Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:25][C:26]([CH3:28])=O>FC(F)(F)C(O)=O>[OH:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:26]([CH3:28])([CH3:25])[O:1][C:2]=2[CH:10]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1ccc(O)cc1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2ccc(O)cc2O1
Reaction time: 24 h

Procedure:
A suspension of 2,4-dihydroxybenzoic acid (85.0 g) in trifluoroacetic acid (800 mL) was cooled in an ice/water bath as trifluoroacetic anhydride (500 mL) followed by the addition of acetone (100 mL). After the addition was complete, the ice/water bath was removed and the reaction mixture stirred for 24 hours before the volatiles were removed under vacuum using a rotary evaporator. The residue was cautiously added to a water/sodium bicarbonate suspension to afford a neutralized mixture. The mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with dichloromethane to afford the product (I-1a) as an off-white solid.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]=2[CH2:26][CH2:27][N:28]2C(=O)C3[C:30](=CC=CC=3)[C:29]2=[O:38])=[CH:9][CH:8]=1.C(OC(=O)C)(=O)C.O>CC(O)C>[CH3:4][O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]=2[CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH3:30])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN3C(=O)c4ccccc4C3=O)[nH]c3ccc(Cl)cc23)cc1
Agent: NN
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCCc2c(CCNC(C)=O)[nH]c3ccc(Cl)cc23)cc1
Temperature: 70 °C

Procedure:
Hydrazine hydrate (174 g, 3 mol) was added in one portion to a stirred suspension of 4-(2-{5-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid methyl ester (503 g, 1.0 mol) in 5.7 L 2-propanol. The suspension was warmed to 82 C for 3.5 h. HPLC analysis showed remaining starting material was less than 1%. The reaction mixture was allowed to cool to 70° C. and filtered at this temperature. Pyridine (1 L) was added to the filtrate, and the 2-propanol was distilled in vacuo (40C, 50 mmHg). The concentrate was charged to a 12 L 4-neck flask equipped with mechanical stirrer. The mixture was cooled to 5° C. under stirring. Acetic anhydride (113 g, 1.1 mol) was added dropwise maintaining an internal temperature below 10 C. The mixture was stirred for 0.5 h after complete acetic anhydride addition. HPLC analysis showed less 1% of amine remaining. Water (5 L) was added and the resulting suspension was stirred for 12 h at rt. The solid was collected by filtration and washed with water (3×500 mL). The product was dried in a vacuum oven at 50C to an LOD of <1%. 1H-NMR (300 MHz, DMSO−d6): δ1.78 (s, 3H), 2.87 (t, J=7 Hz, 2H), 3.10 (t, J=7 Hz, 2H), 3.36 (t, J=7 Hz, 2H), 3.80 (s, 3H), 4.16 (t, J=7 Hz, 2H), 6.98-7.03 (m, 3H), 7.26 (d, J=9 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.88 (d, J=9 Hz, 2H), 8.00 (t, J=6 Hz, 1H), 10.90 (s, 1H) ppm
Reaction SMILES: [CH3:1][I:2].[F:3][C:4]([F:23])([F:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1>CC(C)=O>[I-:2].[F:23][C:4]([F:3])([F:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:15]([C:16]2[CH:17]=[N+:18]([CH3:1])[CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1
Reactant: CI
Reactant: FC(F)(F)CCCCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nsnc2OCCCCCC(F)(F)F)c1
Product: [I-]

Procedure:
A solution of methyl iodide (852 mg, 6.0 mmol) and 3-(3-(6,6,6-trifluorohexyloxy-1,2,5-thiadiazol-4-yl)pyridine (630 mg, 2.0 mmol) in acetone (25 ml) was refluxed for 7 h. The solution was evaporated and the residue was used directly in the next step.
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:9][S:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH:15]=[N:14]1)(=[O:12])=[O:11].[CH2:23]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29](=O)[CH2:30]2)[CH2:24][CH3:25].[OH-].[Na+]>CO>[CH3:9][S:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][CH:29]3[CH2:28][CH:27]4[N:26]([CH2:23][CH2:24][CH3:25])[CH:31]([CH2:32][CH2:33]4)[CH2:30]3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)(=[O:11])=[O:12]
Reactant: CS(=O)(=O)n1ncc2cc(N)ccc21
Reactant: CCCN1C2CCC1CC(=O)C2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1C2CCC1CC(Nc1ccc3c(cnn3S(C)(=O)=O)c1)C2
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.9 %

Procedure:
Sodium cyanoborohydride (242 mg, 3.85 mmol) and then acetic acid (220 μl, 3.84 mmol) were added to a solution of 1-(methylsulfonyl)-1H-indazol-5-amine (163 mg, 0.772 mmol) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one (150 mg, 0.924 mmol) in methanol (3 ml), and the resulting mixture was stirred at room temperature for 4 days. A 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified successively by a silica gel column chromatography (chloroform/methanol=4/1), a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=4/1) and partition by LC/MS (water containing 0.05% trifluoroacetic acid-acetonitrile containing 0.035% trifluoroacetic acid, 10%–100% gradient, the extraction of the organic layer with aqueous ammonia/ethyl acetate after the partition) to obtain 1-(methylsulfonyl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (8 mg, 3%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][CH:13]=1.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C1COC(c2ccc(Cc3nc4ccccc4n3C)cc2)=N1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc(-c2ccc(Cc3nc4ccccc4n3C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A stirred solution of methyl {2-{4-[(1-methyl-1H-benzimidazol-2-yl)methyl]-phenyl}-4,5-dihydro-1,3-oxazol-4-yl}carboxylate (1.5 g, 5 mmol) in CH2Cl2 was treated with bromotrichloromethane (1.22 g, 6 mmol) and DBU (0.70 g, 4.6 mol), stirred at room temperature overnight and concentrated in vacuo. The resultant residue was purified by column chromatography (silica, CHCl3:MeOH 1%) to give the title compound in 15% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 8.2 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.3 (d, J=8.0 Hz, 2H), 7.27 (m, 4H), 4.3 (s, 2H), 3.95 (s, 3H), 3.63 (s, 3H). LCMS (ESI+) 348 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([N+:40]([O-:42])=[O:41])[C:34]=1[OH:43].[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][CH:51]([CH3:54])[CH2:52]O>O1CCCC1>[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([N+:40]([O-:42])=[O:41])[C:34]=1[O:43][CH2:52][CH:51]([O:50][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][O:44]1)[CH3:54]
Reactant: CC(CO)OC1CCCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(COc1c([N+](=O)[O-])ccc(F)c1F)OC1CCCCO1
Yield: 97.2 %

Procedure:
To a solution of 2.04 g of triphenylphosphine in 10 ml of anhydrous tetrahydrofuran was added dropwise 1.36 g of diethyl azodicarboxylate with stirring under cooling with ice, and the resulting mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 1.05 g of 2,3-difluoro-6- nitrophenol (IV, Xa=Xb=F), 1.01 g of 2-O-(tetra-hydropyran-2-yl)propane-1,2-diol (III, Rc=THP) in 5 ml of anhydrous tetrahydrofuran and then the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and to the residue was added benzene and a saturated sodium bicarbonate aqueous solution. After the mixture was shaken, the organic layer was separated and washed successively with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified through silica gel column to yield 1.85 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].Br[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)C(C)(C)C)CC3)c2n1
Temperature: 70 °C
Reaction time: 76 h
Yield: 32 %

Procedure:
To a stirred mixture of 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 4, Step 4, 150 mg, 0.446 mmol) and 1-bromo-3,3-dimethylbutan-2-one (72 μL, 0.670 mmol) in N,N-dimethylformamide (4.4 mL) were added sodium iodide (67 mg, 0.670 mmol) and triethylamine (0.156 mL, 1.12 mmol). The reaction mixture was stirred at 70° C. for 76 h. After removal of solvent, the residue was dissolved in ethyl acetate (100 mL), and washed with aqueous sodium bicarbonate (5 mL) and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Flash column chromatography (NH-silica gel) of the residue eluting with hexane/ethyl acetate (9:1 to 1:1) afforded a pale brown solid, which was recrystallized from ethyl acetate to afford 62 mg (32%) of the title compound as off-white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21]CC)=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:37]([NH:36][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[O:38])=[CH:5]1)[N:16]=[C:15]([C:19]([OH:21])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Agent: Cl
Product: O=C(NCc1ccn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)c1)Nc1cccc2ccccc12
Yield: 22.5 %

Procedure:
Using the compound (200 mg, 519 μmol) of Example 5 and 1-naphthyl isocyanate (89.4 μl, 622 μmol) and through the process similar to Example 38, 57.1 mg of title compound were obtained as yellowish brown powder. Yield 22%.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH:7]1[CH2:9][O:8]1.C(O)(=O)C.[Li+].[Br-:17]>C1COCC1>[Br:17][CH2:9][CH:7]([OH:8])[CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:11])([CH3:10])[CH3:1]
Reactant: [Br-]
Reactant: C[Si](C)(C)C#CCCC1CO1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[Si](C)(C)C#CCCC(O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a stirred solution of trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (4.5 g, 27 mmol) in THF (90 mL) containing acetic acid (4.81 g, 80.21 mmol), was added at 0° C. anhydrous LiBr (3.71 g, 42.78 mmol). The reaction mixture was left stirring overnight at room temperature. The reaction was quenched with saturated NaCl and extracted with Et2O. The organic phase was washed once with a solution of 1M K2CO3 saturated with NaCl, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from Cyclohexane 100% to DCM 100% as eluent) to afford 2.5 g of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (Yield: 38%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C[Al](C)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@@:24]([OH:50])([CH2:44][N:45]1[CH:49]=[N:48][CH:47]=[N:46]1)[C@H:25]([S:27][C@@H:28]1[CH2:33][O:32][C@@H:31]([C:34]2[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][CH:35]=2)[O:30][CH2:29]1)[CH3:26]>>[C:10]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[NH:1][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([C@H:31]2[O:30][CH2:29][C@H:28]([S:27][C@H:25]([CH3:26])[C@:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])([OH:50])[CH2:44][N:45]3[CH:49]=[N:48][CH:47]=[N:46]3)[CH2:33][O:32]2)=[CH:35][CH:36]=1)#[N:11]
Reactant: N#Cc1ccc(N)cc1C#N
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)c(C#N)c3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-aminophthalonitrile (170 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (129 mg, yield 71%) as a yellow oil which was recrystallized from ethyl acetate-hexane to give pale yellow powdery crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH:38]=O)[C:32](=[O:40])[CH:31]=[CH:30]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:33]4[C:34]5[C:29](=[CH:28][C:27]([Cl:26])=[CH:36][CH:35]=5)[CH:30]=[CH:31][C:32]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2cc(Cl)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To 4 mL of a chloroform solution containing 0.68 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.44 g of (6-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.62 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.65 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)c(F)c2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2c(ccc(Cl)c2F)/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 72.8 %

Procedure:
To the mixture of 6-chloro-7-fluoroindolin-2-one (1.1 g, 5.9 mmol) (Natrochem) and 3-chloro-2-fluorobenzaldehyde (1.4 g, 8.9 mmol) (Aldrich) in methanol (50 mL) was added piperidine (1.5 g, 17.8 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to half its volume. The mixture was filtered and resulting precipitate was collected, dried to give the first batch of desired product (1.4 g). The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product (0.44 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.84 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([O:38]CC3C=CC(OC)=CC=3)[CH:17]([CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH:16]([OH:38])[CH:17]([CH2:25][CH2:26][N:27]3[C:28](=[O:37])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]3=[O:36])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccc(Cl)cc3)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of the compound (120 mg) obtained from step 8 above in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and stirred the reaction mixture for 2 hours at room temperature. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by preparative thin layer chromatography (eluant: 60% ethyl acetate in hexane) to furnish the title compound (68 mg).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(O[C:28](=[O:30])[CH3:29])(=O)C>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:1][CH2:2][C@H:3]2[O:4][C@@H:11]([O:12][C:2](=[O:1])[CH3:3])[C@H:9]([O:10][C:5](=[O:6])[CH3:7])[C@@H:7]([O:8][C:9](=[O:10])[CH3:11])[C@@H:5]2[O:6][C:28](=[O:30])[CH3:29])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 11 h

Procedure:
D-Glucose (20.0 g, 0.111 mol) was placed in a 1000-mL round-bottomed flask, and pyridine (300 ml) was added. Some of glucose remained undissolved. p-Toluensulfonyl chloride (22.0 g, 0.115 mol) was added at ambient temperature. After stirring for 11 h, acetic anhydride (80 ml, 0.83 mol) was added in one portion. Gentle exothermic reaction took place. After being stirred for 1.5 h, the mixture was evaporated. Ethanol (200 ml) was added to a residual oil. The oil was dissolved and soon a white crystal appeared. After the mixture stood undisturbed at −10° C. for 27 h, the crystal was collected on a glass filter, washed with cold ethanol (25 ml, twice), and dried under reduced pressure. 6-O-(p-Toluenesulfonyl)-1,2,3,4-tetra-O-acetyl-β-D-glucose (compound 5) was obtained in 33% yield (18.5 g, 36.8 mmol).
Reaction SMILES: C([CH:3]([C:5]([CH:7]([Cl:10])CC)=[O:6])[Cl:4])C.[CH3:11][O:12]CCCl>>[Cl:4][CH2:3][C:5](=[O:6])[CH3:7].[CH3:11][O:12][CH2:7][Cl:10]
Reactant: COCCCl
Reactant: CCC(Cl)C(=O)C(Cl)CC
Product: CC(=O)CCl
Product: COCCl

Procedure:
In the same manner as given in the foregoing, but using ethylchloromethyl ketone and chloroethyl methyl ether in Steps 1 and 3, respectively, in place of chloroacetone and chloromethyl methyl ether, the title compound is produced.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[I:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([I:18])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cccc(I)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2cccc(I)c2)n1
Temperature: 120 °C
Yield: 0 %

Procedure:
A solution of 2,4-dichloropyrimidine (3.0 g, 20 mmol) and N,N-diisopropylethylamine (4.2 mL, 24 mmol) in N-methylpyrrolidinone (20 mL) was treated with 3-iodoaniline (2.4 mL, 20 mmol) dropwise and heated at 120° C. for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), and washed with water (150 mL). The aqueous layer was separated and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (3.2 mg, 48%) as a tan solid. LCMS for C10H8ClIN3 (M+H)+: m/z=331.9.
Reaction SMILES: CN(C)CCO[C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl:23]C1C2C(=O)C3C(=CC=CC=3)NC=2C=CC=1.ClC1C=C(NC2C=CC=CC=2C(O)=O)C=CC=1.S(=O)(=O)(O)O>C(O)C>[Cl:23][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c2ccccc2[nH]c2cccc(Cl)c12
Reactant: CN(C)CCOc1cccc2c1c(=O)c1ccccc1n2C
Agent: O=C(O)c1ccccc1Nc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1c2ccccc2c(=O)c2c(Cl)cccc21

Procedure:
1-(2-Dimethylaminoethoxy)-10-methyl-9(10H)-acridinone [III; R' is CH3, R" is H, --O--Y--N=Z is 1-O-CH2CH2N(CH3)2 ], hydrochloride salt, m.p. 237°-241° C. (tan granules from methanol-ether). The intermediate 1-chloro-10-methyl-9(10H)-acridinone, m.p. 183°-186° C. (pale yellow granules from ethanol) was prepared by N-methylation of 1-chloro-9(10H)-acridinone, in turn prepared by cyclization of 2-(m-chlorophenylamino)benzoic acid with sulfuric acid.