Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[NH:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)C>[CH2:29]([O:28][C:26]([C:25]1[N:8]=[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]([C:10]2[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[CH:24]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(Nc1c(Cl)cccc1Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Temperature: 95 °C
Reaction time: 17 h
Yield: 67.2 %

Procedure:
A stirred mixture of 5-bromo-N-(2,6-dichlorophenyl)-thiophene-2-carboxamidine (3.9 g, 11 mmol) and sodium bicarbonate (1.85 g, 22 mmol) in isopropanol (55 mL) was charged with ethyl bromopyruvate (2.5 mL, 20 mmol) and then heated at 95° C. After 17 h the reaction mixture was allowed to cool to ambient temperature, filtered and the solids rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 15:85 to 65:35) to give the title compound (3.3 g, 67%) as a tacky yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 7.60 (s, 1H), 7.49-7.59 (m, 3H), 6.89 (d, 1H), 6.56 (d, 1H), 4.37 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C(=[NH:51])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:37][C:33]1[CH:32]=[C:31]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([NH2:51])[CH:3]=3)[N:7]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:6]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 2.0 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole obtained in Production Example II-9-c in 20 ml toluene at room temperature were added 0.73 g of benzophenoneimine, 95 mg of tris(dibenzylideneacetone)(chloroform)dipalladium(0), 0.17 g of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 0.53 g of sodium tert-butyrate, and the mixture was heated under reflux for one day. The mixture was diluted with water and ethyl acetate, and the organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 30 ml of tetrahydrofuran, 10 ml of 5 N hydrochloric acid was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:3), and the resulting obtained crystals were washed with diethyl ether, to give 0.86 g of the title compound as colorless crystals.
Reaction SMILES: C([Sn](CCCC)(CCCC)C1C=CN=CC=1)CCC.C([O:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30](Br)[CH:29]=1)C1C=CC=CC=1.[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=CC=1>>[F:34][C:32]1[CH:33]=[C:28]([OH:27])[CH:29]=[C:30]([C:40]2[CH:41]=[CH:36][O:42][CH:39]=2)[CH:31]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: Oc1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: Oc1cc(F)cc(-c2ccoc2)c1

Procedure:
Following the procedures described in Phenol 1, Steps 2 and 3, but substituting 3-tributylstannylfuran for 4-tributylstannylpyridine, and O-(3,4-dimethoxy)benzyl-3-bromo-5-fluorophenol from Phenol 2, Step 1 for O-benzyl-3-bromo-5-fluorophenol, the title compound was obtained as an oil.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[NH:13][C:14]2[C:15]3[C:22]([CH3:23])=[C:21]([C:24]([OH:26])=O)[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3][CH2:2]1.[NH3:27]>CO>[CH:1]1([O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[NH:13][C:14]2[C:15]3[C:22]([CH3:23])=[C:21]([C:24]([NH2:27])=[O:26])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c12
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-(2-cyclobutoxy-4-fluoro-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (127 mg) and 7 M ammonia in MeOH (1 ml).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][C:42]=1[Cl:43])[NH:39][N:38]=[C:37]2[C:44]([OH:46])=[O:45].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO>[NH2:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][C:42]=2[Cl:43])[NH:39][N:38]=[C:37]3[C:44]([OH:46])=[O:45])=[CH:3][CH:4]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: NC(=O)Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: NC(=O)Cc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 130 °C
Yield: 2.8 %

Procedure:
A suspension of 2-(4-bromophenyl)acetamide (85.0 mg, 0.37 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136 mg, 0.37 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg, 0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1 N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 10.5 min, HOLD at 0% H2O/100% MeCN to 12.0 min. Flow: 25 mL/min) to afford the title compound (3.3 mg, 3% yield). MS (ES+) 330.1 (M+H)+. Retention time=2.04 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:11][CH:10]=1.B(F)(F)F.CC[O:28]CC.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>[BH4-].[Na+].COCCOCCOC.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:28])=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: C=CCCC[C@@H](O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: OO
Solvent: O
Solvent: COCCOCCOC
Product: OCCCCC[C@@H](O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reaction time: 1 h

Procedure:
Impure (R)-1-(2′,4′-dichloro-biphenyl-4-yl)-hex-5-en-1-ol (1 g) was dissolved in 0.5 M NaBH4 in diglyme (9 mL) and chilled in an ice bath. BF3.OEt2 (1 mL) in diglyme (4 mL) was added with vigorous stirring. Stirring was continued for 1 hour and water (1 mL) was added. 3 M NaOH (2 mL) was added followed by 30% H2O2 (3 mL). Anhydrous K2CO3 (5 g) was added and the solvent was decanted. The K2CO3 was washed with ethyl acetate and the combined organics were dried (Na2SO4) and evaporated. Distillation under vacuum removed most of the remaining diglyme. The residue was purified by column chromatography (light petroleum:diethyl ether 2:1) to give a clear oil which crystallised on standing to give the title compound as white needles. 13C NMR (CDCl3): δ 25.7, 25.7, 32.6, 39.1, 62.9, 74.3, 125.7, 127.2, 129.5, 129.7, 132.1, 133.2, 133.7, 137.5, 138.7 and 144.6.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[BH4-].[Na+].C([N:35]1[C:43]2[C:38](=[N:39][C:40]([N:45]3[CH:49]=[C:48]4[CH2:50][N:51]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:52][C:47]4=[N:46]3)=[C:41]([Cl:44])[CH:42]=2)[N:37]=[C:36]1[O:57][C@@H:58]1[CH2:62][O:61][C@@H:60]2[C@H:63]([O:66][Si](C(C)(C)C)(C)C)[CH2:64][O:65][C@H:59]12)C=C.C1COCC1>C(O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:44][C:41]1[CH:42]=[C:43]2[NH:35][C:36]([O:57][C@H:58]3[C@H:59]4[O:65][CH2:64][C@@H:63]([OH:66])[C@H:60]4[O:61][CH2:62]3)=[N:37][C:38]2=[N:39][C:40]=1[N:45]1[CH:49]=[C:48]2[CH2:50][N:51]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:52][C:47]2=[N:46]1
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-n3cc4c(n3)CN(S(C)(=O)=O)C4)c(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1Cc2cn(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)nc2C1
Reaction time: 0.33 h

Procedure:
A mixture of palladium acetate (2.5 mg, 0.011 mmol) and DPPP (1.6 mg, 0.0039 mmol) in ethanol (0.1 mL) was stirred for 20 minutes under nitrogen. The resulting dark suspension was added to a mixture of sodium borohydride (18 mg, 0.476 mmol) and [(3R,3aR,6R,6aS)-3-[1-allyl-6-chloro-5-(5-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-2-yl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (50.6 mg, 0.079 mmol) in ethanol (0.9 ml). The reaction was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction mixture was then purified directly on preparative silica plates (1×1000 u developed with 5% MeOH/DCM). The resulting solid was dissolved in 1M TBAF in THF (0.1 mL, 0.1 mmol) and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL). The organic layer was washed with brine (1×5 mL), dried with MgSO4, filtered and the solvent was removed under vacuum. The resulting solid was dissolved in methanol (1.0 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. LC-MS: calculated for C1-8H19ClN6O6S 482.08 observed m/e: 483.12 (M+H)+ (Rt 0.97/2 min); 1H NMR δ (ppm) (CD3OD): 7.92 (s, 1H), 7.86 (s, 1H), 5.56 (m, 1H), 4.61 (s, 4H), 4.47 (dd, 1H), 4.29 (m, 1H), 4.18-4.10 (m, 2H), 3.90 (dd, 1H), 3.60 (dd, 1H) and 3.02 (s, 3H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([C:15](N)=[O:16])[OH:14].C([OH:21])(C)C>O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([C:15]([OH:16])=[O:21])[OH:14]
Reactant: CC(C)O
Reactant: NC(=O)C1(O)CCSc2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1(O)CCSc2ccc(Cl)cc21

Procedure:
Potassium hydroxide (5.1 g, 91 mmol) and 6-chloro-4-hydroxythiochromane-4-yl-carboxamide (1.36 g, 5.58 mmol; from step (ii) above) were dissolved in water (25 mL) and isopropanol and refluxed for 2 d. The isopropanol was removed under reduced pressure and the aqueous residue was washed with diethyl ether. Acidification with aq. HCl, extraction with ethyl acetate, and then drying and concentration in vacuo afforded the sub-title compound. Yield: 0.87 g (64%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=[O:18])[NH:12]2>ClCCl>[OH:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=[O:18])[NH:12]2
Reactant: COc1ccc(C)c2c1CCC(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)c2c1NC(=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
A 2N dichloromethane solution (52 ml) of boron tribromide was added dropwise at −20° C. to a dichloromethane solution (100 ml) of 5-methoxy-8-methyl-3,4-dihydro-1H-quinolin-2-one (10.0 g). After stirring for 1 hour, the reaction mixture was poured into ice water and separated into layers. The organic layer was washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to thereby obtain 9.4 g (yield: quantitative) of 5-hydroxy-8-methyl-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[S:11][C:12](Br)=[CH:13][CH:14]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cu][C:17]#[N:18].O.N>CN1CCCC1>[N:1]1([CH:6]([C:10]2[S:11][C:12]([C:17]#[N:18])=[CH:13][CH:14]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#C[Cu]
Reactant: CCCC(c1ccc(Br)s1)n1ccnc1
Agent: CN1CCCC1
Agent: N
Solvent: O
Product: CCCC(c1ccc(C#N)s1)n1ccnc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 30.8 %

Procedure:
0.04 g of bromine compound (of example 1) is dissolved in 2 ml of N- methylpyrrolidine, 0.05 g of copper(I) cyanide is added and stirred under argon for 5 hours at 180° C. Ammonia water is added to the reaction solution and then extracted with ethyl acetate. The organic phase is concentrated by evaporation in a vacuum and the remaining oil is distilled on a bulb tube, boiling point 180° C./0.03 mbar. 0.01 g of 5-[1-(1-imidazolyl)-butyl]thiophene-2-carbonitrile is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[F:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33](=[O:34])[C:32]3[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:31]=3[F:30])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3cc(C(F)(F)F)ccc3F)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 91, Step 3, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-fluoro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:26])[CH2:14][CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH:8]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[C:4]([O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:26])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1cccc(C)c1C(=O)Oc1cccc(C(=O)CCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(=O)Oc1cccc(C(=O)CCC(=O)O)c1

Procedure:
To a stirred solution of 3-(4-(Benzyloxy)-4-oxobutanoyl)phenyl 2,6-dimethylbenzoate (Step C, 2.75 g, 6.6 mmol) in ethyl acetate was added Pd—C (5%, 0.230 g) under an argon atmosphere. The starting material was hydrogenated under a H2 atm for 14 hours and filtered through a celite pad. The filtrate was concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 92.5:7.5 spiked with acetic acid) to provide the title compound.
Reaction SMILES: CN1CCOCC1.[OH:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C:10]1=[O:19].[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>O1CCCC1>[CH3:20][Si:21]([CH3:24])([CH3:23])[O:8][C@@H:9]1[C@@H:14]([O:15][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@H:13]([O:16][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@@H:12]([CH2:17][O:18][Si:21]([CH3:24])([CH3:23])[CH3:20])[O:11][C:10]1=[O:19]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of N-methylmorpholine (246.8 mL, 2.24 mol) and (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-one 1a (50 g, 0.28 mol, bought from Aladdin) in anhydrous tetrahydrofuran (500 mL) was added dropwise trimethylchlorosilane (213 mL, 1.68 mol) over a period of 2 hours. The mixture was stirred at room temperature (rt) for 8 hours and quenched with 1 L of water. The resulting mixture was partitioned. The organic layer was washed with saturated aqueous dipotassium hydrogen phosphate (100 mL×8.3) and saturated aqueous sodium chloride (100 mL×8.3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=40/1 to give the title compound 1b as colorless oil (125.2 g, 100%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 4.17 (m, 1H), 3.99 (d, 1H), 3.89 (t, 1H), 3.81 (m, 3H), 0.18 (s, 9H), 0.17 (s, 9H), 0.15 (s, 9H), 0.11 (s, 9H).
Reaction SMILES: [CH:1]([F:10])([C:6]([Cl:9])([Cl:8])[F:7])[C:2]([F:5])([F:4])[F:3].[F:11][CH:12]=[C:13]([F:15])[F:14].[Cl:16][C:17](Cl)([F:19])[F:18]>>[Cl:16][C:17]([F:19])([F:18])[CH:12]([F:11])[C:13]([Cl:8])([F:15])[F:14].[Cl:8][C:6]([Cl:9])([F:7])[CH:1]([F:10])[C:2]([F:5])([F:4])[F:3]
Reactant: FC=C(F)F
Reactant: FC(F)(Cl)Cl
Agent: FC(C(F)(F)F)C(F)(Cl)Cl
Product: FC(C(F)(F)Cl)C(F)(F)Cl

Procedure:
Until HCFC-225eb becomes available in commercial quantities, HCFC-225eb may be prepared by a standard and well-known organic synthesis technique. For example, 1,1-dichloro-1,2,3,3,3-pentafluoropropane may be prepared by reacting trifluoroethylene with dichlorodifluoromethane to produce 1,3-dichloro-1,1,2,3,3-pentafluoropropane and 1,1-dichloro-1,2,3,3,3-pentafluoropropane. The 1,1-dichloro-1,2,3,3,3-pentafluoropropane is separated from its isomer using fractional distillation and/or preparative gas chromatography. Alternatively, 225eb may be prepared by a synthesis disclosed by O. Paleta et al., Bull. Soc. Chim. Fr., (6) 920-4 (1986). The 1,1-dichloro-1,2,3,3,3-pentafluoropropane can be separated from its two isomers using fractional distillation and/or preparative gas chromatography.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:37])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:14]=2)[C:11]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:37][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:24]3)[N:16]=[C:15]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:14]=2)[C:11]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:10]=2[N:9]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCOCC2)nc(N2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Methanesulfonyl chloride (0.07 mL, 0.904 mmol) was added drop-wise to a mixture of the above amine (102 mg, 0.229 mmol) and powdered K2CO3 (253 mg, 1.83 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and allowed to warm to room temperature. After 5 hrs, additional K2CO3 (127 mg, 0.919 mmol) and methanesulfonyl chloride (0.04 mL, 0.517 mmol) were added and the mixture stirred at room temperature for another 16 hrs. Water was added and the layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole (73 mg, 61%): mp (CH2Cl2/MeOH) 242-244° C.; 1H NMR (CDCl3) δ 8.00 (dd, J=8.4, 0.6 Hz, 1H), 7.55 (t, JHF=53.5, 1H), 7.40 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 4.14-4.09 (m, 6H), 4.06 (s, 3H), 3.56 (m, 2H), 3.37 (br s, 4H), 2.96 (m, 1H), 2.83 (s, 3H), 1.99 (ddd, J=12.1, 7.9, 4.0, 4H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.6; H, 5.4; N, 18.6%.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 4-azido-1-(p-nitrobenzyloxycarbonyl)-piperidine (2.81 g, 9.17 mmol) (obtained as described in Reference Example 51(3)) in acetonitrile (84 ml) was added triphenylphosphine (2.53 g, 9.63 mmol), and the mixture was stirred in an oil bath (70° C.) for 3 hours. After checking the completion of the reaction, sodium sulfate decahydrate (3.10 g, 9.63 mmol) was added thereto and the reaction mixture was stirred for 3 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give 4-amino-1-(p-nitrobenzyloxycarbonyl)-piperidine (2.33 g, yield 91%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:11]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2].[ClH:41].CCOC(C)=O>CO.C(Cl)Cl>[ClH:41].[ClH:41].[CH2:1]([NH:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:11]([C:17]4[CH:18]=[CH:19][C:20]([C:23]5([NH2:27])[CH2:24][CH2:25][CH2:26]5)=[CH:21][CH:22]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2]
Reactant: CCNc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3ccn12
Temperature: 25 °C

Procedure:
To a solution of 3-1(108 mg, 0.202 mmol) in MeOH (2 mL) and DCM (5 mL) was added a 4N solution of HCl in EtOAc (5 mL, 20 mmol). The capped reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was concentrated in vacuo to give 1-{4-[3-(ethylamino)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine dihydrochloride (3-2) as a yellow solid. HRMS (M+H)+: observed=435.2302, calculated=435.2292.