Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[F:11][C:12]1[CH:13]=[C:14]([C@H:19]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:20][C:21]([N:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:24]2=[O:34])=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=1.CC(C1C=C(C(C)C)C(S([N:57]=[N+:58]=[N-:59])(=O)=O)=C(C(C)C)C=1)C.CC(O)=O>C1COCC1.C([O-])(=O)C.C[N+](C)(C)C>[N:57]([C@@H:20]([C@H:19]([C:14]1[CH:15]=[C:16]([F:18])[CH:17]=[C:12]([F:11])[CH:13]=1)[C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:21]([N:23]1[C@@H:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][O:25][C:24]1=[O:34])=[O:22])=[N+:58]=[N-:59]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C(C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1)N1C(=O)OC[C@@H]1c1ccccc1
Agent: CC(=O)[O-]
Agent: C[N+](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Reaction time: 0.03 h

Procedure:
10 mL of THF under an atmosphere of nitrogen was cooled to −78° C. in a dry ice-acetone bath and to the stirred solution was added sodium hexamethyldisilazide (9.1 mL of a 1.0 M solution in THF, 9.1 mmol). A solution of (4S)-3-[(3S)-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoyl]-4-phenyl-1,3-oxazolidin-2-one (3.5 g, 8.2 mmol) in 20 mL of THF under nitrogen atmosphere was cooled to −78° C. in a dry ice-acetone bath and added via cannula to the cold sodium hexamethyldisilazide solution. The resulting mixture was stirred at −78° C. for 30 min when trisyl azide (3.3 g, 11 mmol) was added as a solid. The solids dissolved and the cold solution was stirred for 2 min. To the cold solution was added HOAc (2.8 mL, 49 mmol) and solid tetramethylammonium acetate (4.4 g, 33 mmol). The cooling bath was removed and the mixture was stirred at ambient temperature for 4 h. The reaction was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc, and the combined EtOAc layers were washed with aqueous Na HCO3 and brine, then dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 120 g SiO2 column using a gradient elution of 0-40% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[CH2:32]([N:35]([CH2:49][CH2:50][CH3:51])[C:36]([C:38]1[CH:39]=[C:40](C=C(CC)C=1)[C:41](O)=[O:42])=[O:37])[CH2:33][CH3:34]>>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([F:30])[CH:27]=1)[CH2:23][C@H:9]([NH:8][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][C:36]([N:35]([CH2:32][CH2:33][CH3:34])[CH2:49][CH2:50][CH3:51])=[O:37])[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)CCCC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(OC)c1

Procedure:
Following the general procedure of EXAMPLEs 6 and making non-critical variations and using (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 5) with 5-(dipropylamino)-5-oxopentanoic acid (IX), the title compound is obtained, MH+=534.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.FC(F)(F)C(O)=O>C(OCC)(=O)C>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(C2CCCNCC2)cc1
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a vial containing tert-butyl 4-(4-cyanophenyl)azepane-1-carboxylate (compound 40.3, 77 mg, 0.257 mmol, 1.0 equiv) was added DCM (500 μL) and trifluoroacetic acid (198 μL, 2.57 mmol, 10 equiv) and the mixture was stirred vented for 90 min. The mixture was diluted into ethyl acetate (5 mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous was adjusted to pH 10-11 and extracted with addition ethyl acetate until no product remained. The combined organics were dried (Na2SO4), filtered and concentrated to obtain the title compound as a yellow oil (51 mg, theoretical). m/z (ES+) 201 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[S:5][CH:6]=[C:7]([C@@H:9]2[CH2:13][C@@H:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[N:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:3]([C:4]1[S:5][CH:6]=[C:7]([C@@H:9]2[CH2:13][C@@H:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[N:8]=1)=[O:2]
Reactant: COC(OC)c1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(C=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 95.7 %

Procedure:
To a solution of (2S, 4R)-2-[2-(dimethoxymethyl)-thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (2.6 g) in acetone (100 ml) was added p-toluenesulfonic acid (0.49 g) at room temperature. After stirring under reflux for 1 hour, the mixture was evaporated. The residue was dissolved in ethyl acetate, washed in turn with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The organic layer was evaporated to give (2S,4R)-2-(2-formylthiazol-4-yl) -4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (2.26 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:14][CH:11]1[CH2:10][C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: COC(=O)c1cc2c(s1)CC(C)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCc2cc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 704 mg of 6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (obtained in step b) in a mixture of THF (5ml) and methanol (2 ml) were added 8.37 ml of 1N LiOH and the reaction mixture was stirred at RT for 16 h. Then the pH was adjusted to 2 by addition of 2N HCl and the suspension was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The remaining residue was then purified by crystallization from hot dichloromethane to give 574 mg (87%) of 6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid as brown solid. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.CN(C)C=O>[CH2:12]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CCCC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: OC1CCCC(COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
50% Sodium hydride (5.77 g; 120 mmol) is washed with n-hexane, and dimethylformamide (50 ml) is added thereto. To the resultant mixture, 3-hydroxymethylcyclohexanol (9) (10.0 g; 76.8 mmol) is dropwise added under ice-cooling, and then benzyl bromide (13.15 g; 76.8 mmol) is dropwise added thereto under ice-cooling. The resulting mixture is stirred at a temperature of 0° to 10° C. for 5 hours. The reaction mixture is poured into ice-water, extracted with toluene. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanol (10) (9.55 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C[Si](C#N)(C)C.[C:22](=O)([OH:24])[O-:23].[Na+]>ClCCl.[I-].[Zn+2].[I-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[C:22]([OH:24])=[O:23])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C(O)(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
Zinc iodide (0.5 g) was added to a stirring solution of 4-bromobenzophenone (54.81 g, 0.21 mol) in dry dichloromethane (500 ml) at room temperature under N2 atmosphere. Trimethylsilyl cyanide (25 g, 0.25 mol) was added dropwise from an addition flask over a period of 1 hour and the mixture stirred at room temperature for 72 hours. The reaction mixture was treated with saturated sodium bicarbonate (200 ml) and stirred for 1 hour. The organic layer was separated, washed with water (2×150 ml) and concentrated. The residue was suspended in H2O:HCl:AcOH (1:33; 500 ml) and heated at 85°-90° C. for 48 hours. The solution was concentrated under vacuum to about 100 ml and treated with saturated sodium bicarbonate (400 ml) and extracted with ether (3×100 ml). The aqueous layer was acidified with 6N hydrochloric acid and the separated solid was dissolved in ether (300 ml). This organic layer was washed with water, filtered and the filtrate was evaporated to provide a colorless crystalline solid of (RS)-4-bromobenzilic acid in 19% yield (12 g); mp 125°-126° C.; TLC [silica gel, toluene-acetic acid] Rf 0.32; 1H NMR (DMSO-d6) δ2.38 (bs, 2H, COOH and OH) and 7.38-7.70 (m, 9H, AR-H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CCN(C(C)C)C(C)C>>[CH3:37][S:38]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)[CH2:15][CH2:16]1)(=[O:40])=[O:39]
Reactant: CC1CCN(c2cc(N3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1CCN(c2cc(N3CCN(S(C)(=O)=O)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 90.5 %

Procedure:
The procedure of Example 17 was followed using 40.0 mg (0.0546 mmol) of 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide tris(trifluoroacetic acid salt) (as prepared in Example 16), 7.6 μL (0.0655 mmol) of is methanesulfonyl chloride and 47.6 μL (0.716 mmol) of DIEA. Chromatography on a 2-g silica SPE column with 5-10% EtOAc-dichloromethane followed by concentration from EtOAc-hexane (1:1, 2 mL) afforded 23.3 mg (91%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.59 (br s, 1H), 8.33 (d, 1H, J=8.8 Hz), 7.22, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl3 peak), 6.79 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.8, 2.7 Hz), 3.39-3.41 (m, 4H), 3.25-3.27 (m, 4H), 2.98-3.01 (m, 2H), 2.84 (s, 3H), 2.70-2.76 (m, 2H), 1.83-1.87 (m, 2H), 1.50-1.65 (m, 1H), 1.42-1.58 (m, 2H) and 1.08 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C23H29N5O4S, 472.2 (M+H), found 472.2.
Reaction SMILES: Br[CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:20].[Na+]>CC(C)=O>[I:20][CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [I-]
Reactant: CCOC(=O)C(Br)c1ccc2cc(OC)ccc2c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 0.1 moles of ethyl α-bromo-6-methoxy-2-naphthylacetate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-6-methoxy-2-naphthylacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16]OS(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:16][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (560 mg) was reacted with imidazole to obtain the desired (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide (152.3 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:4]([CH3:18])[C:3]=1[CH3:19].O>C1(C)C(C)=CC=CC=1>[CH3:19][C:3]1[C:2]([OH:1])=[CH:17][C:16]2[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][O:6][C:5]=2[C:4]=1[CH3:18]
Reactant: Cc1c(O)ccc(OCC(=O)c2ccccc2)c1C
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1c(O)cc2c(-c3ccccc3)coc2c1C
Temperature: 150 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 2-(4-hydroxy-2,3-dimethyl-phenoxy)-1-phenyl-ethanone (1.2 g, 4.70 mmol) and polyphosphoric acid (ca. 100 mg) in xylene (10 mL) was stirred at 150° C. for 5 h. The mixture was poured into water, extracted with ethylacetate, washed and dried to give 6,7-dimethyl-3-phenyl-benzofuran-5-ol (560 mg) as a light brown solid. 1H NMR (CDCl3, 300 MHz) δ: 7.71 (s, 1H), 7.60-7.20 (m, 5H), 7.06 (s, 1H), 4.76 (s, 1H, OH), 2.47, 2.29 (2s, 6H) ppm. 13C NMR (CDCl3, 75 MHz), δ: 150.43, 150.30, 141.15, 132.58, 129.00, 127.32, 123.48, 122.13, 121.31, 120.59, 102.25, 12.31, 11.95 ppm. MS (m/z): 239 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:13]([F:12])([F:21])[F:22])=[CH:15][CH:16]=1)=[O:9]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(Cl)ccc1O
Yield: 75 %

Procedure:
Using 5-chlorosalicylic acid and 4-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[C:4]1=[O:9])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: O=c1[nH]cccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cccc(CO)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 3-hydroxymethyl-2(1H)-pyridone (7-008-01) (0.63 g) in DMF (15 mL), and to the reaction mixture were added potassium carbonate (1.4 g) and 1-iodobutane (1.86 g). After stirring at 70° C. for 2 h, the solvent was removed. To the residue were added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was separated, and then the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by column chromatography (toluene/ethyl acetone=2/1) to give 1-butyl-3-hydroxymethyl-2-pyridone (7-008-02) (0.56 g, 61%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11](O)[CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.P(Br)(Br)([Br:16])=O.O.C(Cl)Cl>ClCCCl>[Br:16][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccnc(-c2ccncc2)n1
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Brc1ccnc(-c2ccncc2)n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
2-Pyridin-4-yl-pyrimidin-4-ol (200 mg, 1.16 mmol) was suspended in DCE (10 mL) then POBr3 (497 mg, 1.73 mmol) was added in one portion. The reaction mixture was heated to 95° C. (bath) for 18 h then cooled to 20° C. H2O (30 mL) and CH2Cl2 (30 mL) were added, then the biphasic mixture was stirred vigorously for 30 min. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organics were evaporated to dryness to afford the title compound: m/z (ES+)=236, 238 (1:1) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([NH:8][CH3:9])[CH:7]=1.[Sn](Cl)Cl.[CH:16](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][N:8]([CH3:16])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Sn]Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1cnc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a suspension of (5-bromo-2-nitro-phenyl)-methyl-amine (1.2 g, 5.19 mmol) in ethanol (25 mL) was added tin(II) chloride (1.97 g, 10.39 mmol). The reaction mixture was stirred at 80° C. for 4 h, then it was concentrated in vacuo. To the residue was added toluene (12 mL), trimethyl orthoformate (0.625 mL, 5.71 mmol), and para-toluenesulfonic acid (49 mg, 0.26 mmol). The reaction mixture was stirred at 110° C. for 15 h, then it was concentrated in vacuo and the residue was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 482 mg of 6-bromo-1-methyl-1H-benzoimidazole as a dark orange solid (44% yield): 1H NMR (DMSO-d6) δ 3.83 (s, 3H), 7.33 (dd, 1H), 7.59 (d, 1H), 7.86 (d, 1H), 8.21 (s, 1H); MS (m/z) 211, 213 [M+H+]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:12][CH:13]=[CH2:14])[CH2:9]C=C)[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH:14]=[CH:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: C=CCC(CC=C)c1ccc(OC)c(Br)c1
Solvent: ClCCl
Product: COc1ccc(C2CC=CC2)cc1Br
Temperature: 45 °C
Yield: 105.6 %

Procedure:
To a solution of 2-bromo-4-(hepta-1,6-dien-4-yl)-1-methoxybenzene (2.0 g, 7.11 mmol) in DCM (36 mL) was added Zhan catalyst (47 mg). The mixture was flushed with N2 and refluxed at 45° C. overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography, eluting with 10% of EtOAc/isohexane to give 2-bromo-4-(cyclopent-3-en-1-yl)-1-methoxybenzene (1.9 g) as a colorless oil. 1H NMR (500 MHz, CDCl3:) δ 7.46 (s, 1H), 7.18 (d, 1H), 6.83 (d, 1H), 5.80 (s, 2H), 3.91 (s, 3H), 3.40 (m, 1H), 2.81 (m, 2H), 2.40 (m, 2H).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][C:7]([CH2:10][NH:11][C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH3:21])[C:15]=2[Cl:22])=[O:13])=[CH:8][N:9]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH:1]([S:4]([C:5]1[S:6][C:7]([CH2:10][NH:11][C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH3:21])[C:15]=2[Cl:22])=[O:13])=[CH:8][N:9]=1)=[O:31])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nn(C)c(C(=O)NCc2cnc(SC(C)C)s2)c1Cl
Solvent: ClC(Cl)Cl
Product: CCc1nn(C)c(C(=O)NCc2cnc(S(=O)C(C)C)s2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
0.65 g of N[2-(isopropylthio)thiazol-5-ylmethyl]-4-chloro-3-ethyl-1-methylpyrazole-5-carboxamide was dissolved in 20 ml of chloroform, to which was added little by little 0.40 g of metachloroperbenzoic acid, and the mixture was stirred at room temperature overnight. The resultant solution was washed with saturated aqueous sodium hydrogencarbonate, then with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica-gel chromatography (developing solvent: ethyl acetate/hexane=2/1) to obtain 0.46 g of the titled compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH:17]([CH3:19])[O:16][N:15]=2)=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH:17]([CH3:19])[O:16][N:15]=2)=[C:12]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)C2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)=NO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3.52 g (88 mmol) of sodium hydroxide, dissolved in 100 ml of methanol, was slowly added dropwise to a mixture of 15.00 g (45 mmol) of methyl 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate and 200 ml of methanol. The suspension was stirred for 48 hours at room temperature. After the solvent had been distilled off, the residue was taken up in water, and the aqueous phase was washed three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were subsequently washed to neutrality with water, dried and concentrated. This gave 13.20 g (92% of theory) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:20]=1[CH3:30])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:30])[C:21]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(C)c1CCC(=O)O

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (43 mg, 0.23 mmol) to give the title compound.