Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][O:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[O:24][CH2:25][CH2:26][O:27][CH:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 13.0 g (35.7 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 200 ml dioxane were added 20.1 g (53.6 mmol) tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane, 616 mg (1.07 mmol) bis(dibenzylideneacetone)palladium, 1.33 g (5.71 mmol) trifurylphosphine and 7.46 ml (53.6 mmol) triethylamine. The mixture was heated at 100° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4-1/2 acetone/hexane) followed by trituration in ether afforded 5.20 g (45%) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester as a white solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: C(Cl)C=C.[S].[CH2:6]([CH:8]([CH2:11][CH3:12])[CH:9]=O)[CH3:7].CC(CC)C=O.[N:19]1[C:20](=[S:24])[N:21]=CC=1>>[CH3:9][CH:8]([C:11]1[CH:12]=[N:21][C:20](=[S:24])[N:19]=1)[CH2:6][CH3:7]
Reactant: S=C1N=CC=N1
Reactant: CCC(C=O)CC
Agent: CCC(C)C=O
Agent: [S]
Solvent: C=CCCl
Product: CCC(C)C1=NC(=S)N=C1
Yield: 61 %

Procedure:
Allyl chloride was used for protecting the sulfur before oxidation for all of these examples. Racemic 4-(2-butyl)imidazole-2-thione 7G was prepared from racemic 2-ethylbutanal by this approach. The synthesis was repeated with optically active 2-methylbutanal to show that an aldehyde with a chiral carbon adjacent to the carbonyl leads to an enantiomerically enriched imidazole-2-thione. The chiral aldehyde was obtained in 61% yield by oxidizing (S)-(−)-2-methyl-1-butanol with oxalyl chloride and DMSO at −50° C. The Strecker reaction followed by Dibal-H reduction gave desired diamine 18H in 21% yield for two steps. Treatment with 1,1′-thiocarbonyldiimidazole, protecting the sulfur with allyl chloride followed by Swern oxidation gave 21H in 56% yield for three steps. The desired imidazole-2-thione 7H was obtained in 40% yield by deprotecting 21H with p-toluenesulfinic acid in the presence of a catalytic amount of Pd(P Ph3)4. Hplc analysis showed an enantiomeric ratio of 98:2 indicating scant racemization through the several steps.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].Br.Br.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: N#CCCCCl
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 80 %

Procedure:
A mixture of 11 parts of 4-chlorobutanenitrile, 48.5 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 30 parts of sodium carbonate and 270 parts of DMF was stirred and heated overnight at 70° C. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 2.2 parts (80%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinebutanenitrile; mp. 130.5° C. (90).
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([C:18]([OH:20])=O)[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)([O-:7])=[O:6]>CN(C)C=O>[N+:5]([C:8]1[CH:9]=[C:10]([C:18]([Cl:3])=[O:20])[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cc2c1OCCO2
Yield: 100 %

Procedure:
112 ml of thionyl chloride, 56 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a thermometer and a reflux condenser. The mixture was stirred and 1 ml of dimethylformamide was added with heating. After stirring for one hour at the reflux temperature, the excess of thionyl chloride was removed by distillation under vacuum. 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 108° C.; yield: 100%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:14](Cl)(=[O:25])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:2][C:3]1[CH:4]=[C:5]([NH:6][C:14](=[O:25])[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
3-Methyl-5-(trifluoromethyl)aniline monohydrochloride (2.93 g) synthesized in reference to a known method (U.S. Pat. No. 4,532,353) was dissolved in THF (25 mL), and 4-nitrophenyl chlorocarbonate (3.07 g) and N,N-diisopropylethylamine (1.97 mL) were added dropwise at 5° C. The reaction mixture was stirred at 5° C. for 1 hr, poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure to give the title compound (4.66 g) as a white powder.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:20][CH:21]([S:23]([NH:26][C@@H:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:36](Cl)=[O:37])[CH:33]=2)[CH2:28]1)(=[O:25])=[O:24])[CH3:22].O>C(Cl)Cl>[CH3:22][CH:21]([S:23]([NH:26][C@@H:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:36]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[O:37])[CH:33]=2)[CH2:28]1)(=[O:25])=[O:24])[CH3:20]
Reactant: CS(=O)(=O)Nc1ccccc1N
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(C(=O)Cl)cc2C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(C(=O)Nc3ccccc3NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of triethylamine (0.083 mmol, 0.012 mL, 8.38 mg) and N-(2-aminophenyl)methanesulfonamide (0.083 mmol, 15.43 mg) in DCM (2 mL) was added to a solution of (S)-2-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carbonyl chloride (0.083 mmol, 25 mg) in DCM (1 mL) was added. The reaction mixture was stirred at room temp overnight. H2O was added and the reaction mixture filtered through a hydrophobic frit and the DCM layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give desired product (10.7 mg, 28.6%). MS (ESI): m/z [M−H]− 450.2
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:16])([CH3:15])[CH2:9]OS(C)(=O)=O)[C:5]([F:17])=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.C(OCC)(=O)C>[N:20]([CH2:9][C:8]([C:6]1[C:5]([F:17])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([OH:16])[CH3:15])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)(COS(C)(=O)=O)c1nc(Br)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(O)(CN=[N+]=[N-])c1nc(Br)ccc1F
Temperature: 80 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A mixture of methanesulfonic acid 2-(6-bromo-3-fluoro-pyridin-2-yl)-2-hydroxy-propyl ester (5 g, 15.24 mmol), ammonium chloride (4.08 g, 76 mmol) and sodium azide (2.476 g, 38.1 mmol) in ethanol (100 ml) was stirred at 80° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. 3.1 g (74% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.35; LCMS RtH5=0.97 min. (ES+ 275, 277); 1H-NMR (360 MHz, CDCl3): 7.51 (dd, 1H), 7.36 (dd, 1H), 5.18 (s broad, 1H, OH), 3.68-3.60 (AB system, 2H), 1.59 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)=[O:6])([CH3:4])[CH3:3].[F-].[Cs+].C[Si]([C:20]#[N:21])(C)C>C1COCC1>[C:20]([CH:8]([C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])#[N:21]
Reactant: CC1(/C=N/S(=O)C(C)(C)C)COC1
Reactant: C[Si](C)(C)C#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(C#N)NS(=O)C(C)(C)C)COC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a solution of (NE)-2-methyl-N-[(3-methyloxetan-3-yl)methylene]propane-2-sulfinamide (CAN 1450658-44-2, 1.3 g, 6.39 mmole) in dry THF (35 ml) under argon atmosphere was added cesium fluoride (1.17 g, 7.67 mmol) followed by trimethylsilyl cyanide (761 mg, 1.03 ml, 7.67 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo followed by dilution with ethylacetate. The organic phase was extracted with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.21 g, 82%). MS (ESI, m/z): 231.6 (M+H+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:38])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:39][S:40](O)(=[O:42])=[O:41]>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:38])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:40]([Cl:39])(=[O:42])=[O:41])=[CH:18][C:17]=2[O:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[O:25])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(COc1ccccc1OCC(=O)OCCS(=O)(=O)c1ccccc1)OCCS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(COc1ccc(S(=O)(=O)Cl)cc1OCC(=O)OCCS(=O)(=O)c1ccccc1)OCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
To a solution of [2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)phenoxy]acetic acid 2-benzenesulfonyl-ethyl ester (Intermediate 28, 7.4 g, 13.2 mmol) in 10 mL of CH2Cl2 was added drop-wise ClSO3H (5.0 mL, 8.8 g, 75.8 mmol, 5.7 eq) at 0° C. with vigorous stirring. The mixture was stirred at 0° C. for 1.5 h. and then poured onto crushed ice with vigorous stirring, resulting in a thick mass. This was extracted with CH2Cl2. The organic layers were dried and concentrated under reduced pressure. The residual oil was dried under vacuum overnight to give Intermediate 29 (8.0 g, 92%) as an off-white foam.
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1[CH2:10][CH2:11]2)=[O:7])(C)(C)C.Cl.[CH3:28][O:29][C:30]([NH:32][CH:33]([CH:37]([CH3:39])[CH3:38])C(O)=O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.O1CCOCC1>[CH3:28][O:29][C:30](=[O:31])[NH:32][CH:33]([C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1[CH2:10][CH2:11]2)=[O:7])[CH:37]([CH3:39])[CH3:38]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 2.4 mmol) in methanol (20 mL) was added 4.0 M solution of HCl in dioxane (4.0 mL, excess). The mixture was stirred for 3 hours at 50° C. and concentrated under reduced pressure. The residue was treated with ether to remove excess HCl. The obtained white solid was dissoved in DMF (20 mL). To the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (0.46 g, 2.6 mmol), HATU (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.4 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with 1 N NaOH solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (1.0 g, 89%). m/z 475.1, 477.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:9][C:10]1[C:14]([C:15](=[O:17])[NH2:16])=[CH:13][N:12]([C:18]2([CH2:32][C:33]#[N:34])[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[CH2:20][CH2:19]2)[N:11]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:14]1[C:10]([NH:9][C:2]2[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[N:11][N:12]([C:18]2([CH2:32][C:33]#[N:34])[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1)(=[O:17])[NH2:16]
Reactant: Clc1ccc(Br)cn1
Reactant: N#CCC1(n2cc(C(N)=O)c(N)n2)CCN(C(=O)OCC(F)(F)F)CC1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(Cl)nc3)n2)CCN(C(=O)OCC(F)(F)F)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-chloropyridine (206 mg, 1.07 mmol), 2,2,2-trifluoroethyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (400 mg, 1.07 mmol), Pd2(dba)3 (98 mg, 0.11 mmol), 2-di-t-butylphosphino-3,4,5,6-teramethyl-2′,4′,6′-triisopropylbiphenyl (154 mg, 0.321 mmol), and potassium phosphate (454 mg, 2.14 mmol) were combined in a 40 mL vial and dissolved in 1,4-dioxane (5.3 mL). The vial was capped, flushed with argon, and stirred at 90° C. for 2 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH/DCM) to afford 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-((6-chloropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH2:14]([O:16][CH2:17][CH2:18][NH2:19])[CH3:15].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>Cl.C(#N)C>[CH2:14]([O:16][CH2:17][CH2:18][NH:19][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1)[CH3:15]
Reactant: CCOCCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CCOCCNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 19 h

Procedure:
3-Fluoro-4-nitrobenzoic acid 5.55 g, 2-ethoxyethylamine 3.15 mL, N,N-diisopropylethylamine 5.23 mL, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride 8.63 g, 1-hydroxybenzotriazole monohydrate 5.96 g and acetonitrile 77 mL were mixed and stirred for 19 hours. The reaction liquid was poured in diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, saturated aqueous sodium hydrogencarbonate solution and saturated brine, by the order stated, and dried over magnesium sulfate. Distilling the solvent off, 6.86 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:11]=[C:10](I)[CH:9]=[C:8]2[C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Ba+2].[OH-].COCCOC>CCOC(C)=O.O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=[C:8]2[C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(I)cn1Cc1ccc(F)cc1
Reactant: OB(O)c1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)c1cc(-c2ccccc2)cn1Cc1ccc(F)cc1
Temperature: 20 °C

Procedure:
To a 100 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 1-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2-yl]ethanone AIII-1-1 (1.00 g, 2.91 mmol), phenylboronic acid (0.431 g, 3.54 mmol), tetrakis(triphenylphosphine)palladiumo (0.20 g, 0.17 mmol), barium hydroxide (1.37 g, 4.37 mmol), DME (40 mL), and H2O (5 mL). This well stirred mixture was heated at reflux 4 h. The reaction mixture was cooled to 20° C. and diluted with EtOAc. This solution was washed with H2O, 1N HCl, H2O, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an amorphous material. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-[1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-1-1 as an oil. 1H NMR (CDCl3) δ 2.47 (3H, s), 5.57 (2H, s), 6.98 (2H, m), 7.13 to 7.28 (5H, complex multiplet), 7.36 (2H, m), 7.51 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:10][C:11]3[C:12]4[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30]([O:32][CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:31].CO>C(OCC)(=O)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][CH:33]([N:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[C:22]([CH3:23])=[CH:21][C:5]=2[N:6]([CH2:10][C:11]2[C:12]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=3[S:14][CH:15]=2)[C:7]1=[O:9])[O:32][CH2:30][CH3:31])[CH3:39]
Reactant: CCOC=CC(=O)OCC
Reactant: Cc1cc2[nH]c(=O)n(Cc3csc4cccc(C)c34)c2cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC(OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 130 °C
Yield: 31.1 %

Procedure:
To a mixture of 5,6-Dimethyl-1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol) and K2CO3 (86 mg, 0.62 mmol) in a microwave vial was added Ethyl 3-ethoxyacrylate (0.45 g, 3.1 mmol). The reaction mixture was heated to 130° C. for 20 min in a microwave. The reaction mixture was then diluted with ethyl acetate (since there was some insoluble material left, MeOH was added to the solution mixture to solubilize the material). This organic phase was washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 45 mg of the desired product as an oily foam. LCMS (ESMS): m/z 467.32 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH:19](OCC)=[O:20].P([O-])([O-])([O-])=O.P([O-])(O)(O)=O.[K+]>C1COCC1.C(#N)C>[CH:19]([CH:13]([CH2:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20]
Reactant: CCOC(=O)CCc1ccc2c(c1)OCO2
Reactant: CCOC=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
First 2.0 g of 606 NaH was suspended in 30 ml of THF and the suspension solution was cooled to 0° C. Then, 6.0 g of ethyl 3-(3,4-methylenedioxyphenyl)-propionate (purity: 92.1% by weight) was dissolved in 20 ml of THF and added dropwise to the suspension solution prepared above. After 4 ml of ethyl formate was added at 0° C., the solution was returned to room temperature and stirred for a further 20 minutes. The reaction solution was heated to 40° C. and stirring was further continued. About 30 minutes after heating, gas generation was observed. After completion of gas generation, the reaction solution was analyzed by HPLC (Column: LiChrosphere 100 PR-8(E), 250 mm×4.0 mm I.D., manufactured by Merck Ltd., Mobile phase: an aqueous solution of phosphate/potassium dihydrogenphosphate: acetonitrile=1:1, flow rate: 1 ml/minute, detection wavelength: 210 nm, column temperature: 30° C.), it was observed that raw materials remained. Then, 1 g of NaH and 4 ml of ethyl formate were added to the reaction solution and stirred at 40° C. Gas generation started again and completed in about 15 minutes. As the reaction solution was analyzed again, the raw materials were observed to still remain. Then, 1 g of NaH and 4 ml of ethyl formate were added to the reaction solution. After completion of gas generation, the reaction solution was analyzed again. Since the raw materials were observed to slightly remain, further 1 g of NaH and 8 ml of ethyl formate were added to the reaction solution. Since the raw materials were observed to completely disappear, the reaction was terminated. After pH was adjusted to 7 to 8 with hydrochloric acid, ethyl acetate was added to perform extraction. Mineral oil contained in NaH was removed by a separatory funnel in accordance with a liquid-separatory operation. The obtained ethyl acetate layer was concentrated to obtain 4.75 g of the titled compound as an orange oil. The chemical purity, as analyzed in accordance with the process of Example 1, was 80.20% by weight.
Reaction SMILES: N1C(C)=CC=CC=1C.[F:9][C:10]([F:23])([F:22])[S:11]([O:14]S(C(F)(F)F)(=O)=O)(=[O:13])=[O:12].[Cl:24][C:25]1[CH:33]=[C:29]([C:30]([OH:32])=[O:31])[C:28](O)=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([N+:35]([O-:37])=[O:36])[C:28]([O:14][S:11]([C:10]([F:23])([F:22])[F:9])(=[O:13])=[O:12])=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Yield: 95.2 %

Procedure:
2,6-Lutidine (1.83 ml, 15.7 mmol) and trifluoro-methanesulfonic anhydride (3.67 g, 13 mmol) were added dropwise in turn to a solution of methyl ester of 5-chloro-3-nitrosalicylic acid (2.32 g, 10.0 mmol) in methylene chloride (25 ml) with stirring under ice cooling and the mixture was stirred under ice cooling for 0.5 hrs. Methylene chloride (20 ml) and ice water (30 ml) were added to the reaction mixture and the aqueous layer was separated and extracted with methylene chloride. The organic layers were combined, washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10) to give methyl ester of 5-chloro-2-trifluoromethanesulfonyloxy-3-nitrobenzoic acid (3.33 g, 91%) as a pale yellow oil.