Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[C:9]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[NH2:21].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9]1[N:10]([CH3:11])[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:18]([CH3:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1
Reactant: Cn1c(-c2ccco2)cc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccco5)n(C)c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (92 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 3.5 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL×2), and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (105 mg).
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:54]([CH3:57])([CH3:56])[CH3:55])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:44][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
2,6-Lutidine (0.16 g, 1.49 mmol) was added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example 35-(3); 0.15 g, 0.29 mmol) in dichloromethane (1.5 mL). Trimethylsilyl triflate (0.13 mL, 0.71 mmol) was added at 0° C., and the mixture was stirred at the same temperature for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (0.16 g, 93%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[O:8][N:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:25]=[S:26])=[CH:13][CH:12]=2)[O:8][N:7]=1
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(-c2nc(-c3ccco3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 3-(2-furyl)-5-(4-aminophenyl)-1,2,4-oxadiazole (5.1 g, 0.02 mole) in 150 ml of dry tetrahydrofuran containing 3.1 ml of triethylamine, thiophosgene 2.53 g (0.02 mole) is added and the mixture is stirred at room temperature for 4 hours. After filtration, the solvent is evaporated in vacuo and the product is crystallized from petroleum ether to give 4.0 g (68%) of the title compound, m.p. 136°-137°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(O)[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([F:39])[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-4-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (5.20 g, 11.17 mmol) in CH2Cl2 (100 mL) at −78° C. was added DAST (2.21 mL, 16.75 mmol). The solution was stirred for 16 hours at RT then was washed with sat NaHCO3 (2×100 mL). The organic layer was dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 9:1). MS (UPLC/MS): 468 [M+H]+, 512 [M+HCOO]−; tR (HPLC conditions f): 3.00 min.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].O>CN(C=O)C>[C:8]([NH:1][C@H:2]([C:5]([O:7][CH2:21][CH3:22])=[O:6])[CH2:3][OH:4])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Ser-OH (0.3 g, 1.46 mmol, 1 eq) in dry DMF (4 ml) at 0° C., dry K2CO3 (0.22 g, 1.6 mmol, 1.1 eq) was added. The resulting white suspension was stirred for 15 minute and ethyl iodide (0.68 g, 0.35 ml, 4.38 mmol, 3 eq) was dropwise added. The cooling was removed and reaction mixture was stirred at room temperature under N2 for 24 h. To the formed white emulsion H2O was added, and the mixture extracted by EtOAc. The combined organic layer was washed by H2O and then brine, and dried over MgSO4. The solvent was evaporated and the obtained oil was dried overnight in high vacuum. Yield of the pure F—0.27 g (79%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[C:23]([NH2:25])=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].[OH-].[K+]>CC(C)=O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:27]([CH3:29])[CH3:28])[C:15]=2[C:23]([NH2:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: NC(=O)c1[nH]c2ccccc2c1N1CCC(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)n1c(C(N)=O)c(N2CCC(Cc3ccccc3)CC2)c2ccccc21

Procedure:
To a solution of 200 mg (0.63 mMol) of 4-benzylpiperidinyl-indole-2-carboxamide in 10 ml of acetone was added 321 mg (1.9 mMol) of 2-iodopropane and 106 mg (1.9 mMol) of powdered KOH. The mixture was refluxed for 3 h, then cooled, evaporated and the crude product was purified by silica gel column chromatography using EtOAc:hexane (1:4) to provide the 4-Benzylpiperidinyl-1-(2-propyl)-indole-2-carboxamide as white solids, NMR (DMSO-d6) δ=1.15 (m, 2H), 1.60 (d, 6H), 1.82 (m, 4H), 2.56 (d, 2H), 2.72 (m, 1H), 3.02 (m, 1H), 4.15 (m, 1H), 4.80 (m, 1H), 6.45 (s, 1H), 7.05-7.32 (m, 7H), 7.52 (d, 1H), 7.61 (d, 1H). MS (ESI) m/e 360 (M+).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(F)cc3)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a 50 ml eggplant-shaped flask were added 1.00 g (3.37 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 0.68 g (6.75 mmol) triethylamine, 30 mg (0.25 mmol) DMAP and 25 ml THF, and then added dropwise 0.53 g (3.37 mmol) p-fluorobenzoyl chloride dissolved in 5 ml THF. The resulting mixture was stirred at room temperature for 2 hours, elevated to 35-40° C. and allowed to react for 10 hours, filtrated, washed with THF, the mother liquid was concentrated under a reduced pressure to give a pale brown oily crude product, separated with 50 ml ethyl acetate and 10 ml 1N HCl, the organic layer separated was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with ethyl acetate/petroleum ether (1:2) to obtain a 1.10 g product as a white solid in a yield of 78.0%, mp: 164-165 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.76 (2H, d, J=7.84 Hz, ArH), 6.94 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.24˜7.36 (7H, m, ArH), 7.71 (2H, dd, 3JHH=7.56, 4JFH=5.32 Hz, ArH), 11.62 (1H, br, CONH); EI-MS m/e (%): 418.2 (M+, 100), 123.0 (86); HREI-MS Calcd. for C24H19FN2O2S: 418.1151. found: 418.1138. Anal. Calcd. for C24H19FN2O2S: C, 68.88; H, 4.58; N, 6.69. found: C, 68.77; H, 4.48; N, 6.84.
Reaction SMILES: O=[O+][O-].CC1(C)OC(=O)C(C[CH:13]([OH:16])[CH2:14][Cl:15])=CO1.CO.CSC.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>>[Cl:15][CH2:14][CH:13]([OH:16])[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(C)=O
Reactant: CC1(C)OC=C(CC(O)CCl)C(=O)O1
Agent: O=[O+][O-]
Solvent: CO
Solvent: CSC
Product: CCOC(=O)CC(O)CCl
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Ozone was introduced into a mixture of 225.5 mg (1 mmol) of (+)-2,2-dimethyl-(3-chloro-2-hydroxypropyl)-1,3-dioxin-4-one (96% ee) obtained in Example 4 and 20 ml of methanol at -78° C. for 5 hours, and 2 ml of dimethyl sulfide were added thereto, followed by stirring at the same temperature for 2 hours. The temperature was gradually returned to room temperature, and the solution was then stirred for 5 hours. Afterward, the solvent was distilled off, and the resultant residue was then dissolved in ethanol. 3 drops of concentrated sulfuric acid were added thereto, and the solution was then heated at 80° C. for 30 minutes. Next, ethanol was distilled off, and the residue was diluted with water. The solution was extracted with dichloromethane and then dried over anhydrous sodium sulfate, and the solvent was distilled off and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=5:1), thereby obtaining 109.4 mg (yield 66%) of (+)-ethyl 4-chloro-3-hydroxybutanoate.
Reaction SMILES: [C:1]([O:4]O)(=O)[CH3:2].C([O-])(=O)C.[Na+].[CH:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)CC=[CH:13][CH2:12]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][CH:11]2[CH2:2][CH:1]3[CH:13]([O:4]3)[CH2:12]2)=[CH:22][CH:21]=1
Reactant: C1=CCC(Cc2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(-c2ccc(CC3CC4OC4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Peracetic acid in acetic acid (60 ml; 40%) was added over 5 min. to a cooled mixture of sodium acetate (8g) and 4-(3-cyclopenten-1-ylmethyl)-1,1'-biphenyl (20 g) in chloroform (150 ml). The mixture was stirred vigorously at room temperature for 4 h., then it was cooled and a solution of sodium metabisulphite was slowly added. The chloroform layer was washed with water, dilute sodium hydroxide solution, water and brine, dried and evaporated to give a 1:3 mixture (TLC) of two products (20 g). Crystallisation from methylene dichloride-ether gave two crops, rich in the slower running isomer (TLC). Recrystallisation from methylene dichloride/ether gave pure (±)-(1α,3α,5α)-3-([1,1'-biphenyl]-4-ylmethyl)-6-oxabicyclo[3.1.0]hexane (9.6 g), m.p. 130°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13]([O:15][CH3:16])=[N:12][C:11]([CH2:17][CH3:18])=[C:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:36]([O:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:37])[C:13]([O:15][CH3:16])=[N:12][C:11]([CH2:17][CH3:18])=[C:10]2[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 4 h

Procedure:
Into a well-stirred solution of benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate (27.5 g, 68.75 mmol) and pyridine (9.2 mL) in CH2Cl2 (300 mL) was added 4-nitrophenyl chloroformate (14.49 g, 82.5 mmol) at room temperature. The reaction mixture was stirred for 4 h and then washed with 10% aqueous KOH solution (2×150 mL). The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the residue was used in the next step without further purification: 1H NMR (CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]23[CH2:13][CH:12]2[CH2:11][O:10][C:9]3=[O:14])[CH:7]=1.[NH3:16]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2([C:9]([NH2:16])=[O:14])[CH2:13][CH:12]2[CH2:11][OH:10])[CH:7]=1
Reactant: O=C1OCC2CC12c1cc(Br)ccc1F
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)C1(c2cc(Br)ccc2F)CC1CO
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a suspension of (1SR,5RS)-1-(5-bromo-2-fluoro-phenyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (intermediate B5A) (4.6 g, 17 mmol) in dioxane (20 ml) at 23° C. was added ammonia (7 M in MeOH, 40 ml) and the mixture was stirred at 23° C. for 2 days (not complete). Evaporated all volatiles and directly subjected to silica gel chromatography with n-heptane/ethyl acetate to give recovered starting material (0.98 g, 21%) and the title compound as a white solid (3.5 g, 72%). MS (ISP): m/z=287.9 [(M+H)+] and 290.0 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[F:16][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (3 g, 12.6 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.2 g, 25.2 mmol), and Na2CO3 (2.7 g, 25.2 mmol) in DME (18 mL)/water (6 mL) was sparged with nitrogen for 20 min. Pd(PPh3)4 (729 mg, 0.63 mmol) was added and the resulting mixture was heated to 100° C. for 16 h. The solvent was removed under reduced pressure and the crude product was suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo and purified via silica gel chromatography to give 2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (2 g, 56% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1 H), 8.21 (s, 1 H), 7.92 (s, 1 H), 7.12 (d, J=2.4 Hz, 1 H), 6.96 (m, 1 H), 6.85-6.72 (m, 2 H), 6.56 (m, 1 H), 5.15 (s, 2 H), 3.84 (s, 3H); MS (ESI) m/z: 285.0 (M+H+).
Reaction SMILES: C([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=O)C.[O:28]=[CH:29][C@@H:30]([C@H]([C@H]([C@@H](CO)O)O)O)O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>ClC(Cl)C>[C:25]([O:24][C@@H:23]1[O:4][C@H:5]([CH2:6][O:7][C:29](=[O:28])[CH3:30])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=[O:27])[CH3:26]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The synthesis of compounds 26-31 are depicted in FIGS. 19A and 19B and are set forth in the examples hereinbelow. In this figure, the synthesis of compounds 26, 27, 28, and 36 parallels that of compounds 17, 18, 19, and 20 as set forth above and illustrated in FIG. 18. In this regard, benzyl 4,6-O-benzylidene-2-O-benzoyl-3-O-chloroacetyl-β-D-thiogalactopyranoside (compound 31) has been produced without the necessity of chromatography. D-Galactose pentaacetate 26 is produced by slurring D-galactose and about an equimolar amount (e.g., about 1.1 equivalents) of sodium acetate (NaOAc) in dichloroethane (DCE), heating to reflux and adding at least 5 equivalents of acetic anhydride (AcOAc) dropwise to the refluxing solution (about 80°-85° C.) and then maintaining the reaction system at this temperature for a sufficient period of time (about 16-32 hours) to result in formation of compound 26. This procedure optimizes the yield of β-D-galactose pentaacetate 26 and controls the exotherm of heretofore known procedures.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20]>CO>[N+:8]([C:7]1[C:2]([NH:18][CH:19]([CH3:20])[C:21]([OH:23])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: C[C@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A mixture of 2-fluoro-3-nitro-pyridine (12 g), Et3N (30 mL), and racemic alanine (11.87 g) was refluxed in methanol (200 mL) overnight. The mixture was cooled to ambient temperature and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was dried over Na2CO3, filtered, and concentrated in vacuo to afford 2-(3-nitro-pyridin-2-ylamino)-propionic acid (7.8 g). This material was dissolved in AcOH (50 mL) and iron (8.2 g) was added. The mixture was refluxed for 1.5 h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was washed with water and dried to afford 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.4 g). This material was mixed with 5% aq NaOH (92 mL) and water (18 mL) before 30% aq hydrogen peroxide (9.2 mL) was added. The mixture was stirred at 60° C. for 10 h. After cooling to ambient temperature the pH was adjusted to neutral to precipitate 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (1.2 g). This material was dissolved in DMF (10 mL) and treated with PyBroP (4.6 g) and DIPEA (1.6 mL) at ambient temperature of 16 h. The precipitated white solid was filtered off, washed with ethanol and dried to afford 2-(benzotriazol-1-yloxy)-3-methyl-pyrido[2,3-b]pyrazine (0.4 g). This material (0.4 g) and hydrazine hydrate (0.5 mL) were refluxed in ethanol (5 mL) for 10 min. After cooling to ambient temperature, the precipitated white solid was filtered off, washed with ethanol and dried to afford give IIa (0.2 g) sufficiently pure for the next step.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: C[C@@H]1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Product: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of (R)-3-methylmorpholine (2.02 g, 20 mmol) in ethanol (25 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (3.33 g, 17.4 mmol), hydroxybenzotriazole (HOBt) (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.0 g, 14.5 mmol). After stirring for 18 h at room temperature, the reaction suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 248a as white solid (1.6 g, 36%). MS-ESI: [M+H]+ 222.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:14]2[CH:15]=[C:16]([CH:23]=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][F:22])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[N:6]=1.[C:27]1([C:33]#[C:34]B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:14]2[CH:15]=[C:16]([CH:23]=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][F:22])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:34]#[C:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=2)[N:6]=1
Reactant: CN1C(=O)C(c2cccc(Br)c2)(c2cc(C=O)n(CCCF)c2)N=C1N
Reactant: OB(O)C#Cc1ccccc1
Product: CN1C(=O)C(c2cccc(C#Cc3ccccc3)c2)(c2cc(C=O)n(CCCF)c2)N=C1N

Procedure:
Using essentially the same procedure described in Example 200 and employing 4-{2-amino-1-methyl-5-oxo-4-(3-bromophenyl)-4,5-dihydro-1H-imidazol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde and phenylethyneboronic acid, the title compound was obtained as a white solid, mp 85-90° C., identified by NMR and mass spectral analyses.