Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[C:13]([CH:23]=O)=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[NH2:27]O.C(OC(=O)C)(=O)C.Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[C:13]([C:23]#[N:27])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1ccc(-n2cc(C=O)c3ccc([N+](=O)[O-])cc32)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc([N+](=O)[O-])cc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of 4-(6-nitroindol-1-yl)benzoic acid ethyl ester (0.53 g) in N,N-dimethylformamide (6 mL) was added phosphoryl chloride (0.31 g) under ice cooling and this mixture was stirred at 70° C. overnight. After cooling to ambient temperature, to this reaction mixture was added 2 mol/L aqueous sodium hydroxide solution and this mixture was stirred at 30 minutes. This reaction mixture was poured into 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give 4-(3-formyl-6-nitroindol-1-yl)benzoic acid ethyl ester (0.46 g). To a solution of this aldehyde (0.46 g) in tetrahydrofuran (10 mL) were added hydroxylamine hydrochloride (0.19 g) and pyridine (0.43 g) at room temperature, and this mixture was stirred at 80° C. for 8 hours. To this reaction mixture was added acetic anhydride (0.42 g) at 80° C., this mixture was stirred at same temperature overnight. After cooling to ambient temperature, to this reaction mixture was added 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration. This solid was washed with water, n-hexane and diethyl ether to give the title compound (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([Cl:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:36][C:30]1[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=[C:28]([NH:27][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])[CH:29]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.2) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2) at RT for 3 days. tR: 1.24 min (LC-MS 2); ESI-MS: 529 [M+H]+ (LC-MS 2); Rf=0.52 (5% MeOH/CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[C:11]([F:17])[CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[C:23](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:23])=[C:11]([F:17])[CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(C=O)c(F)c2)c(C)c(N)c1Cl
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2C)cc1F
Yield: 69.9 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(3-fluoro-4-formylphenyl)-5-methylpicolinate (358 mg, 1.1 mmol) and potassium carbonate (537 mg, 3.9 mmol) in methanol (11 mL) at room temperature was added 1 mL of dimethyl(1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent, crude reagent) for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were dried organics over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-50% ethyl acetate/hexanes) provided the title compound as a yellow solid (245 mg, 69%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=[O:22])=[CH:15][C:14]=1[NH:23][C:24](=[O:40])[CH2:25][CH:26]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:33][C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH3:12])([CH3:11])[CH3:10]>O1CCCC1.C(OCC)(=O)C>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[CH2:4][O:22]2)=[CH:15][C:14]=1[NH:23][C:24](=[O:40])[CH2:25][CH:26]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:33][C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH3:12])([CH3:10])[CH3:11]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)c1ccc(CCC=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC2CO2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A suspension of 690 mg (15.8 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil, which had previously been washed with hexane) in 10 ml of dimethyl sulfoxide was stirred for 30 minutes, after which 2.66 g (12.1 mmol) of trimethylsulfoxonium iodide were added. The resulting mixture was stirred for 1 hour at 40° C., and then a solution of 4.50 g (10.5 mmol) of N-[2-t-butyl-5-(3-oxopropyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 19) in 25 ml of tetrahydrofuran was added dropwise over a period of 5 minutes. The reaction mixture was then stirred for 1 hour, after which the reaction mixture was cooled to room temperature and then diluted with ethyl acetate. The diluted mixture was washed several times with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 250 g of silica gel, using a 9:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 3.00 g (yield 65%) of the title compound as crystals, melting at 156°-157° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: C(Cl)(Cl)(Cl)F.[CH:6]([O:15][C:16](Cl)([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].[F:20][C:21]([F:33])([F:32])[CH:22]([O:27]C(F)(F)F)[C:23]([F:26])([F:25])[F:24]>>[F:8][C:7]([F:10])([F:9])[CH:6]([O:15][C:16]([F:18])([F:17])[O:27][CH:22]([C:23]([F:26])([F:25])[F:24])[C:21]([F:33])([F:32])[F:20])[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(Cl)OC(C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)OC(C(F)(F)F)C(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: FC(F)(OC(C(F)(F)F)C(F)(F)F)OC(C(F)(F)F)C(F)(F)F

Procedure:
Fractionation of the combined products afforded 23.2 g of a mixture, boiling point up to 39.5° C. shown by 1H and 19F NMR and GC to contain mainly CFCl3 and (CF3)2CHOCF2Cl along with a small amount of trifluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. There was then distilled 120.1 g, boiling point 40° to 45° C., identified by GC and NMR as chlorodifluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. Next came 2.7 g, boiling point 75° to 79° C., of dichlorofluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, identified by GC and NMR. Finally, there was obtained 24.4 g of 2,6-bis(trifluoromethyl)1,1,1,4,4,7,7,7-octafluoro-3,5-dioxaheptane, ((CF3)2CHOCF2OCH(CF3)2), boiling point 89° to 94° C., identified by GC and NMR analyses. NMR and mass spectroscopic (MS) analyses of (CF3)2CHOCF2OCH(CF3)2 are as follows: 1H-NMR (CDCl3) δ4.78 (septet, JHF, 5.4 Hz, OCH(CF3)2); 19F-NMR (CDCl3) Φ-60.9 (m, 2F, OCF2O), -74.3 (m, 12F, CF3). MS, m/e 364.966156 (M+ -F; mass meas. C7H2F13O2), 314.9808 (M+ -CF3), 216.983002 (mass meas. (CF3)2CHOCF2+), 150.9758 (CF3CHCF3+).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5].[CH2:22]([Mg]Cl)[CH2:23][CH3:24]>C1COCC1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH2:22][CH2:23][CH3:24])[CH2:7]2)=[CH:18][CH:17]=1
Reactant: CCC[Mg]Cl
Reactant: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Solvent: C1CCOC1
Product: CCCC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Yield: 94.4 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amide (401.0 mg, 1.37 mmol) and THF (10 mL) at 0° C. under a Nitrogen atmosphere. By dropwise addition, add Propylmagnesium chloride (4.0 mL, 8.22 mmol). Reflux the reaction for 5 hours then cool the reaction to room temperature and quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and add to an SCX (5 g) column pre-treated with 5% AcOH/MeOH. Wash with MeOH and elute product using 1N NH3 MeOH to give 356.0 mg (94% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.8 (3H, t), 1.3 (1H, qd), 1.4-1.5 (3H, m), 1.6-1.8 (1H, m), 1.9 (1H, dd), 2.0 (1H, td), 2.1 (1H, t), 2.4 (2H, t), 2.5-2.6 (1H, m), 2.7 (1H, d), 2.9 (1H, d), 3.4 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); TLC 4% 1N NH3 MeOH:CH2Cl2 Rf=0.42.
Reaction SMILES: C[O-].[K+].CO.CO.[NH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].[CH2:14](Cl)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>COCCOCCOC>[CH2:14]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCl
Reactant: O=C1CCCN1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOCCOC
Product: CCCCCCCCN1CCCC1=O
Reaction time: 6 h

Procedure:
230 g of a 31.98 wt. % strength potassium methoxide-methanol solution (1.05 mol) is added dropwise at about 155° C., while distilling methanol to a solution of 85.2 g of 2-pyrrolidone (butyrolactam, 1.0 mol) in 500 ml of diethylene glycol dimethyl ether. For complete removal of all the methanol, the clear solution is evacuated for a short period until reaching 500 mbar. 156 g of n-octyl chloride (1.05 mol) is then metered in likewise at 155° C. over a period of 20 minutes, and the reaction is brought to completion over a period of another 6 hours.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O.C(N(CC)CC)C.CN(C)C=O>[CH2:34]([O:33][C:31]([CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:7]3[S:6][C:5]4[N:4]=[CH:3][CH:2]=[N:1][C:10]=4[NH:9][C:8]=3[CH:11]=2)[CH2:30][CH2:29]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C1CCN(CCCN)CC1
Reactant: O=C(O)Cc1ccc2c(c1)Nc1nccnc1S2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(CCCNC(=O)Cc2ccc3c(c2)Nc2nccnc2S3)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 68.3 %

Procedure:
To 10 ml of N,N-dimethylformamide were added 0.6 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetic acid, 0.8 g of ethyl 1-(3-aminopropyl)piperidine-4-carboxylate dihydrochloride, 0.38 g of 1-hydroxybenzotriazole, 1.07 ml of triethylamine and 0.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and the resulting mixture was stirred at room temperature for 22 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of sodium. chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol). The crystals thus obtained were washed with ether and thus 0.72 g of the title compound was obtained as a pale brown powder.
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][OH:16])=[CH:5][CH:4]=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19].CO>C(O)(C)C>[C:22]([C@@H:20]([C@H:18]([C:17]([O-:26])=[O:25])[OH:19])[OH:21])([O-:24])=[O:23].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][OH:16])=[CH:5][CH:4]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: OC[C@@H]1CNCC[C@H]1c1ccc(F)cc1
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Yield: 35.5 %

Procedure:
Subsequently, 10.00 g (44.0 mmol) of the trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate, 6.60 g (44.0 mmol) of L-tartaric acid, and 50 ml of methanol were mixed together, and 50 ml of isopropanol was added to the resulting mixture under ice-cooling. The mixture was allowed to stand to precipitate crystals, and the resulting crystals were filtered. The crystals were washed with a 10 ml mixed solvent of 5 ml of methanol and 5 ml of isopropanol and dried, to give 5.60 g (15.6 mmol) of L-tartrate of trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (yield: 35.5%).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:21][CH2:22][CH2:23][CH3:24])=[CH:25][CH:26]=1
Reactant: CCCSc1ncc(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1ncc(CO)n1Cc1ccc(O)cc1
Yield: 26.5 %

Procedure:
A solution of 1.40 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-hydroxymethylimidazole in 15 mL of trifluoroacetic acid was refluxed for 0.25 hour. After cooling, the reaction was poured into water containing an excess of sodium bicarbonate, and the resulting emulsion was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-5% methanol/chloroform) afforded 0.28 g of 1-(4-hydroxybenzyl)-2-propylthio-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ 9.41 (s, 1 h); 6.88 (s, 1 h); 6.79 (A2B2, 4H); 5.14 (t, 1 h); 5.07 (s, 2H); 4.33 (d, 2H); 2.89 (t, 2H); 1.54 (sext., 2H); 0.88 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 73 (303 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 341 mg (83%) of white solids. M.P. 262° C. 1H NMR (DMSO-d6): δ 3.57 (s, 3H), 3.64 (m, 4H), 3.91 (m, 4H), 7.16 (m, 1H), 7.50 (d, J=3.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.79 (m, 2H), 7.86 (s, 1H). EIMS m/z 414 (M+1). Anal. (C20H17ClN4O2S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1/[C:35](/[NH:38]O)=[N:36]/[H])[NH:31][CH:30]=[C:29]2[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:36]=[C:35]([C:34]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][NH:31]4)=[CH:27][C:26]=3[F:25])[N:38]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: [H]/N=C(\NO)c1cc2[nH]cc(CCC(=O)OCC)c2cc1F
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (132 mg) in tetrahydrofuran (THF) (12 mL) was added EDC (235 mg) and HOBt (188 mg) and the mixture was stirred at RT for half an hour. Ethyl 3-{5-fluoro-6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D155) (180 mg) was then added and the resulting mixture was stirred for another 1 hour. Finally, TBAF (642 mg) was added to the solution and the reaction vessel was sealed and heated in Biotage Initiator using initial high at 120° C. for 2 hours. After cooling the reaction, the solution was diluted with ethyl acetate (80 mL) and washed with water (2×60 mL). The organic layer was then concentrated under vacuo and the residue was chromatographed on silica gel eluting with EA and PA to give the designed product ethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D156) (200 mg). MS (ES): C24H23ClFN3O4 requires 471.1. found 472.2 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[C:22]([Cl:31])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:32]#[N:33])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:31][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([C:32]#[N:33])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH3:30])=[O:28]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
After adding N-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]-N′-methylurea (968 mg) and thioanisole (3.7 ml) to trifluoroacetic acid (10 ml), the mixture was stirred overnight at 50° C. It was then concentrated under reduced pressure, ethyl acetate and aqueous sodium bicarbonate were added and the precipitated crystals were filtered out and washed with ethyl acetate to obtain the title compound (849 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22](=[O:24])N)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:35][C:36]([O:38]CC)=[O:37])=[O:5])C.[OH-:41].[Na+]>CCO>[C:4]([CH2:6][C:7]1[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=2)[C:9]2[C:14]([C:35]=1[C:36]([OH:38])=[O:37])=[CH:13][C:12]([O:15][C:16]1[C:21]([C:22]([OH:24])=[O:41])=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH:11][CH:10]=2)([OH:3])=[O:5]
Reactant: [OH-]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ncccc3C(N)=O)ccc2n1-c1ccc(OC(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ncccc4C(=O)O)ccc32)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(3-carbamoylpyridin-2-yloxy)-2-ethoxycarbonylmethyl-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (63 mg, 0.12 mmol, see step (a) Example 65), NaOH (aq, 2M, 0.35 mL) and EtOH (2 mL) was stirred at 90° C. for 8 h, concentrated, diluted with MeOH and filtered through Celite®. EtOAc was added to the filtrate which was cooled for 4 h at 5° C. The solid was collected and dissolved in H2O. The mixture was acidified to pH 4 with HCl (aq, 2 M). The solid was filtered off and dried for 4 h at 60° C. to give the title compound. Yield 34 mg (60%), mp 212-214° C. after recrystallisation from EtOAc/MeOH.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[CH2:46][NH2:47]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:47][CH2:46][C:41]4[CH:42]=[N:43][CH:44]=[CH:45][N:40]=4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: NCc1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1cnccn1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.4 %

Procedure:
Add 10 ml dry DMF to a flask under N2 containing 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (500 mg, 1.33 mmol, 1.0 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (279 mg, 1.46 mmol, 1.1 eq), Dimethyl-pyridin-4-yl-amine (16 mg, 0.132 mmol, 0.1 eq), and C-Pyrazin-2-yl-methylamine (217 mg, 1.99 mmol, 1.5 eq). Stir for 18 hours at room temperature. Remove solvent on rotovap and purify by silica gel chromatography to give 4-(3-Phenyl-indole-1-sulfonyl)-N-pyrazin-2-ylmethyl-benzamide (127 mg, 20% yield). Mass Spectrum (m/e): 468.95 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid at ambient temperature in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:30][NH:31][C:32](=[O:37])C(Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:32]([NH:31][CH3:30])=[O:37])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(F)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(F)ccc1OC

Procedure:
4-(5-Fluoro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman ##STR42## 4-(5-Fluoro-2-methoxy-benzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman is synthesized analogously to Example 1 from 4-(5-fluoro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point: 193°-194° C.