Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)phenol (200 mg) in dry N,N-dimethylformamide (2 ml) were added ethyl bromoacetate (138 μl) and potassium carbonate (216 mg), and the mixture was reacted with stirring at room temperature for 1 hour, and then for 1 hour at 60° C. To the reaction mixture was added ethyl acetate, and ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 270 mg of ethyl 2-(2,2,2-trifluoroethoxy)phenoxyacetate as an oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][C@@H:2]([OH:1])[C@@H:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Brc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cncnc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 31.4 %

Procedure:
Prepared according to the method described in Example 21b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.200 g, Example 21a)), 5-bromopyrimidine (0.159 g), ethanol (3 ml), 2M aqueous sodium carbonate (0.67 ml) and tetrakistriphenylphosphine palladium(0) (0.030 g) with heating at 90° C. for 4 hours. After work up, the residue was purified by reverse phase HPLC, eluting with a gradient of 15:85 to 95:5 acetonitrile in 0.1M ammonium acetate. The compound was subsequently purified by flash chromatography on silica gel, eluting with 1:1 isohexane/acetone to give the title compound as an oil (0.070 g).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][S:27][C:14]1[N:13]=[C:12]([CH3:20])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[CH:17]=[C:8]([NH:9][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:33]
Reactant: CCOC(=O)CS
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: CCO
Product: CCOC(=O)CSc1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 49 %

Procedure:
A solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in EtOH (10 mL) was added ethyl 2-mercaptoacetate (0.12 mL, 1.10 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (120 mg, 49%): LCMS RT: 3.07 min, MH+: 446.2.
Reaction SMILES: CC(C)=CCCC(C=C)=C.ClC(CCCCC)C(Cl)=C(C)C.C([O:26][CH2:27]/[CH:28]=[C:29](\[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])/[CH3:30])(=O)C.C([O-])(=[O:39])C.[Na+].[OH-].[Ca+2].[OH-]>C1C=CC=CC=1.C(N(CC)CC)C>[OH:39][CH2:36]/[C:34](=[CH:33]\[CH2:32][CH2:31][CH:29]([CH2:28][CH2:27][OH:26])[CH3:30])/[CH3:35]
Reactant: CC(=O)OC/C=C(/C)CCC=C(C)C
Reactant: CC(=O)[O-]
Agent: C=CC(=C)CCC=C(C)C
Agent: CCCCCC(Cl)C(Cl)=C(C)C
Agent: [Ca+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C/C(=C/CCC(C)CCO)CO

Procedure:
Prod.: (many methods) e.g. from Myrcene, via Myrcene dihydrochloride to Dichloro di-methyloctene. This is converted to Chloro di-hydrogeranyl acetate (and-neryl acetate) with Sodium Acetate in Benzene in presence of Triethylamine. The acetates are saponified with Calcium hydroxide to yield Hydroxycitronellol, from which the aldehyde is prepared by oxidation.
Reaction SMILES: C[C:2]1(C)[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11]([CH3:13])=[O:12])=[CH:10][C:4]=2[O:3]1.BrBr.[Br:17]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Br:17][CH2:13][S:11]([C:9]1[CH:8]=[CH:7][C:5]2[O:6][CH2:2][O:3][C:4]=2[CH:10]=1)=[O:12]
Reactant: CS(=O)c1ccc2c(c1)OC(C)(C)O2
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(CBr)c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution, cooled to 0° C., of 16.5 g of 2,2-dimethyl-5-(methylsulphinyl)-1,3-benzodioxol and 6.2 g of pyridine in 230 ml of methylene chloride, there were added in succession 5.43 g of bromine and 12.1 g of N-bromosuccin-imide. The reaction mixture was stirred at 0° C. for 3 hours and then at 20° C. for a further 12 hours. The orange colored solution was cooled to 0° C., treated with 40 ml of 1M aqueous sodium sulphite solution and the pH of the mixture was adjusted to 7 by the addition of 17% aqueous sodium carbonate solution. After stirring for 10 minutes, the phases were separated. The organic phase was washed in succession with 50 ml of 1N aqueous hydrochloric acid, 50 ml of 5% sodium hydrogen carbonate solution and 3 times with 100 ml of water each time, dried over sodium sulphate and evaporated in a vacuum. The residue was chromatographed on silica gel, with elution being carried out with ethyl acetate/hexane (1:2, v/v). After crystallization from acetone/water, there was obtained 5-[(bromomethyl)-sulphinyl]-1,3-benzodioxol as white crystals having a melting point of 88°-89° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[C:30]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:36][CH:37]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](NCc1ccc(OC(C)(C)C)cc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butoxy)benzaldehyde (0.229 mL, 1.25 mmol, Lancaster) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 25 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.9 and 0.55. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.55) was isolated by flash chromatography (30% EtOAc in hexanes). Forty-four percent (0.311 g) of the pure titled compound was obtained as a white foam: mp 56-61° C. APCI-MS m/z 564.5 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([O:11]C)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CO.ClCCl>[N:1]1([CH2:7][CH2:8][C:9]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCN1CCOCC1
Reactant: NCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCN1CCOCC1)NCc1ccccn1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of methyl 4-morpholinepropionate (5.0 g, 28.9 mmol) in MeOH (25 mL) was added 2N NaOH (17.3 mL, 34.6 mmol). The mixture was stirred for 1 h then concentrated in vacuo. The residue was suspended in dichloromethane (125 mL) and DMF (30 μL) was added followed by oxalylchloride (10 mL, 115.6 mmol). The mixture was allowed to stir for 2 h. then concentrated in vacuo. The resulting solid was added portion-wise to a solution of 2-(aminomethyl)pyridine (2.88 mL, 28.2 mmol) and triethylamine (9.0 mL, 64.86 mmol) in dichloromethane (200 mL). The mixture was stirred at ambient temperature for 1 h. then washed with water (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.56 g, 77%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][C:12]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:15]=[C:14]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=4)[C:29]#[N:30])[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>COCCOC>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][C:12]3[CH:13]=[C:14]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([C:29]5[NH:38][N:37]=[N:36][N:30]=5)[CH:31]=4)[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:17]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cncc(-c2cc(NCc3cccc4[nH]ccc34)nc(-c3ccccn3)n2)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: c1ccc(-c2nc(NCc3cccc4[nH]ccc34)cc(-c3cncc(-c4nnn[nH]4)c3)n2)nc1
Temperature: 25 °C

Procedure:
A solution of 5-(6-[(1H-indol-4-ylmethyl)-amino]-2-pyridin-2-yl-pyrimidin-4-yl)-nicotinonitrile (Ex. 2.9) (50 mg, 0.124 mmol) in DME (2 ml) under an inert atmosphere of argon is treated with trimethylsilyl azide (5 eq, 70 mg, 0.248) and dibutyltin oxide (0.3 eq, 9.3 mg). The resulting mixture is heated at reflux for 4 hours and then allowed to cool to room temperature. On cooling, a solid precipitates which is collected by filtration, washed with MeOH and dried in vacuo at 40° C. overnight to afford the title compound [M+H]+=447.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.Br[CH2:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1>O>[N:35]1([CH2:34][CH2:33][CH2:32][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1
Reactant: BrCCCn1nnc2ccccc21
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2nnc3ccccc32)CC1
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.7 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.8 parts of 1-(3-bromopropyl)-1H-benzotriazole and stirring is continued overnight at reflux temperature. The reaction mixture is cooled, water is added and the undissolved product is filtered off and set aside. The organic phase is separated from the filtrate, dried, filtered and evaporated. The residue is combined with the undissolved product (see above) and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2 parts (25%) of 1-{1-[3-(1H-benzotriazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 203.4° C.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([O:15]CC)=O)#[N:2].Cl.C(OCC)(=O)C>[Pd].C(O)C>[C:13]1(=[O:15])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:1][NH:2]1
Reactant: CCOC(=O)c1cc2ccccc2n1CC#N
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1NCCn2c1cc1ccccc12
Reaction time: 6 h
Yield: 70.1 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 3.47 g dry weight), 102a (8.00 g, 35.0 mmol), 12% hydrochloric acid (17.5 mL, 70 mmol), ethyl acetate (150 mL) and ethanol (100 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and 10% aqueous potassium carbonate (300 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to afford a 70% yield (4.57 g) of 102b as an off-white solid: mp 228-230° C.; 1H NMR (300 MHz, CDCl3) d 7.73 (d, 1H, J=8.1 Hz), 7.34 (m, 3H), 7.18 (m, 1H), 6.75 (br s, 1H), 4.29 (t, 2H, J=5.4 Hz), 3.84 (m, 2H); MS (ESI+) m/z 187.1 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH3:17])=[N:9][C:10]([O:15][CH3:16])=[C:11]([CH2:13][CH3:14])[CH:12]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])#[N:19]>O1CCCC1>[CH2:13]([C:11]1[CH:12]=[C:7]([CH:23]([OH:24])[C:22]2[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=2)[C:18]#[N:19])[C:8]([CH3:17])=[N:9][C:10]=1[O:15][CH3:16])[CH3:14]
Reactant: CCc1cc(Br)c(C)nc1OC
Reactant: N#Cc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(O)c2cccc(C#N)c2)c(C)nc1OC
Temperature: -50 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Butyl lithium (2.5M in hexane, 2.09 mL, 5.22 mmol) is added to a solution of 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (1.0 g, 4.35 mmol) in tetrahydrofuran (10 mL) cooled to −50° C. and the reaction mixture is stirred for 45 min after which 3-cyanobenzaldehyde (0.71 g, 5.44 mmol) is added in two portions. After 1 hr at −50° C., the dry ice/acetone bath is removed, the reaction is warmed to room temperature, quenched with sat. aq ammonium chloride (30 mL) and extracted with ether (40 mL). The extract is dried, filtered, concentrated and the residue is purified by chromatography eluting with cyclohexane and 10 to 15% ethyl acetate. Product containing fractions are combined and concentrated to afford 3-[(5-ethyl-6-methoxy-2-methylpyridin3-yl)hydroxymethyl]benzonitrile (0.69 g, 56% yield).
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCc2ccccc2)cc1

Procedure:
A stirred mixture of 18.5 g. of phenethylbromide, 20.4 g. of p-hydroxyacetophenone, 17.3 g. of anhydrous potassium carbonate and 150 ml. of acetone was refluxed under argon for 22 hours. The reaction was then cooled and partitioned between ether and water. The ether layer was washed with water and then extracted with two 100 ml. portions of cold 1N sodium hydroxide. These extracts were combined, washed with water and brine, dried and evaporated to an oil. The oil was purified by chromatography, giving the desired intermediate as a light yellow oil.
Reaction SMILES: [B:1]([OH:28])([OH:27])[C@@H:2]([NH:7][C:8]([C@@H:10]([NH:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:26]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:29]([C@H:32]([C@@H:34]([C:36]([O-:38])=[O:37])[OH:35])[OH:33])([O-:31])=[O:30]>CS(C)=O>[B:1]([OH:28])([OH:27])[C@@H:2]([NH:7][C:8]([C@@H:10]([NH:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:26]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:29]([CH:32]([CH:34]([C:36]([O-:38])=[O:37])[OH:35])[OH:33])([O-:31])=[O:30]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B(O)O
Solvent: CS(C)=O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
3.8 g (5+5) bis-bortezomib tartrate III, prepared as described in example 2, were dissolved in 100 ml DMSO (mother solution). An aliquot of 1 ml of such solution was diluted with 1 ml DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].S(Cl)(Cl)(=O)=O.[CH3:21][CH2:22]O>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CCO
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 98 %

Procedure:
A 0° C. solution of 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 88 mmol) in EtOH (150 mL) was treated with sulfuryl dichloride (21 g, 0.17 mol), then heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure and treated with satd. Na2CO3 to pH 7-8. The resultant mixture was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated to give ethyl 2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 98% yield). 1H NMR (400 Hz, DMSO-d6): δ 8.32 (d, J=8.0 Hz, 1H), 7.91 (d, J=11.2 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.92 (s, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4Cl)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4[NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O)o1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(NC5CCOCC5)ncnc43)[C@H](O)[C@@H]2O)o1
Yield: 77.1 %

Procedure:
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-(6-chloro-purin-9-yl)-tetrahydro-furan-3,4-diol (41 mg) was heated under reflux with 4-aminotetrahydropyran hydrochloride (59 mg), diisopropylethylamine (0.11 ml), and isopropanol (5 ml) for 15 h. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol 100:0-90:10, to give the title compound (37 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[CH:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.C([Li])CCC.[O:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>O1CCCC1>[F:17][C:2]([F:16])([F:1])[C:3]1[N:4]=[C:5]([C:26]2([OH:29])[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=1
Reactant: O=C1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C1(O)CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 216.2, 5 g, 18.77 mmol) in tetrahydrofuran (50 mL). This was followed by the addition of n-butyllithium (9 mL, 22.5 mmol, 2.5N in hexane) dropwise at −78° C. and stirred for 1 h at -60° C. To this was added dihydro-2H-pyran-4(3H)-one (6 g, 59.93 mmol). The resulting solution was stirred for 4 h at 0° C. in an ice/salt bath, then quenched with 10 mL of water. The resulting solution was diluted with 100 mL of NH4Cl (sat.). The aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 6 g (87%) of the title compound as a light yellow oil.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22][CH2:23]O.N1C=CC=CC=1.O>C(Cl)Cl>[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22][CH2:23][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCCc1occc1Br
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCc1occc1Br
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (4.47 g) was added to a solution of 2-(3-bromofuran-2-yl)-ethanol (Intermediate 35, 2.94 g) and pyridine (2.43 g) in DCM (40 mL) and the mixture was stirred for 90 minutes. Water was added and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane with a gradient of 0-25% to give [2-(3-bromo-furan-2-yl)-ethoxy]-tert-butyldimethylsilane (3.98 g) as a colourless oil. The material was used without further characterisation.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]3[N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:26]=[CH:27][C:17]=23)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:31]1([S:28]([N:25]2[C:18]3=[N:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]([NH:15][CH:11]4[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]4)=[C:17]3[CH:27]=[CH:26]2)(=[O:29])=[O:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCNC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (60 ml) was added to 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.11 g, 12.2 mmol) dissolved in 1,4-dioxane (30 ml) at 25° C. The resulting suspension mixture was stirred at 50° C. for 2 h, then was cooled to 25° C. and was concentrated under reduced pressure. Toluene (80 ml) was added to the residue and the mixture was again concentrated under reduced pressure to give crude (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl-amine hydrochloride as a yellow solid. This material was used in the next step below without additional characterization or purification.