Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.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>[CH3:28][N:27]1[C:23]([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=2)=[CH:24][CH:25]=[N:26]1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1csc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83 mmol) in dioxane/H2O (5:1, 16 mL) was added K2CO3 (2.7 g, 19 mmol), tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (−1 g, quant.): LCMS (ES) m/z=209 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=1)=[O:29]>CCOC(C)=O>[Br-:26].[Cl:37][C:32]1[CH:31]=[C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(F)c(Cl)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (75 mg, 0.22 mmol) in EtOAc (5 ml), was added 2-bromo-1-(3-chloro-4-fluorophenyl)ethanone (61.7 mg, 0.24 mmol), and the reaction was stirred at room temperature for 15 hours. The precipitate was collected by suction filtration to obtain (R)-1-(2-(3-chloro-4-fluorophenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (120.3 mg, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[C:5](=[N:7]/[OH:8])/[NH2:6].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[C:19]([Cl:26])[CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(=O)OCC.C(#N)C>[Cl:26][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:20]=1[C:21]1[O:8][N:7]=[C:5]([C:4]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:2]([Cl:1])[CH:3]=2)[N:6]=1)[NH2:16]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3Cl)n2)cc1Cl
Temperature: 120 °C
Yield: 67 %

Procedure:
(Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.5 g, 2.187 mmol), 4-amino-2-chlorobenzoic acid (0.413 g, 2.405 mmol), DCC (0.496 g, 2.405 mmol), HOBT (0.368 g, 2.405 mmol) were placed in an 80 ml microwave vial and Acetonitrile (12.01 ml) was added. The reaction mixture was stirred for 5 minutes at room temperature before the addition of DIEA (0.840 ml, 4.81 mmol). The reaction mixture was heated to 120° C. for 30 min in a microwave. TLC (50% EA/Hept) indicated 4 spots Rf 0.8, 0.6, 0.5 and 0.3. LCMS (2007—9349) indicated by UV 16% (2.61 mins) to (M+H) 364.31. The solvent was removed and the crude material purified by FCC (50% EA/Hept) to afford 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (534 mg, 1.466 mmol, 67.1% yield). LCMS (Table A, Method b) indicated a 99% by UV (3.10 mins) and 92% by ELSD (3.06 mins) to (M+H)+ 364.12.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 100.2 %

Procedure:
A solution of ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.40 g, 3.89 mmol) in a mixture of ethyl acetate (300 ml) and ethanol (75 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (200 mg) and under one atmosphere of hydrogen for four hours to give 1.05 g (100% yield) of the title compound as light yellow needles; mp 155-156° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH3), 3.46 (2H, m, CH2), 3.75 (2H, t, J=8.3 Hz, CH2), 3.92 (2H, m, CH2), 4.20 (2H, t, J=8.3 Hz, CH2), 4.43 (2H, q, J=7.1 Hz, OCH2), 10.20 (1H, s, OH). Anal. Calcd for C11H15N3O5: C, 49.06; H, 5.61; N, 15.60. Found: C, 49.09, H, 5.73; N, 15.58.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Br:15]([O-])(=O)=O.[Na+].S(=O)(O)[O-].[Na+]>C(OC(C)C)(=O)C>[Br:15][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
1.0 g of 4-methyl-3-(trifluoromethyl)benzoic acid was dissolved in isopropyl acetate (q.s.). To the mixture, sodium bromate aqueous solution (10 ml, containing 2.2 g of sodium bromate) and sodium bisulfite aqueous solution (10 ml, containing 1.52 g of sodium bisulfite) were added alternatively with stirring. After addition, the solution became brownish red. The mixture was heated to reflux until the solution became colorless. Then the organic layer was separated. Again, to the mixture, sodium bromate aqueous solution (10 ml, containing 2.2 g sodium bromate) and sodium bisulfite aqueous solution (10 ml, containing 1.52 g sodium bisulfite) were added alternatively and the mixture was heated to reflux until the solution became colorless. Then the organic layer was separated. Continually, to the mixture, a sodium bromate aqueous solution (10 ml, containing 2.2 g sodium bromate) and a sodium bisulfite aqueous solution (10 ml, containing 1.52 g sodium bisulfite) were added alternatively, and the mixture was heated to reflux until the solution became colorless. Then the organic layer was separated. The organic layer was washed with 5% sodium sulfate solution twice and 15% sodium chloride solution twice, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to dry. The is residue was stirred in petroleum ether, and filtered to give a white solid. m.p. 140-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:20])[CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[O:20][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A mixture of 3-benzyloxy-5-methoxy-4-nitrophenol(3.85 g), N,N-dimethyl formamide (20 mL), potassium carbonate(2.8 g) and methyl bromoacetate(2.42 g) was stirred at ambient temperature for 3 h. The mixture was treated with water and ethyl acetate and the organic phase was separated, washed with brine, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (4.6 g), (m/e348, MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][C:8](C)(C)[CH2:7][CH:6]2[C:16]([O:18][CH3:19])=[O:17])#[N:2].[OH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[C:28]([O:27][C:25]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:33][CH:32]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)c(C#N)cc21
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (from Example 3, Step E) (700 mg, 2.98 mmol), tert-butyl 4-hydroxybenzoate (578 mg, 2.98 mmol) and K2CO3 (494 mg, 3.57 mmol) were diluted with N-methylpyrrolidone (6 mL) and bubbled with argon for 10 minutes. The reaction was heated to 110° C. and stirred for 5 hours. The reaction was loaded directly onto a Biotage 40M cartridge and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (400 mg, 32.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:17]=3)[CH2:12][N:11]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:41]1[N:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:41]4[N:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=4)=[CH:16][CH:17]=3)[CH2:12][N:11]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:29])=[O:30])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC3c2ccc(Cl)c(Cl)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cnc(-c2ccc3c(c2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC3c2ccc(Cl)c(Cl)c2)cn1
Temperature: 90 °C
Yield: 14.1 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 0.51 mmol), 5-bromopyrazin-2-amine (174 mg, 1.0 mmol) and cesium carbonate (490 mg, 1.5 mmol) in water (1.5 mL) and N,N-dimethylformamide (5 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 90° C. for 3 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate) to give 5-(4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (40 mg, 14%) as a yellow oil: ESI MS m/z 556 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[N-:12]=[N+:13]=[N-:14].[Na+]>CO>[N:12]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4])=[N+:13]=[N-:14]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
A solution of 2,4′-dibromoacetophenone (1.390 g, 5.0 mmol) in MeOH (10 mL) was poured over 10 mL of an aqueous solution of sodium azide (0.325 g, 5.00 mmol) in an ice bath. The mixture was stirred at room temperature for 18 hours. The solvent was removed and then extracted with ethyl ether (20 mL) and water (20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to obtain 2-azido 4′-bromoacetophenone (1.0 g, 4.17 mmol, 83% yield). 1H NMR (CDCl3) 5.45 (s, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nn2c(-c3ccc(F)c(N(C)S(C)(=O)=O)c3)ccnc2c1C#N
Yield: 55.7 %

Procedure:
A mixture of 0.041 g (0.33 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 66 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 55%).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].S(=O)(=O)(O)O.O>O(CC)CC>[C:11]([O:10][C:5]1[C:4]2[CH2:3][CH2:2][CH2:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc2c1CCC2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 115 %

Procedure:
A mixture of 2,3-dihydro-1H-inden-4-ol (0.37 mol) and acetic anhydride (0.37 mol) in sulfuric acid (300 mol) was stirred for 1 hour at room temperature. The reaction mixture was poured out into a mixture of water and 1,1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 75 g (>100% crude residue) of 2,3-dihydro-1H-inden-4-ol acetate (ester) (interm. 1-a).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:7]=1[F:23]>CS(C)=O.O>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:7]=1[F:23])#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 32.3 %

Procedure:
To a solution of sodium cyanide (99 mg) in dimethyl sulfoxide (5 ml), a solution of the compound (605 mg) obtained in Example 249 in dimethyl sulfoxide (10 ml) was added dropwise at 60° C. and stirred at 60° C. for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate-diethyl ether (1:1); thereafter, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 164 mg of the titled compound (yield, 32%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[OH:41])(=[O:37])[CH3:36].[H-].[Na+].O>COCCOC>[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[O:41][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4])(=[O:37])[CH3:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CBr)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](OCC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-3′,4′,5′-tribenzyloxyacetophenone (11) (2.59 g, 5 mmol) and β-D-glucose-2,3,4,6-tetraacetate (8) (1.74 g, 5 mmol) were dissolved in dry DME (50 mL) and sodium hydride (0.18 g, 7.5 mmol) (0.3 g 60% NaH suspension in oil) was added in small portions. The reaction mixture was allowed to be stirred at room temperature overnight. Water (50 mL) was added and the water phase extracted with DCM (3×25 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO4) and evaporated to give a dark viscous oil. The product was isolated by dry flash chromatography (PE/EtOAc 6:4) (PE=petroleum ether). Recrystallisation from a mixture of methylcyclohexane and ethyl acetate afforded the desired compound as white crystals, m.p. 156-158° C. Yield 0.51 g (13%). 1H NMR (300 MHz, CDCl3): δ=1.98 (3H, s), 2.00 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 3.63-3.73 (2H, m), 4.08-4.30 (5H, m), 4.62-4.94 (1H, m), 5.02-5.34 (7H, m), 7.20-7.56 (17H, m); 13C NMR (75 MHz): δ=20.5, 20.6, 61.6, 68.2, 70.5, 70.8, 71.2, 71.8, 72.4, 75.0, 100.1, 107.9, 127.4, 127.9, 128.0, 128.1, 128.4, 128.5, 129.6, 136.4, 137.1, 143.2, 152.6, 169.3, 169.5, 170.0, 170.5, 193.4.
Reaction SMILES: [Na].[OH2:2].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[OH:3][CH2:4][C@@H:5]([C@H:7]([C@@H:7]([C@@H:5]([CH2:4][OH:3])[OH:6])[OH:2])[OH:8])[OH:6]
Reactant: OCC(O)CO
Reactant: O
Agent: [Na]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A high speed propeller mixer provided with a scraper was charged with the PEG-400, and the cross-linked CMC sodium was added, while stirring. After all lumps were broken up and a uniform slurry was obtained, the ground limestone was added in portions, and stirring was continued until all of the solids were suspended. The resulting slurry was homogenized and dearated and then filled into #11 oblong A size soft gelatin capsules by means of a rotary die encapsulator. The shell of the capsules was formed from gelatin, water, sorbitol and glycerin, and contained vanillin flavoring agent and titanium dioxide opacifier.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:20]=1)CC(OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:40]1C=C(C=CC=1)CN(C)C(=O)OCC1C=CC=CC=1.BrC1C=CC(CCO)=C(C)C=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:12][C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH3:40])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Reactant: CN(Cc1cccc(N)c1)C(=O)OCc1ccccc1
Agent: Cc1cc(Br)ccc1CCO
Product: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(CN(C)C(=O)OCc2ccccc2)c1
Yield: 69 %

Procedure:
Using a procedure analogous to that used to prepare 34D, 60B (1.6 g, 5.9 mmol) was reacted with 30B to give 60C (2.0 g, 69%) as an oil. MS (ESI) m/z 512.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([C:13]3[C:17]([CH:18]=O)=[CH:16][NH:15][N:14]=3)[CH:11]=[CH:12][C:4]=2[O:3]1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:26][CH:27]=1>C(Cl)Cl.CO.C(O)(=O)C>[F:36][C:21]([F:20])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:18][C:17]3[C:13]([C:10]4[CH:11]=[CH:12][C:4]5[O:3][C:2](=[O:1])[NH:7][C:6](=[O:8])[C:5]=5[CH:9]=4)=[N:14][NH:15][CH:16]=3)[CH2:30][CH2:29]2)=[N:26][CH:27]=1
Reactant: O=Cc1c[nH]nc1-c1ccc2oc(=O)[nH]c(=O)c2c1
Reactant: FC(F)(F)c1ccc(N2CCCNCC2)nc1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=O)c2cc(-c3n[nH]cc3CN3CCCN(c4ccc(C(F)(F)F)cn4)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 3-(2,4-dioxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-1H-pyrazole-4-carbaldehyde (51.4 mg, 0.2 mmol) and 1-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepane (24.5 mg, 0.1 mmol) in methylene chloride (1.0 mL), methanol (0.5 mL) and acetic acid (15 μL) is stirred for 30 minutes at room temperature. Then Na(AcO)3BH (84 mg, 4.0 equiv.) is added and the reaction is stirred overnight at room temperature. After evaporation, the residue is redissolved in DMF (1.0 mL) which is subject to reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90% CH3CN in 7.5 min, Ultro 120 5 uM C18Q, 75×30 mmID) The collected water/MeCN solution of the TFA salt of the product is evaporated to remove the acetonitrile. A saturated aqueous solution of NaHCO3 is added to raise the pH to about 8-9. Then ethyl acetate is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yields the free-based 6-{4-[4-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepan-1-ylmethyl]-1H-pyrazol-3-yl}-benzo[e][1,3]oxazine-2,4-dione.