Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.COCCN(S(F)(F)[F:36])CCOC.S(=O)(=O)(O)O.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([F:36])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][C:17]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(C2(F)CCNCC2)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (2.8 g) was dissolved in methylene chloride (20 ml) and the mixture was cooled to −78° C. DEOXO-FLUOR (trademark) (APOLLO CO., 1.8 g) was added, and the mixture was stirred for 2 hr. Then, after stirring at room temperature for 2 hr, water was added, and the mixture was extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate(10:1-5:1)) to give a solid. 1,4-Dioxane (20 ml) and 10% aqueous sulfuric acid (5 ml) were added to the solid, and the mixture was stirred with heating at 70° C. for 1.5 hr. After completion of the reaction, the reaction system was basified (pH=9) with a 1N aqueous sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-fluoropiperidine (655 mg, yield 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](=[O:31])[CH2:12][C@H:13]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[CH2:5]2>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](=[O:31])[CH2:12][C@H:13]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([OH:16])=[O:15])[CH2:5]2
Reactant: O=C(OCc1ccccc1)[C@H](CC(=O)N1Cc2ccc(F)cc2C1)Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CC(=O)N1Cc2ccc(F)cc2C1)Cc1ccccc1
Reaction time: 2.5 h
Yield: 64.8 %

Procedure:
150 mg of 10% palladized carbon are added to a solution of 1.18 g (2.83 mmol) of phenylmethyl 5-fluoro-γ-oxo-α(S)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoate in 5 ml of ethyl acetate and the mixture is hydrogenated at the pressure of 20 psi (137,921 Pa) for 2.5 h. After filtration on celite and then evaporation of the solvent, the product is crystallized from diethyl ether. 0.6 g of a white solid is obtained. Yield 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:26])[CH:16]=2)[N:11]=1
Reactant: Cc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of intermediate 22 (0.041 mol) in phosphoryl chloride (105 ml) was stirred at 100° C. for 4 hours then cooled. The solvent was evaporated. The residue was taken up DCM. The solvent was evaporated. The residue was taken up in DCM. The mixture was poured out into ice water, basified with K2CO3 10% and extracted. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 11.4 g (70%) of intermediate 23. The mother layer was evaporated and purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 90/10; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.7 g (10.5%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-methylphenyl)-methanone (intermediate 23), mp. 156° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14]([N:21]1[C@@H:26]([CH3:27])[CH2:25][C:24](=O)[CH2:23][C@H:22]1[CH3:29])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:14]([N:21]1[C@H:26]([CH3:27])[CH2:25][CH:24]([NH:1][C:2]2[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:23][C@H:22]1[CH3:29])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Reactant: COC(=O)c1cc(F)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a stirred solution of methyl 3-amino-5-fluoro-2-methylbenzoate (520 mg, 2.84 mmol) in THF (20 mL) and TFA (813 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (679 mg, 3.12 mmol) at 0° C. The mixture was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then the mixture was cooled to 0° C. in an ice bath, sodium triacetoxyborohydride (1.27 g, 5.68 mmol) was added. The reaction mixture was stirred at rt for 2 hours. Then aq. NaHCO3 was added at 0° C. until pH8-9, and the content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give titled compound as a colorless oil (331 mg, 30% yield.). 1H-NMR (400 MHz, CDCl3) δppm; 7.35-7.39 (m, 2H), 7.27-7.30 (m, 2H), 7.21-7.26 (m, 1H), 6.76 (dd, J=2.4, 9.2 Hz, 1H), 6.45 (dd, J=2.4, 11.2 Hz, 1H), 3.94 (d, J=14.4 Hz, 1H), 3.87 (s, 3H), 3.58-3.65 (m, 2H), 3.46 (d, J=14.4 Hz, 1H), 3.06-3.12 (m, 1H), 2.94-3.01 (m, 1H), 2.21 (s, 3H), 2.02-2.07 (m, 1H), 1.82-1.89 (m, 1H), 1.15-1.22 (m, 1H), 1.12 (d, J=6.0 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(OCC)C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 821 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added ethyl phenyl ether (2.76 g) and 324 mg (5.50 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 384 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 77%) and 2.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:29])[C@@H:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:9][C:2]([NH:10][C:11](=[O:29])[C@@H:12]([NH:28][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To 80 ml of a methylene chloride solution containing 2.14 g of (2S)-N-(α,α-dimethylbenzyl)-2-amino-6-(benzyloxycarbonylamino)hexanamide (prepared as described in Preparation 9) and 0.51 g of pyridine were added dropwise, whilst ice-cooling, 30 ml of a methylene chloride solution containing 0.76 g benzoyl chloride, over a period of 10 minutes, with stirring. The mixed solution was stirred for a further 1.5 hours at room temperature, and then the solvent was distilled off. The residue was dissolved in ethyl acetate containing a small amount of water. A 10% w/v aqueous solution of citric acid was added, and then the solution was extracted with ethyl acetate. The extract was washed with a 5% w/v aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. The fraction eluted with a 1:1 by volume mixture of ethyl acetate and hexane gave 2.06 g of the title compound as an amorphous substance melting at 53°-58° C. (with decomposition)
Reaction SMILES: Br[C:2]1[C:6]([N:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[S:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)C.[S:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])(=[O:27])[NH2:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[S:4][C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:30][CH:31]=3)[C:6]=2[N:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1Br
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of Ethyl 3-bromo-5-(4-chlorophenyl)-4-(dimethylamino)thiophene-2-carboxylate (compound 34d, 2.20 g, 5.65 mmol) in a mixture of toluene:ethanol (10 ml:30 ml) was added (4-sulfamoylphenyl)boronic acid (1.25 g, 6.22 mmol) and potassium carbonate (1.56 g, 11.30 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) under nitrogen and the reaction mixture was heated at about 95 to about 100° C. for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was then washed with ethanol (2×25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 55% ethyl acetate in hexanes as an eluent to obtain the title compound (2.0 g, 76.05%).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:31])[F:30])=[CH:4][CH:3]=1.[Cl:33]C1C2SC(I)=NC=2C(C(F)(F)F)=CC=1>>[Cl:33][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:30])[F:31])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)c2sc(I)nc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(Cl)c2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 7-chloro-2-iodo-4-trifluoromethyl-1,3-benzothiazole and conducting the Suzuki coupling at 70° C. for 3 h, the title compound was obtained as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6): δ=2.14-2.36 (m, 4H), 3.05-3.18 (m, 2H), 3.37-3.44 (m, 2H), 4.01 (brs, 2H), 4.45-4.56 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 8.25 (brs, 1H), 8.46 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.86 (brs, 1H), 9.06 (brs, 1H). MS(ES+): m/z=478.98/481.00 (100/76) [MH+]. HPLC: tR=2.37 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:29])[C:25]=1[CH:26]([OH:28])[CH3:27].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([Cl:29])[C:25]=2[CH:26]([OH:28])[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(O)c1c(Cl)cncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(O)c1c(Cl)cncc1-c1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Yield: 32.8 %

Procedure:
To the solution of 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (412 mg, 1.56 mmol), 1-(3-Bromo-5-chloro-pyridin-4-yl)-ethanol (370 mg, 1.56 mmol) and PdCl2(dppf). CH2Cl2 adduct (64 mg, 0.08 mmol) in DMF (10 mL) was added 2M Na2CO3 solution (2.35 ml, 4.70 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (0-30%, EtOAc/Heptane, v/v) to give 2-Chloro-4-[5-chloro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (150 mg, 33%) as colorless solid; ESI-MS m/z: 293 [M+H]+,
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=3[O:32][CH3:33])=[O:22])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:35].O1CCOCC1>C1COCC1>[ClH:35].[C:30]([C:28]1[CH:27]=[CH:26][C:25]([O:32][CH3:33])=[C:24]([NH:23][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][C:16]=2[F:34])=[O:22])[CH:29]=1)#[N:31]
Reactant: COc1ccc(C#N)cc1NC(=O)Nc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1NC(=O)Nc1ccc([C@H]2CNCCO2)cc1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a solution of (S)-2-{4-[3-(5-Cyano-2-methoxy-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (97 mg, 106 μmol, Eq: 1.00) in THF (4 ml) was added 4M−HCl in dioxane (0.773 ml, 3.09 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 5 h. To the cooled mixture was then added ethyl acetate and the suspension was filtered off and dried under high vacuo to give the target compound as an off-white solid (63 mg, 75%). MS (ISP): 369.1 ([M+H]+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].O.[C:19](OCC)(=O)[CH3:20]>C1COCC1>[OH:2][CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)[CH2:19][CH3:20]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 200 ml of anhydrous THF under nitrogen stream. 7.9 ml of ethyl Grignard reagent was dropped in slowly under ice bath temperature and stirred at 0° C. for 1 hour. The reaction mixture was then heated to 70° C. in oil bath for 4 hours. The solution was monitored by thin layer chromatography to determine whether the reaction was completed. 50 ml of water and 300 ml of ethyl acetate were added and the ethyl acetate extract was purified by column chromatography. From the eluate of ethyl acetate/n-hexane (1/9) fraction, yellow solid was obtained and recrystallized to give granulate crystal. The melting point of the product was 89°-90° C. and the yield was about 70%.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH2:4].[CH2:21]([O:23][C:24]1[C:27](=O)[C:26](=[O:29])[C:25]=1[O:30]CC)[CH3:22]>C(O)C>[OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH:4][C:27]1[C:26](=[O:29])[C:25](=[O:30])[C:24]=1[O:23][CH2:21][CH3:22]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: NCC(O)COCc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: CCOc1c(NCC(O)COCc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Reaction time: 5 h

Procedure:
2.78 g (0.01 mol) of 2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propylamine in 10 ml of ethanol are slowly added dropwise to 1.70 g (0.01 mol) of 1,2-diethoxycyclobutene-3,4-dione and the mixture is stirred for 5 hours. The title compound, which is obtained after the reaction solution has been concentrated by evaporation, is subsequently reacted without further purification.
Reaction SMILES: C1(P(=[O:20])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:73][N:74]1[CH2:79][CH2:78][S:77][CH2:76][CH2:75]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[NH:63][S:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.OOS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O1CCCC1.O.C(O)C>[CH3:62][O:61][CH2:60][CH2:59][O:58][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([NH:63][S:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=3)(=[O:66])=[O:65])[CH:53]=1)[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:73][N:74]3[CH2:75][CH2:76][S:77](=[O:20])[CH2:78][CH2:79]3)[CH2:45][N:46]=1)=[CH:57]2
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CSc1ccccc1
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Reaction time: 0.5 h
Yield: 6.1 %

Procedure:
To a solution of triphenylphosphine oxide (470 mg) in dichloromethane (3 mL) was added trifluoromethanesulfonic anhydride (480 mg) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (570 mg) and thioanisole (210 mg) in dichloromethane (20 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 3 hr under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:9, volume ratio) to give colorless crystals. To a mixture of the obtained crystals, ethanol (20 mL), water (10 mL) and tetrahydrofuran (10 mL) was added OXONE (registered trade mark, 43 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. Aqueous sodium sulfite solution was added to the reaction mixture, the mixture was stirred for 30 min, and the organic solvent was evaporated under reduced pressure. The residue was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio) to give colorless crystals. The obtained crystals was further purified by preparative HPLC, and recrystallized from acetone-methanol to give the title compound (30 mg, yield 6.1%) as colorless prism crystals. melting point 235-236° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=2)[C:21]([OH:23])=O)[CH:11]=[CH:12][CH:13]=1.CN(C)C=O.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][C:33]=1[CH3:44]>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([C:21]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][C:33]=3[CH3:44])=[O:23])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2C)c(C)c1
Temperature: 20 °C
Reaction time: 1.25 h

Procedure:
Oxalyl chloride (15.1 ml, 173 mmol) was added over approx 1 minute to a stirred suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoic acid (31.8 g, 115 mmol) in dichloromethane (1.14 L) at 20° C. under argon. This was followed by the addition of N,N dimethylformamide (2 ml, 25.8 mmol) over 3 minutes with accompanying gas evolution but no noticeable temperature rise. Within approx 15 minutes the suspension dissolved and turned a darker brown. The mixture was stirred under argon at 20° C. for a total of 75 minutes. After 75 minutes the reaction mixture was evaporated in vacuo to a cream solid which was dried under vacuum at room temperature for 1 h. The solid was then redissolved in dichloromethane (900 ml) and to the stirred solution at 20° C. under argon was simultaneously added a solution of ethyl (4-amino-3-methylphenyl)acetate (24.4 g, 126 mmol) in dichloromethane (240 ml) and triethylamine (24 ml) over 10-15 minutes. The temperature rise in the reaction was from 20° C. to 30° C. over this time and thereafter slowly cooled to ambient. The brown solution was stirred under argon at room temperature for 14 h. After 14 h stirring the brown solution was washed with water (2×1 L). The combined aqueous washes were re-extracted with dichloromethane (500 ml) and all the organic extracts were combined, dried (MgSO4) and evaporated in vacuo to a brown oily solid which was dried at room temperature, under vacuum for 0.5 hours (wt=51.7 g). This material was dissolved in dichloromethane (200 ml) and the solution column chromatographed on Biotage 75 L system eluting with an ethyl acetate/iso-hexane gradient mixture and collecting 400 ml fractions as follows: