Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CN(C=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O>[Br:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]([N:8]2[C:19](=[O:20])[C:11]3[S:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(CNc2cccc(Br)c2CO)c(C(=O)O)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(s1)C(=O)N(c1cccc(Br)c1CO)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 114f (540 mg, 1.36 mmol), triethylamine (275 mg, 2.72 mmol) and anhydrous DMF (10 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 782 mg, 1.77 mmol) was added, and the reaction was stirred at room temperature for 16 h. After this time, the reaction was diluted with water (20 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (40 mL), and the solution was washed with saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 60% yield of 114g (305 mg) as a white solid: mp 55-56° C.; 1H NMR (500 MHz, CDCl3) δ 7.65 (d, 1H, J=8.0 Hz), 7.25 (m, 1H), 7.20 (d, 1H, J=8.0 Hz), 6.89 (s, 1H), 4.68 (s, 2H), 4.66 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: OCC1C=CC(C2C=CN=C(NC3C=C(OC)C(OC)=C(OC)C=3)N=2)=CC=1.C([O:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH:52][C:53]3[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=3)[N:47]=2)=[CH:41][CH:40]=1)=O)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:35][CH2:36][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH:52][C:53]3[CH:54]=[C:55]([O:63][CH3:64])[C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=3)[N:47]=2)=[CH:41][CH:40]=1
Reactant: COc1cc(Nc2nccc(Nc3ccc(CC(=O)OCc4ccccc4)cc3)n2)cc(OC)c1OC
Agent: COc1cc(Nc2nccc(-c3ccc(CO)cc3)n2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Product: COc1cc(Nc2nccc(Nc3ccc(CCO)cc3)n2)cc(OC)c1OC

Procedure:
In a manner analogous to the preparation of the compound of Example 62 (267 mg, 0.5 mmol) from the compound of Example 106 and LiAlH4 (40 mg, 1.1 mmol) to give the title compound (108 mg) as a light pink solid m.p. 172°. MS m/z 397 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=2)[N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:17]=1.N1C=CC=CC=1>C(Cl)Cl>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:6])[CH:23]=2)[N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:17]=1
Reactant: O=C=NC1CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CC1
Reaction time: 24 h
Yield: 53.4 %

Procedure:
Cyclopropylisocyanate (4 g, 0.048 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (15 mg, 0.045 mmol) and pyridine (0.01 mL, 0.126 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (2% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.93 (d, 1H, J=8.8 Hz), 7.83 (m, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.27-7.24 (m, 2H), 7.17 (s, 1H), 5.71 (dd, 1H, J=2.4 and 9.2 Hz), 4.04 (m, 1H), 3785 (m, 1H), 2.59 (m, 2H), 2.17-2.07 (m, 2H), 1.74 (m, 5H), 0.84 (q, 2H, J=5.2 Hz).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:9][C:10]([F:25])([F:26])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([OH:24])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
Add hexyl magnesium bromide (2.0M in ethyl ether, 8 mL, 16 mmol) to 4′-trifluoromethyl-biphenyl-4-carbaldehyde (2.0 g, 8 mmol) (prepared in a manner substantially similar to preparation 25, or other methods known in the art) in tetrahydro-furan (30 mL) at 0° C. under inert atmosphere. Stir 1.5 hours. Quench reaction with saturated solution of ammonium chloride, dilute with ethyl acetate. Wash organic phase with water then saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter, and concentrate under reduced pressure. Purify on silica gel chromatography (0-30% Ethyl acetate/hexanes gradient) to provide 1.95 g of title compound (73%).
Reaction SMILES: [Na+:1].N[C@H:3]1[C@@H:6]([CH2:7][O:8][C:9](=[O:11])[NH2:10])[N:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:4]1=[O:16]>CC(C)=O.O>[Na+:1].[C:9]([O:8][CH2:7][CH:6]1[N:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:4](=[O:16])[CH2:3]1)(=[O:11])[NH2:10]
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)OCC1CC(=O)N1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.62 g (6.20 mmol) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 180 ml of acetone/water (2:1) and the solution is treated with 3.27 g (6.83 mmol) of (Z)-2-(2-amino-4-thiazolyl)-2-[[1-[t-butoxycarbonyl]-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl thioester. The mixture is stirred at room temperature for 12 hours. A further 60 mg (0.12 mmol) of the aforementioned thioester are added thereto and the stirring is continued for a further 3 hours. Acetone is removed under reduced pressure and 50 ml of water are added thereto. The crystals obtained are filtered off and washed with water. The mother liquor is partially evaporated (37° C., 15 mmHg) and chromatographed (MCI gel, water). After lyophilization, there are obtained 2.28 g (77%) of (3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido] -4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=2)[C:21]([O:23][CH3:24])=[O:22])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CCCc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Yield: 82.6 %

Procedure:
To a solution of 0.484 g (2.91 mmol) of the product of Step I dissolved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromophenylacetate, 0.804 g (5.82 mmol) of anhydrous K2CO3 and the mixture was stirred and heated at reflux for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[O:23]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]1[CH2:25][OH:26]>CC#N.C([O-])(O)=O.[Na+]>[OH:23][CH:24]([CH:27]([N:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][OH:26]
Reactant: COc1cccc2c1CCN2
Reactant: OCC1OC1c1ccccc1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc2c1CCN2C(c1ccccc1)C(O)CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.00 g (6.62 mmol) of 4-methoxyindoline (Gangjee et al., J. Med. Chem. 1997, 40, 479-485) and 1.90 g (8.51 mmol) of magnesium perchlorate in 20 mL of CH3CN was treated in a dropwise manner with a solution of 1.00 g (6.62 mmol) of 2,3-epoxy-3-phenyl-1-propanol (Ogata and Tomizawa, Bull. Chim. Soc. Jap. 1977, 50, 261-265) in 10 mL of CH3CN. The reaction was stirred at ambient temperature for 2.5 hours and was diluted with 30 mL of saturated aqueous NaHCO3. The organic layer was separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The oil was purified by radial chromatography (SiO2; 10% then 20% then 30% EtOAc in hexanes) to afford 1.55 g (5.17 mmol; 78%) of the subtitled compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:3]1.[Li+].[OH-]>C1COCC1.O.CCOC(C)=O>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:3]1
Reactant: COC(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)COC(c2ccc(C(=O)O)cc2)=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
To a solution of methyl 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)benzoate (78 mg, 0.33 mmol) in THF (1 mL) and H2O (1 mL) was added LiOH (23 mg, 1 mmol). The mixture was stirred at RT for 4 h before it was diluted with EtOAc (5 mL) and quenched by addition of aqueous HCl (5 ml of a 0.5 M aqueous solution, 2.5 mmol). After extraction with EtOAc (3×10 mL), the combined organic extracts were washed with brine (10 mL), dried (MgSO4), filtered and concentrated at reduced pressure. The crude residue (12 mg, 16% yield) was obtained as colourless oil and was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH2:31][CH3:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:33]1([C@H:39]([NH:41][C:42]([NH2:44])=[O:43])[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1COCC1>[CH2:31]([NH:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:44][C:42]([NH:41][C@@H:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:40])=[O:43])=[CH:3][C:4]=2[N:10]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]=1)[CH3:32]
Reactant: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 50 °C

Procedure:
6-Chloro-N-ethyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (3 g, 6.83 mmol), (R)-1-(1-phenylethyl)urea (1.68 g, 10.25 mmol), and BrettPhos pre-catalyst (546 mg, 0.68 mmol) were taken up in THF (13 mL). The resulting mixture was degassed for 5 min followed by addition of sodium tert-butoxide (6834 μL, 13.67 mmol) at room temperature. After the mixture was degassed again for 5 min, the reaction was heated to 50° C. under N2 for 6 h, Room temperature was attained, sat NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with water, dried, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc/Hexanes) gave (R)-1-(3-(ethylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C36H34N6O [M+1]+ 567. found 567.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])(=[O:7])[CH3:6].[Br:23]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:19]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(=O)Oc1ccc(CC(=O)O)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(C(Br)C(=O)O)cc1OC(C)=O
Temperature: 70 °C
Yield: 91.5 %

Procedure:
Thionyl chloride (60 ml) was added to a suspension of 3,4-diacetoxyphenylacetic acid (51.1 g) in carbon tetrachloride (105 ml) and the mixture was heated at 70° C. for one hour. After cooling to room temperature, N-bromosuccinimide (42.3 g), carbon tetrachloride (105 ml) and a little amount of hydrobromic acid were added, and the mixture was heated for an additional one hour. The resulting mixture was concentrated under reduced pressure, and the residue was redissolved in carbon tetrachloride. After filtering off the insoluble matters, the filtrate was dissolved in acetone (400 ml) and the pH of the solution was adjusted to 4.0 with saturated sodium bicarbonate aqueous solution under ice cooling. The resulting mixture was extracted with chloroform. The chloroform layer was washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, giving 61.4 g of the objective compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14](C)=[N:15][N:16]=[C:9]1[CH:8]=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])([O-:3])=[O:2].I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](=O)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7](=[O:26])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]=1[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc([N+](=O)[O-])ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-nitro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-chloro-5-nitro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [C@@H:1]12[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:5][CH2:4][C:3](=[O:11])[NH:2]2.[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:13]1([CH3:12])[CH:21]=[CH:20][C:16]([C:17]([N:2]2[C:3](=[O:11])[CH2:4][CH2:5][C@@H:6]3[C@H:1]2[CH2:9][CH2:8][C:7]3=[O:10])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CC[C@H]2C(=O)CC[C@H]2N1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2C(=O)CC[C@H]3C(=O)CC[C@H]32)cc1
Yield: 65.9 %

Procedure:
In 20 ml of dichloromethane were dissolved 0.3 g of Compound 6b obtained in Example 11 and 0.39 g of 4-methylbenzoyl chloride. Thereto was added dropwise 0.38 ml of triethylamine with ice cooling. The mixture was reacted at room temperature for 12 hours. The reaction mixture was washed with 0.1N hydrochloric acid, with 0.1N aqueous solution of NaOH and then with water, and dried over anhydrous sodium sulfate. After dried, the solvent was removed and the residue was recrystallized to obtain 0.35 g of Compound mentioned above (yield: 66%). Table 6 shows analytical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C:44]1([C:75]1[CH:80]=[C:79]([CH:81]=[O:82])[C:78]([CH3:83])=[CH:77][C:76]=1[O:84][CH2:85][C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.O1CCCC1.CCCCCC>[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:46][C:44]1([C:75]1[CH:80]=[C:79]([CH:81]([OH:82])[C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:6][CH:7]=2)[C:78]([CH3:83])=[CH:77][C:76]=1[O:84][CH2:85][C:86]1[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=1)[OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reactant: Brc1ccc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(O)c1ccc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a tetrahydrofuran solution (3 mL) of 2-(4-bromophenyl)-N-tritylethaneamine (0.814 g, 1.84 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.66 M hexane solution of n-butyllithium (0.69 mL, 1.84 mmol), and the mixture was stirred for 30 minutes at the same temperature. Then a tetrahydrofuran solution (3 mL) of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-D-glucopyranose (0.670 g, 0.876 mmol) was added dropwise, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (0.634 g, 64%) as a yellow oily compound.
Reaction SMILES: CS(NC1C=CC=CC=1)(=O)=O.[C:12]([C:15]1[CH:25]=[CH:24][C:18]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:16]=1)(=O)[CH3:13].Cl.[NH2:36][NH:37][C:38]([NH2:40])=[O:39].N1C=CC=CC=1>C(O)C>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[S:26][C:17]1[CH:16]=[C:15]([C:12](=[N:36][NH:37][C:38]([NH2:40])=[O:39])[CH3:13])[CH:25]=[CH:24][C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: NNC(N)=O
Agent: CS(=O)(=O)Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NNC(N)=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 101.2 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide methanesulfonanilide (1.16 g), semicarbazide hydrochloride (0.4 g), and pyridine (0.29 ml) in ethanol (15 ml) was stirred and refluxed for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtered, washed with water, and recrystallized from methanol to give a powder of 3'-(2,4-difluorophenylthio)-4'-methanesulfonamidoacetophenone semicarbazone (0.92 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Yield: 93.1 %

Procedure:
In a 1500 ml sulfonation flask, 135.6 g (1.13 mol) of 4-hydroxystyrene and 220.2 g (1.13 mol) of tert-butyl bromoacetate are dissolved in 800 ml of acetone and to the solution are added 195.0 g (1.41 mol) of potassium carbonate and 0.8 g of potassium iodide. The resultant suspension is stirred for 4 hours at 60° C. bath temperature. After cooling, the inorganic salts are removed by filtration and the filtrate is concentrated. The oily residue is taken up in 1000 ml of diethyl ether, washed twice with 800 ml of 1.0N sodium hydroxide solution and then three times with 1000 ml of water. The organic phase is separated, dried over magnesium sulfate and concentrated, giving 246.5 g of the desired product as a clear oil (93.2 %).
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].Br.[CH3:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([CH2:25][O:26][C:27]4[C:36]5[C:31](=[CH:32][C:33]([OH:37])=[CH:34][CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[N:23][N:24]=3)[CH:21]=2)[O:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(O)=O>[F:7][CH:2]([F:6])[O:37][C:33]1[CH:32]=[C:31]2[C:36]([C:27]([O:26][CH2:25][C:22]3[N:20]4[CH:21]=[C:16]([C:14]5[O:13][N:12]=[C:11]([CH3:10])[CH:15]=5)[CH:17]=[CH:18][C:19]4=[N:24][N:23]=3)=[CH:28][CH:29]=[N:30]2)=[CH:35][CH:34]=1
Reactant: Cc1cc(-c2ccc3nnc(COc4ccnc5cc(O)ccc45)n3c2)on1
Reactant: O=C([O-])C(F)(F)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: Cc1cc(-c2ccc3nnc(COc4ccnc5cc(OC(F)F)ccc45)n3c2)on1
Yield: 13.4 %

Procedure:
A 48 mL tube was charged with sodium 2-chloro-2,2-difluoroacetate (0.15 g, 1.0 mmol), 4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol hydrobromide (0.200 g, 0.44 mmol), cesium carbonate (0.43 g, 1.3 mmol), and DMF (1.7 ml, 22 mmol), flushed with argon, sealed, then placed in a 100° C. oil bath for 5 hours. The reaction mixture was concentrated, then diluted with DCM and chloroform. This was washed with water, sat. NaHCO3, and brine, then dried with MgSO4, filtered, and concentrated to give a brown oil. This was purified by HPLC to give 7-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (0.025 g, 13% yield) as the formic acid salt. MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C21H15F2N5O3: 423.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]I)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.[O-:30][S:31]([O-:33])=[O:32].[Na+].[Na+].C(O)C.O1CCCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][S:31]([OH:33])(=[O:32])=[O:30])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: O=S([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(CCS(=O)(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Yield: 24.4 %

Procedure:
A mixture of 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.25 g), Na2SO3 (0.28 g), tetrabutylammonium iodide (16 mg), ethanol (5 mL), tetrahydrofuran (5 mL) and water (3 mL) was heated at reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: ethyl acetate:methanol=5/1) to obtain the title compound (56 mg) as a yellow amorphous.