Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@@H]1CCCC[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 22.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 177 mg, 0.397 mmol), (1R*,2R*)-2-phenylcyclohexanol (70.0 mg, 0.397 mmol), sodium hydride (63%; 30.3 mg, 0.794 mol) and DMSO (5.0 mL), to yield the title compound (53.0 mg, 22%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1ccncc1
Yield: 78.8 %

Procedure:
A solution of 2.1 g (7.04 mmol) of ethyl 5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylate and 1.18 g (21.12 mmol) of potassium hydroxide in 80 ml of ethanol and 2 ml of water is heated at reflux for 2 hours. The reaction mixture is subsequently concentrated under reduced pressure. 100 ml of water are added and the pH of the solution is brought to pH 8 by addition of a concentrated hydrochloric acid solution. A precipitate is collected by filtration and is washed with water and then dried under reduced pressure. 1.5 g of the expected product are thus obtained.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
70.2 g (409.7 mmol) of a-bromopropionic acid chloride is added in drops at 0° C. to 40 g (341.4 mmol) of valine and 103.7 g (1024 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[C:26]([OH:32])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([NH:24][C:25]1[C:26](=[O:32])[NH:27][CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)cnc1O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(Cl)c[nH]c1=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 3-amino-5-chloropyridin-2-ol. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (CH2Cl2/MeOH, 99:1→97:3). tR: 1.15-1.18 min (LC-MS 2); ESI-MS: 527.1/529.1/531.1 [M+H]+ (LC-MS 2); Rf: 0.41 (CH2Cl2/MeOH 9:1).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[OH-].[K+].CCO>[CH:27](=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)[CH:17]=2)[C:22]1=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 47.8 %

Procedure:
According to the method of Example 6, the product of Step 1 (0.271 g, 0.76 mmol) was reacted with benzaldehyde (0.121 g, 1.14 mmol) in 5 mL of 4% KOH in EtOH for 3 hours at room temperature to afford 0.125 g (46%) of the title compound as a foam which solidified on standing to give a yellow solid, mp 53-56° C.: CI-MS m/e 345 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2I)[C:12](=[O:18])[C:13]#[C:14][CH:15]([CH3:17])[CH3:16])[CH:5]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[C:14]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH:15]([CH3:17])[CH3:16])[C:12]2=[O:18])[CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2C(=O)C(=C(c3ccc(Cl)cc3)C(C)C)c3ccccc32)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
A mixture of 3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester (0.93 g, 2.02 mmol), 4-chlorophenylboronic acid (0.63 g, 4.04 mmol), triphenylphosphine (53 mg, 0.202 mmol), palladium acetate (23 mg, 0.10 mmol) and cesium fluoride (0.92 g, 6.06 mmol) in THF (15 ml) was stirred for 3 hours at 60° C. After removal of solvent, the residue was purified by flash chromatography, eluting with ethyl acetate/hexane=1:5 to afford the product 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (0.40 g, 44%) as a yellow solid. MS calcd. for C27H24ClNO3 445.5, obsd. (ESI+) [(M+H)+] 446.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, J=6.82 Hz, 6H) 3.91 (s, 3H) 4.99 (dt, J=13.71, 6.92 Hz, 1H) 5.06 (s, 2H) 5.73 (d, J=7.58 Hz, 1H) 6.62 (t, J=7.71 Hz, 1H) 6.73 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz, 1H) 7.19 (d, J=8.34 Hz, 2H) 7.46 (t, J=7.83 Hz, 1H) 7.55 (d, J=8.08 Hz, 3H) 7.94 (d, J=7.58 Hz, 1H) 8.02 (s, 1H) MS calcd. for C27H24ClNO3 445.5, obsd. (ESI+) [(M+H)+] 446.0.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:16]([CH3:26])([CH3:25])[C:17]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[OH-].[Na+].CN([CH:38]=[O:39])C>>[CH:38]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]([CH3:26])([CH3:25])[C:17]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])[CH:10]=2)[NH:6][CH:7]=1)=[O:39]
Reactant: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Phosphorus oxychloride (0.01 mL, 0.11 mmol) was added to anhydrous DMF (0.5 mL) under argon. The mixture was stirred at rt for 15 min before 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 101, 18 mg, 0.048 mmol) was added. The reaction mixture was stirred at rt for 1 hr. Aqueous sodium hydroxide solution (1N, 2 mL) was added, the mixture was stirred at 80° C. for 8 min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (1 mL) and water (1 mL) and extracted with dichloromethane (10 mL). The dichloromethane extract was dried (Na2SO4) and concentrated. Silica gel flash chromatography gave 3-(3-formyl-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 109, 16 mg, 0.04 mmol, 83% yield) as a glassy solid. MS found: (M+H)+=404. 1H NMR (400 MHz, CDCl3) δ ppm 9.93-9.95 (1 H, s) 9.92 (1H, s) 9.25 (1H, s) 8.34 (1H, s) 7.66 (1H, d, J=3.05 Hz) 7.34-7.39 (3 H, m) 7.12-7.28 (5H, m) 6.92 (1H, d, J=3.56 Hz) 4.51 (1H, s) 1.42 (6H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([Br:39])=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.CO>CO>[Br:39][C:30]1[N:21]2[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:19][C:20]2=[N:32][C:31]=1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(Br)n4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(Br)n4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 5-4 (59 mg, 0.1 mmol) in 1 mL of MeOH was added 4M HCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 5-5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1N
Reaction time: 1 h

Procedure:
After dissolving 2-amino-3-nitrobenzoic acid methyl ester (661 mg, 3.37 mmol) in methanol (30 ml), 10% palladium-carbon powder (5 mol %) was added under a nitrogen stream, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to obtain 2,3-diaminobenzoic acid methyl ester. The compound was identified by NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[C:17]([NH2:22])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(OC2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1nc(OC2CCN(Cc3ccccc3)C2)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To a solution of 6-(1-benzyl-pyrrolidin-3-yloxy)-2-methoxy-3-nitro-pyridine (0.38 g, 1.15 mmol) in acetic acid (4 ml) at 80° C. was added iron (0.32 g, 5.77 mmol) slowly in portions. The exothermic reaction was stirred for 3 h at 80° C. After evaporation of the solvent under reduced pressure the solid residue was dissolved in 1N NaOH, which was extracted 6 times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent evaporated to obtain 240 mg (68.9%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH:23][C:24](=[O:33])[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:20][O:21][CH3:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[OH-].[Na+:36]>C1COCC1>[Na+:36].[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[C:24]([NH:23][CH:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:20][O:21][CH3:22])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][CH:9]=1)[C:3]([O-:34])=[O:2])=[O:33]
Reactant: COCC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)[O-])cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-(tetrahydro-4-(methoxymethyl)-2H-pyran-4-yl)phenyl]pent-4-enoic acid methyl ester (86 mg) in THF (1.7 ml), 0.1N aqueous sodium hydroxide solution (1.7 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. After washing the reaction solution with ether, aqueous layer was concentrated to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(tetrahydro-4-(methoxymethyl)-2H-pyran-4-yl)phenyl]pent-4-enoic acid sodium salt (66 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=2[F:42])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-])=O)[N:18]=2)[CH:12]=[CH:11][C:10]=1[Br:43])([CH3:4])([CH3:3])[CH3:2]>[Fe].CO.C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH2:29])[N:18]=2)[C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=2[F:42])[CH:12]=[CH:11][C:10]=1[Br:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(F)c(C(Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ccccc3[N+](=O)[O-])c(=O)[nH]2)cc1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(F)c(C(Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ccccc3N)c(=O)[nH]2)cc1OC
Temperature: 60 °C
Yield: 66.3 %

Procedure:
Iron powder (231 mg) was added to [2-bromo-5-({(2-fluoro-4,5-dimethoxyphenyl)-[1-(2-nitrophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]methyl}amino)benzyl]carbamic acid t-butyl ester (232 mg) and a methanol:acetic acid:water (1:1:1) mixed solvent (24 mL), and the mixture was heated for 18 hours at 60° C. under a nitrogen atmosphere. The solvent in the mixture was distilled off under reduced pressure, and ethyl acetate (100 mL) and water (25 mL) were added to the residue. Sodium hydrogen carbonate was gradually added to the mixture to adjust the pH to 8. After sufficiently shaking the mixture, the organic layer was separated off and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (147 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:26])[CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=1
Reactant: O=C(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2,4-dichloroaniline (2.67 g, 0.0165 mol) in dichloromethane (20 ml) was slowly added a solution of 2-[3-(phenylmethoxy)phenyl]acetyl chloride (3.84 g, 0.015 mol) in dichloromethane (10 ml). After stirring for three hours, triethylamine (2 ml, 0.015 mol) was added to the reaction and the reaction was allowed to stir overnight. To the reaction was added an aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with ether and hexane, then filtered to provide the title compound (4.0 g, 70% yield): ES−MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc2nc(C)sc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc2nc(C)sc2c1

Procedure:
Next, a solution of (E)-3-(2-methyl-benzothiazol-6-yl)-acrylic acid methyl ester in ethyl acetate (10 mL) is hydrogenated over 10% Pd/C (22 mg, 10% w) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 2:1) to give 3-(2-methyl-benzothiazol-6-yl)-propionic acid methyl ester. MS 236.3 (M+1).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[F:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>C(O)C.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(F)cc3)cc2)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.0 g) and sodium hydroxide (205 mg) in 50% ethanol (12 ml)-DMF (20 ml) was added 4-(4-fluorobenzoyl)benzyl bromide (1.48 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.44 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.C(N(CC)CC)C.Cl[CH2:27][C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1.[Cl-].[Na+]>ClCCl>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([CH2:27][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)c1
Yield: 34.7 %

Procedure:
A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H),4'-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethane (100 ml) and 3-(chloromethyl)anisole (1.95 g) was stirred overnight at ambient temperature, under nitrogen. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flashed chromatographed (silica gel), eluting with 10% anhydrous acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.3 g (35%) of product, mp 100°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42](Cl)=[O:43])[CH:36]=[CH:35]2.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=1)=[O:43])[CH:36]=[CH:35]2
Reactant: O=C(Cl)c1ccc2cc(F)ccc2c1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Yield: 54.4 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (1.4 mL) were dissolved in dichloromethane (15 mL). In an ice bath, dichloromethane solution (10 mL) of the prepared 6-fluoro-2-naphthoyl chloride (about 1.2 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was removed under reduced pressure, and the resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 262 mg, at a total yield over two steps of reactions of 54.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of 2,6-dichloro-4-nitrobenzoic acid (1.53 g, 6.5 mmol), thionyl chloride (1.0 cm3, 13.7 mmol) and N,N-dimethylformamide (0.1 cm3) were heated under reflux for 1.5 h. The mixture was evaporated under reduced pressure to an oil which was purified by evaporative distillation yielding 2,6-dichloro-4-nitrobenzoyl chloride as a pale yellow oil (1.37 g, bp 140° C. at 0.2mm Hg) which solidified with cooling. (mp 63°-5° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH3:8])[N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4](=[O:5])[C:3]=1[NH2:15].I(C1C=CC=CC=1)=[O:17]>P([O-])([O-])([O-])=O>[CH3:8][N:7]1[C:2]([CH3:1])=[C:3]([NH:15][OH:17])[C:4](=[O:5])[N:6]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Ic1ccccc1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: O=P([O-])([O-])[O-]
Product: Cc1c(NO)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
4-Aminoantipyrine (0.12 mmol, Aldrich) and octachloro-octachloro tetrasulfonato Fe(III) porphyrin (0.6 μmol) were dissolved in 4 ml of pH 7 phosphate buffer and cooled to 0° C. To this was added iodosobenzene (66 mg, 0.3 mmol) was added in portions over 10 min. The reaction was stirred for 4 hr and extracted with 3×2 ml of methylene chloride and dried over Na2CO3. The organic layer was chromatographed over silica gel, eluting with methylene chloride, to yield 2,3-dimethyl-4-hydroxyamino-1-phenyl-3-pyrazolin-5-one (AP-3) in 30% yield.