent: CC(=O)O
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc(N)c3)n2)s1
Reaction time: 0.17 h

Procedure:
To a mixture of {4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine (3.97 mmol, 1.3 g) in 2-methoxyethanol (15 mL) was added AcOH (1 mL). The reaction mixture was stirred under N2 for 10 min. Palladium catalyst (660 mg; 10% on activated carbon) was the added and the reaction mixture was allowed to stir under H2 for 18 h. The reaction mixture was passed through Celite 521 and the precipitates were washed several times with MeOH. The filtrate was concentrated and recrystallised from MeOH/EtOAc to afford grey crystals of N-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine. An aliquot of this material (500 mg) in 2-methoxylethanol was cooled on an ice bath and was treated with HCl (conc. 1 mL). Cyanamide (50% aq soln., 4 mL) was added dropwise. After completion of the addition the reaction mixture was warmed to r.t. and heated at reflux for 20 h. The reaction mixture was concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic phase was evaporated and purified by chromatography, using EtOAc/MeOH (3:1, v/v) to elute the title compound. DE MALDI-TOF MS: {M+H}+=339.16 (C16H17N7S requires 339.42).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH2:17][CH3:18])(=[O:3])[CH3:2].[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH2:17][CH3:18])=[C:7]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[O:13][C:19]1([CH2:22][CH2:21][CH2:20]1)[CH2:15][C:14]2=[O:16])(=[O:3])[CH3:2]
Reactant: CCc1c(OC(C)=O)c(C)c(C)c(O)c1C(C)=O
Reactant: O=C1CCC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCc1c(OC(C)=O)c(C)c(C)c2c1C(=O)CC1(CCC1)O2

Procedure:
To a solution of 3-acetyl-2-ethyl-4-hydroxy-5,6-dimethylphenyl acetate (3.5 g) in 20 mL of toluene was added cyclobutanone (1.16 mL) and pyrrolidine (1.4 mL). The reaction was allowed to reflux for 2 hours and Dean-Stark apparatus was used to remove water from the reaction. After the reaction was complete, the mixture was extracted with ethyl acetate and then was washed with 1N HCl and water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 5-ethyl-7,8-dimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate, which was hydrolyzed in 1N NaOH in MeOH/water. After the reaction was complete as indicated by TLC, the mixture was acidified with 1N HCl and extracted with ethyl acetate and dried over anhydrous Na2SO4. Evaporation of the solvents gave 0.8 g of 5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one as a yellow paste.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[NH:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CC(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)C)NCCC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.5 g) in trifluoroacetic acid (15 mL). The reaction mixture was reduced on a Parr apparatus under 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added. The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 1-5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from hexane/ethyl acetate to provide 6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5 ]naphthyridin-4-amine as a solid, m.p. 143-147° C. Analysis: Calculated for C17H27N5: %C, 67.74; %H, 9.03; %N, 23.23; Found: %C, 61.90; %H, 7.51; %N, 19.91.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C=CC(S(O[CH2:21][C@@H:22]2[O:24][CH2:23]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[O:24]1[CH2:23][C@@H:22]1[CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(OC[C@H]2CO2)c(C=O)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of 2-hydroxy-5-methylbenzaldehyde (7.1 g), (R)-glycidyl 4-toluenesulphonate (11.9 g) and potassium carbonate (7.25 g) in anhydrous 1,2-dimethoxyethane (150 ml) was stirred and heated at 60° C. for 5 hours, allowed to stand at ambient temperature for 18 hours, heated at 60° C. for a further 8 hours then allowed to cool for 18 hours. The solvent was removed in vacuo and the residue partitioned between water (250 ml) and ether (250 ml). The mixture was filtered through Celite, the ether layer separated, washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography on silica eluting with a 1:1 mixture of ether and petroleum ether (b.p. 40-60° C.). Appropriate fractions were combined and the solvent evaporated to give (R)-2-(2,3-epoxypropoxy)-5-methylbenzaldehyde (8.91 g) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:1]([N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:19]2[CH:20]=[CH:21][C:22]3[C:13]4[N:12]([CH2:32][CH2:33][CH3:34])[C:11]([CH2:10][CH2:9][O:8][CH3:7])=[N:31][C:14]=4[C:15]([NH2:30])=[N:16][C:17]=3[CH:18]=2)[CH2:29][CH2:28]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)C(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (0.273 mL, 2.61 mmol) was added dropwise to a stirred solution of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Part A of Example 388, 1.00 g, 2.61 mmol) in chloroform at 0° C. After 2 hours, the solution was allowed to warm to ambient temperature for 1 hour. Saturated aqueous sodium carbonate (15 mL) and water (10 mL) were added and the mixture was allowed to stir for 16 hours. The mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile afforded 1.00 g of 7-[(1-isobutyrylpiperidin-4-yl)oxy]-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a flocculent white solid, mp 165-166° C.
Reaction SMILES: O/[N:2]=[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]>[Pd].C(O)C>[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)c1ccccn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)c1ccccn1
Reaction time: 3 h
Yield: 103.9 %

Procedure:
10% Palladium on carbon (100 mg) was added to a solution of ethyl (2Z)-(hydroxyimino)(pyridin-2-yl)ethanoate (592 mg, 2.67 mmol) in ethanol (20 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 3 h, the mixture was filtered and concentrated to give the title compound (500 mg). MS 181.17 (M+1)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:18][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxymethylpiperidine-1-carboxylate (11.50 g, 53.7 mmol) in N,N-dimethylformamide (110 ml) was added sodium hydride (3.22 g, 80.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added methyl iodide (4.35 ml, 69.9 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give tert-butyl (R)-3-methoxymethylpiperidine-1-carboxylate (13.00 g, yield 100%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CO[C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O>>[CH3:20][C:19]1([CH3:21])[N:11]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C@H:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C@H:2]2[O:1]1
Reactant: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Reactant: C=C(C)OC
Agent: CS(=O)(=O)O
Product: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reaction time: 0.33 h

Procedure:
N-(1S,2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and 2-methoxypropene (5 mL) were combined with CH2C12 (70 mL) at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min at rt, the reaction mixture was partitioned between half-saturated NaHCO3 (30 mL) and CH2C12 (2×30 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil as product: MH+260.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].N1C=CC=CC=1.Cl[C:43]([O:45][CH3:46])=[O:44].Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH:21][C:43](=[O:44])[O:45][CH3:46])(=[O:19])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 39.8 %

Procedure:
7-(2-Chlorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.070 g, 0.137 mmol) obtained in Example 6 step 5 was dissolved in dichloromethane (0.7 mL), and the solution was cooled to 0° C. Pyridine (0.325 g, 4.110 mmol) and methyl chloroformate (0.350 g, 3.699 mmol) were added, the mixture was stirred at room temperature for 48 hr, and 1 mol/L hydrochloric acid was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the title compound (0.031 g, 40%).
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:10]1([NH:14][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(CBr)OCC
Reactant: NC1CCC1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(CNC1CCC1)OCC

Procedure:
A solution of 1.75 ml (11.65 mmol) of 1-bromo-2,2-diethoxyethane and 2 ml (23.3 mmol) of cyclobutylamine was heated at 80° C. in a closed vessel overnight. The reaction mixture was mixed with 40% NaOH (in H2O) and extracted, with ether. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 2.39 g of substance were obtained as an orange liquid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]12[CH2:18][CH:14]3[CH2:15][CH:16]([CH2:17]1)[C:12]([C:19]1([CH3:24])OCC[O:20]1)([CH2:13]3)[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:8][CH2:9][C:10]12[CH2:18][CH:14]3[CH2:15][CH:16]([CH2:17]1)[C:12]([C:19](=[O:20])[CH3:24])([CH2:13]3)[CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C23CC4CC2CC(COCc2ccccc2)(C4)C3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)C12CC3CC1CC(COCc1ccccc1)(C3)C2
Yield: 93.5 %

Procedure:
A mixture of 2-[1-(benzyloxymethyl)tricyclo[3.3.1.03,7]non-3-yl]-2-methyl-1,3-dioxolane (2.6 g, 7.9 mmol), p-toluenesulfonic acid (0.3 g, 1.6 mmol), and acetone (31.6 mL) was refluxed for 4 h. The volatiles were removed under vacuum and the residue was diluted with EtOAc, washed with 10% aq. NaHCO3 and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain 1-{1-[(benzyloxy)methyl]tricyclo[3.3.1.03,7]non-3-yl}ethanone (2.1 g) as a viscous liquid in 93% yield. m/z (M+1) 285; 1H NMR (CDCl3) 300 MHz δ 7.40-7.22 (m, 5H), 4.50 (s, 2H), 3.27 (s, 2H), 2.70-2.62 (m, 1H), 2.47-2.40 (m, 1H), 2.16 (s, 2H), 2.0-1.90 (m, 2H), 1.81-1.56 (m, 7H), 1.50 (dd, J=3.0, 11.0 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3](CC)CCN)[CH3:2].CO[C:11]([C:13]1[N:14]=[N:15][N:16]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42]CC3C=CC=CC=3)=[CH:35][C:34]=2[O:50]CC2C=CC=CC=2)[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=1)=[O:12].[Br-]>C(#N)C>[CH2:1]([NH:3][C:11]([C:13]1[N:14]=[N:15][N:16]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([OH:42])=[CH:35][C:34]=2[OH:50])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=1)=[O:12])[CH3:2]
Reactant: CCN(CC)CCNCc1ccc(-c2c(C(=O)OC)nnn2-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Reactant: CCN(CC)CCN
Agent: [Br-]
Solvent: CC#N
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1-c1ccc(CNCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-{4-[(2-diethylamino-ethylamino)-methyl]-phenyl}-1H-[1,2,3]triazole-4-carboxylic acid methyl ester N,N-diethylethylenediamine (0.6 mmol) was added at −10° C. to an acetonitrile solution of the bromide adduct obtained in Step A (125 mg, 0.2 mmol), and the reaction mixture was stirred for 30 minutes at this temperature and then warmed up to RT. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure and the residue was purified by flash chromatography, the column being previously conditioned with ammonia (DCM/MeOH:80/10). The title compound was obtained as an oil (45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:37])[CH2:9][CH2:10][C@@H:11]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)[N:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]2=[O:36])=[CH:4][CH:3]=1.[C:38]([O:41][C@@H:42]1[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:46]([O:52][C:53](=[O:55])[CH3:54])[C@@H:45]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[O:44][C@H:43]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63](Br)[CH:62]=1)(=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:38]([O:41][C@@H:42]1[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:46]([O:52][C:53](=[O:55])[CH3:54])[C@@H:45]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[O:44][C@H:43]1[C:61]1[CH:62]=[C:63]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:14]3[C@@H:11]([CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[OH:37])[C:12](=[O:36])[N:13]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)[CH:64]=[CH:65][CH:66]=1)(=[O:40])[CH3:39]
Reactant: CC1(C)OB(c2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)OC1(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 18.4 %

Procedure:
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (51.3 mg, 0.102 mmol) and (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (35.5 mg, 0.073 mmol) were dissolved in 2.0 mL of toluene and 0.25 mL of ethanol. 0.075 mL of 4 N potassium carbonate was added to the mixture followed by 5.0 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 4 h. The reaction was cooled to room temperature, diluted with 5 mL of water, and extracted with ethyl acetate (3×25 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 10.5 mg (13%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.