Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28]Br.[NH4+].[Cl-]>CN(C=O)C>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][N:15]1[C:16]2[C:12](=[C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: BrCCOC1CCCCO1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3c2ccn3CCOC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
Under argon atmosphere, sodium hydride (121 mg) in DMF (2 ml) was cooled to 0° C. and 4-benzyloxyindole (501 mg) in DMF (5 ml) was added thereto, followed by stirring the resulting solution at 0° C. for 5 minutes. To this solution, 2-tetrahydropyranyloxy-1-bromoethane (599 mg) in DMF (2 ml) was added and the solution was stirred at 0° C. for 30 minutes. The reaction mixture was added to saturated aqueous NH4Cl solution (30 ml) cooled at 0° C., and the resultant was extracted with ethyl acetate (3×20 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (722 mg, yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:24][C:23]#[CH:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
300 mg (0.98 mmol) of the compound from Example 4A were dissolved in 10 ml of acetonitrile, and 122 mg (1.02 mmol) of 3-bromo-1-propyne and 270 mg (1.95 mmol) of potassium carbonate were added. The mixture was heated at reflux for 1 h. For work-up, the reaction mixture was allowed to cool to RT and about 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 166 mg (49% of theory) of the target compound.
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(O)c(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
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: [F:1][C:2]([F:29])([F:28])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:8]=1.[NH3:30]>CN(C)C=O>[F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:30])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:8]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine (0.65 g.), dimethylformamide (10 ml.), ethanolic ammonia solution (5 ml.) and yellow mercuric oxide was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-phthalimidoethylthio)-pyrimidine (0.62 g.), m.p. 192°-195°.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:11]1O)(=O)C1C=CC=CC=1>CO.O>[C@H:12]1([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[O:13][C@@H:14]([CH2:15][OH:16])[C@@H:10]([OH:9])[CH2:11]1
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O
Product: O=c1ccn([C@@H]2C[C@H](O)[C@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
A solution of 1-(3,5-di-O-benzoyl-β-L-xylofuranosyl)-uracil (6a) (1.4 g: 3.21 mmol) in ammoniacal methanol (previously saturated at 10° C. and hermetically closed) (90 ml) is stirred for two days at room temperature. The solution is evaporated several times with methanol under reduced pressure. The crude material obtained is dissolved in water and the resulting solution is washed several times with chloroform. The aqueous phase is evaporated and the residue is directly crystallized from methanol to give 0.6 g (yield 82%) of pure 7a: m.p.: 165-167° C.; 1H NMR (DMSO-d6), δ ppm=11.23 (s, 1H, 3-NH), 7.92 (d, 1H H-6; J=8.1 Hz), 6.04 (dd, 1H, H-1′; J=2.0 and 8.3 Hz), 5.26 (d, H, H-5; J=8.1 Hz), 5.26 (d, 1H, OH-3′; J=3.2 Hz), 4.69 (t, 1H, OH-5′; J=5.3 Hz), 4.20 (m, 1H, H-3′), 3.81 (m, 1H, H-4′), 3.80-3.60 (m, 2H, H-5′ and 5″), 2.6-2.5 (m, 1H, H-2′, partially obscured by DMSO-d5), 1.85 (dd, 1H, H-2″; J=2.0 and 14.7 Hz); mass spectra (matrix: glycerol-thioglycerol: 50:50, v/v): FAB>0 321 [M+glycerol+H]+, 229 [M+H]+, 117 [s]+ and 113 [BH2]+; FAB<0 227 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][C:6](=[O:8])[CH3:7].[O:13]1[CH2:15][C@H:14]1[CH2:16]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>>[O:13]1[CH2:15][C@H:14]1[CH2:16][O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][C:6](=[O:8])[CH3:7]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)NCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)NCc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of N-(2-hydroxybenzyl)acetamide (382 mg, 2.31 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (599 mg, 2.31 mmol) and Cs2CO3 (901 mg, 2.77 mmol) in DMP (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum spirit) to give the subtitled compound (333 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH2:12][O:11][C:10]2=[O:24])=[CH:5][CH:4]=1.FC(F)(F)C1C=C([C@H]2COC(=O)N2)C=CC=1.IC1C=CC(OC)=CC=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH2:12][O:11][C:10]2=[O:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C(=O)OC[C@@H]2c2cccc(C(F)(F)F)c2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(I)cc1
Agent: O=C1N[C@@H](c2cccc(C(F)(F)F)c2)CO1
Solvent: ClCCl
Product: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of (S)-3-(4-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one (57 mg, 0.169 mmol, prepared from (S)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and 1-iodo-4-methoxy-benzene using the same condition as example 4) in CH2Cl2 (1 mL) is cooled down to −78° C. in a dry ice bath when BBr3 (0.371 mmol, 1M in CH2Cl2) is added into the mixture dropwise. After the addition, the mixture is allowed to warm up to 0° C. and stirred for 1 h. The reaction is then quenched at 0° C. by adding MeOH (0.5 mL) and diluted with water (2 mL). After extraction with CH2Cl2 (3×2 mL), the combined organic layers were concentrated and purified by a flash column chromatography (silica gel, EtOAc/hexane 0˜50%) to provide the desired (S)-3-(4-hydroxy-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one (47 mg, 86%). HPLC-MS calculated for C16H12F3NO3 (M+H+) 324.1, found 324.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[I:22]I>>[I:22][C:7]1[CH:6]=[C:5]([C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:8]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: II
Agent: O=S(=O)(O)O
Product: O=C(c1cc(I)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 0 °C

Procedure:
To 2.42 g of 3′-trifluoromethyl-2,2,2-trifluoroacetophenone, 6 mL of 30% fuming sulfuric acid and 1.90 g of iodine were added and the resultant mixture was stirred at 50° C. for 5 hours. After the completion of the reaction, the reaction mixture was charged onto 10 g of ice and the resultant mixture was extracted with diethyl ether (20 mL×1). The organic phase was washed with 10 mL of a saturated sodium sulfite aqueous solution and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure to obtain 2.56 g of the objective substance as a light yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].C[Si](C)(C)N[Si](C)(C)C.[K]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COC(=O)CCl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C

Procedure:
To 870 mg. (4.4 mmoles) of N-methylsaccharin and 0.95 ml. (10.89 mmoles) of methyl chloroacetate in 3 ml. of dimethylsulfoxide under nitrogen was added at the rate of 0.084 ml./minute 3.99 g. (20 mmoles) of potassium hexamethyl disilazane in 9.98 ml. of dimethylsulfoxide.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][CH:22]=1)[C:12]1[N:13]([CH2:16][CH:17](O)[CH3:18])[CH:14]=[CH:15][C:11]=1[CH2:10]2.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([CH:17]([CH3:18])[CH2:16][N:13]1[CH:14]=[CH:15][C:11]2[CH2:10][C:9]3[C:20]([C:12]1=2)=[CH:21][CH:22]=[C:7]([F:6])[CH:8]=3)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ccc2c1-c1ccc(F)cc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Cn1ccc2c1-c1ccc(F)cc1C2)N=[N+]=[N-]
Yield: 24.5 %

Procedure:
1.12 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.66 g of (RS)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.98 ml of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 70 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.82 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.45 g (24%) of (RS)-1-(2-azido-propyl)-6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a yellow oil.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@H:2]([C:10](ON1C(=O)CCC1=O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:37][C@H:38]([C:65]([OH:67])=[O:66])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:45]1[CH:52]=[CH:51][C:48]([O:49][CH3:50])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@H:2]([C:10]([NH:37][C@H:38]([C:65]([OH:67])=[O:66])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:45]1[CH:52]=[CH:51][C:48]([O:49][CH3:50])=[CH:47][CH:46]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C(NCCCC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(NCCCC[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a stirred suspension of Fmoc-Phe-OSu (2.0702 g, 4.2728 mmol, 1.0 eq) and Lys(MMT) (1.7995 g, 4.2995 mmol, 1.01 eq) in DMF (30 ml) was added DIEA (1.5 ml, 8.6112 mmol, 2.02 eq). The solid dissolved gradually and the solution was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 ml) and pH5 buffer (0.05M phthalic acid, adjusted with 10N KOH to pH 5.0, 200 ml). The aqueous solution was extracted with more ethyl acetate (50 ml×2). The combined organic phase was washed with brine (50 ml×3), dried over MgSO4. After removal of solvent and being dried in vacuo, 3.3014 g (98.1%) of pale-yellow foam was obtained. ES(+)-MS: 516(M-MMT+1), 273(MMT).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][NH2:12]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:10])=[C:4](/[CH:5]=[N:12]/[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CN
Reactant: O=Cc1cccc(Cl)c1F
Solvent: ClCCl
Product: C/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of 3-chloro-2-fluoro-benzoaldehyde (Oakwood, 97%) (1.59 g, 10.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 7.5 mL, 15.0 mmol) in CH2Cl2 (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (1.72 g, 100%) as colorless oil which was used in the next step without further purification.
Reaction SMILES: O[C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([C:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1ccc(C2=CCC(=O)CC2)cn1
Reaction time: 10 h

Procedure:
4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone (as prepared in the previous step, 750 mg, 3.40 mmol) in THF (5 mL) was treated with Burgess' reagent (Aldrich, 1.19 g, 5.0 mmol) at room temperature. The reaction was stirred for 10 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:5][CH:4]=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[K].[I-].[K+].O>CN(C=O)C>[O:37]=[C:35]1[C:34]2[C:33](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:32](=[O:42])[N:36]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
1,1-dimethylethyl [3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate (20 g, 45.8 mmol), potassium phthalimide (9.33 g, 50.4 mmol) and potassium iodide (1.52 g, 9.15 mmol) were stirred in DMF (81 mL) at 50° C. overnight. Room temperature was attained, H2O was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in MeOH to give 1,1-dimethylethyl {3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.060 g, 67%). MP: 120-134° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18 (s, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 6.63 (s, 1H), 6.56-6.50 (m, 1H), 6.34-6.29 (m, 2H), 5.53 (br s, 1H), 5.26 (br s, 1H), 4.48-4.42 (m, 1H), 3.86 (s, 3H), 3.09-3.05 (m, 1H), 2.90 (m, 12H), 2.54-2.49 (m, 1H), 2.29-2.24 (m, 1H), 1.68 (t, 3H, J=18.7 Hz). MS: 533 (MH)+.
Reaction SMILES: [F:1][CH:2]([C@H:7]1[C@H:12]([OH:13])[CH2:11][C@H:10]2[C@@H:8]1[O:9]2)[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C@H:7]1[C@H:12]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH2:11][C@H:10]2[C@@H:8]1[O:9]2)[F:1]
Reactant: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of epoxy alcohol 3 (1.60 kg, 8.40 mol) and DMF (3.40 L) was added imidazole (1.26 kg, 18.5 mol) at 10° C. TBSCl (1.52 kg, 10.1 mol) was added to the reaction mixture while maintaining the batch temperature below 8° C. The resulting solution was stirred at 5° C. for 10 min, then allowed to warm to 20° C. over 30 min and stirred for 2 h at the same temperature. The consumption of the starting alcohol was monitored by GC, and the reaction mixture was diluted with cold toluene (17.0 L, 5° C.). The resulting mixture was washed with H2O (5.67 L), saturated aqueous NaHCO3 (5.67 L), H2O (5.67 L×2), and brine (5.67 L). Assay of the organic solution indicated 4. Concentration of the solution gave 4 as yellow liquid, which was used for the next step without further purification. Analytically pure sample was obtained by flash silica gel column chromatography (hexanes/MTBE) as colorless crystals: mp 28-30° C.; 1H NMR (400 MHz, CDCl3) δ 5.00 (dd, J=48.2, 3.5 Hz, 1H), 4.45 (m, 1H), 3.85 (s, 3H), 3.51 (m, 1H), 3.42 (m, 1H), 2.64-2.52 (dm, J=34.5 Hz, 1H), 2.14 (m, 1H), 1.91 (m, 1H), 0.88 (s, 9H), 0.054 (s, 3H), and 0.051 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.8 (d, J=24.1 Hz), 88.3 (d, J=186.1 Hz), 75.4 (d, J=1.6 Hz), 58.3, 57.2 (d, J=7.2 Hz), 52.8 (d, J=19.3 Hz), 52.7, 38.3, 25.9, 18.0, −4.5, and −4.7; 19F NMR (376 MHz, CDCl3) δ −199.9 (dd, J=48.2, 34.5 Hz); LRMS m/z 305 (M+1), 121 (base peak); [α]D25=−27 (c 1.0, CHCl3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1.[O:31]1[CH2:34][CH:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][N:15]1[C:14]([CH2:19][N:38]2[CH2:39][CH2:40][CH:35]([CH:33]3[CH2:34][O:31][CH2:32]3)[CH2:36][CH2:37]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=[C:4]1[CH2:3][CH2:2][OH:1])=[N:10][C:11]=2[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: C1CC(C2COC2)CCN1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21
Reaction time: 18 h
Yield: 19.5 %

Procedure:
A solution of 2-[2-(2-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.49 mmol), 4-oxetan-3-ylpiperidine (83 mg, 0.59 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (5 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (156 mg, 0.74 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 97:3 to 95:5) to afford 512 as a white solid (51 mg, 20%). LCMS (Method I): RT=2.39 min, M+H+=533. 1H NMR (CDCl3, 400 MHz) δ 8.04 (m, 1 H); 7.75 (m, 1 H); 7.33 (m, 2 H); 4.76 (dd, J=7.8, 6.0 Hz, 2 H); 4.45 (t, J=6.0 Hz, 2 H); 4.35 (m, 4 H); 4.19 (t, J=5.5 Hz, 2 H); 3.94-3.80 (m, 9 H); 3.54 (t, J=5.5 Hz, 2 H); 3.02 (m, 2 H); 2.81-2.72 (m, 1 H); 2.29 (m, 2 H); 1.71 (m, 5 H) and 1.28 (m, 1 H)