Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([O:15]CC)=[O:14])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12](=[O:18])[C:13]([OH:15])=[O:14])[CH3:11]
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of ethyl (2,6-diethyl-4-methylphenyl)glyoxylate (320.82 g) in tetrahydrofuran (600 ml) was added 10.7 weight % of aqueous sodium hydroxide solution (900 ml) dropwise at 10° C. of the internal temperature over 2 hours. The resulting mixture was stirred at room temperature for 1 hour. Then, the organic layer was evaporated, and the aqueous layer was washed with tert-butyl methyl ether. To the aqueous layer was added concentrated hydrochloric acid (180 ml) dropwise, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 166.55 g of (2,6-diethyl-4-methylphenyl)glyoxylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C(=O)(O)[O-].[Na+]>O.O1CCCC1.[Cl-].[Na+].O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21](=[O:22])[CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:24][CH:25]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C2CCN(CC(=O)c3ccc(F)cc3)CC2)cc1

Procedure:
To a solution of 3.0 g (12.2 mmol) of N-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide in 10 ml of water and 100 ml of tetrahydrofuran was added 2.3 g (13.4 mmol) of 2-chloro-4'-fluoro-acetophenone followed by 2.0 g (24.4 mmol) of sodium bicarbonate. This mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 500 ml of brine and extracted with chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield a solid which was recrystallized from 2-butanone/cyclohexane. 1-(4-Fluorophenyl)-2-[4-[(4acetamidophenyl)carbonyl]-1-piperidinyl]-ethanone was obtained as an off-white solid having amp of 168°-170° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=2[CH:17]=1)C=C.CN1C[CH2:22][CH2:21][C:20]1=O>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=2[C:17]=1[CH2:22][CH:21]=[CH2:20]
Reactant: C=CCOc1ccc2oc(C(=O)OC)cc2c1
Reactant: CN1CCCC1=O
Product: C=CCc1c(O)ccc2oc(C(=O)OC)cc12

Procedure:
A mixture of methyl 5-hydroxybenzofuran-2-carboxylate (4.14 g), potassium carbonate (5.95 g) and allyl bromide (3.73 ml) in dry acetone (100 ml) was refluxed and stirred for 16 hours. The solvent was evaporated and the residue was partitioned between water and ether. The ether was washed with water, dried and evaporated to give methyl 5-(prop-2-enyloxy)benzofuran-2-carboxylate (4.7 g) as a solid, characterised by NMR and mass spectral data. This ester (3.74 g) in N-methylpyrrolidinone (30 ml) was refluxed under nitrogen for 2 hr, cooled, and partitioned between water and ethyl acetate. The organic phase was washed with water, dried and evaporated to give the title ester (3.5 g), mp 114°-119°.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[Li]CCCC.CN([CH:23]=[O:24])C.O>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COCOc1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To the solution of 4-(trifluoromethyl)phenyl methoxymethyl ether (5 g) in anhydrous ether (50 ml) was gradually added dropwise 1.6M n-BuLi (16.7 ml) at room temperature. After stirring at room temperature for 2 hours, the solution of DMF (4.13 ml) in anhydrous ether (20 ml) was added dropwise over 30 minutes, and the solution was stirred for 1 hour. To the reaction solution was added water, and the ether layer was separated. The ether layer is was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (methylene chloride:hexane=1:1), to give the title compound (4.49 g; 79%).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].C(=O)(O)[O-].[Na+]>C(O)C.O.O1CCCC1>[OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=[N:16][OH:17]
Reactant: NO
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)c(O)c(C=NO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 157 %

Procedure:
A mixture of 12.86 g (50.0 mmol) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)benzaldehyde (see L. C. Felton and J. H. Brewer, Science, 105:409 (1947) as an example of how to obtain this material) and 3.82 g (55.0 mmol) of hydroxylamine hydrochloride in 30 ml of ethanol, 30 ml of water and 30 ml of tetrahydrofuran was cooled in an ice-water bath. Sodium bicarbonate (5.04 g, 60.0 mmol) was added in small portions over 15 minutes. After stirring for 1 hour at ambient temperature, water (200 ml) was added and the solid was filtered and dried. There was obtained 13.2 g (78.5 mmol, 97%) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)benzaldehyde oxime as a white solid; mp 167.5°-168° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([CH:4]1[CH:3]=[C:2]([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1=CCC(=O)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=CC(Cc2ccccc2)C(=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of the above (18) (6.1 g) in dry THF (100 mL) at -78° C. was added a solution of lithium bis-trimethylsilylamide (50 ml, 1N in THF). The solution was stirred for 20 min then benzylbromide (30 mL) was added in one portion. The reaction was stirred for 6 h at -78° C. then allowed to slowly warm to room temperature. After evaporation of the solvent, the remaining mixture was taken up in hexane, washed with saturated NaCl, dried over MgSO4 and evaporated. The product (19) was obtained by flash chromatography on silica gel eluted with 2.5% ethyl acetate in hexane. (4.15 g, 39%): GC RT 7.29 min. (HP 530 mμ×20 m methylsilicone column, He carrier flow rate 20 mL/min., 100° C., 1 min. , 100°-180° C. 10° C./min.; TLC Rf 0.31 (5% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.73(3H, br s), 2.2-3.3(7H, m), 5.35(1H, br s), 7.28(5H, m).
Reaction SMILES: N1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21][C:22]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[O:23])=[N:18][C:17]=3[CH3:29])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])C=CN=C1.[F:30]C1C=C(C2SC(N)=NC=2C)C=CC=1S(C)(=O)=O>>[F:30][C:6]1[CH:7]=[C:8]([C:16]2[S:20][C:19]([NH:21][C:22]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[O:23])=[N:18][C:17]=2[CH3:29])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
The title compound is prepared by the same procedure as imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Example 150a) by replacing 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) with 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21](OC)=[CH:20][C:19]2=[O:25])=[CH:4][CH:3]=1>CN(C)CCN.Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:9][CH2:8][CH2:16][N:11]([CH3:12])[CH3:10])=[CH:20][C:19]2=[O:25])=[CH:4][CH:3]=1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Agent: CN(C)CCN
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Temperature: 140 °C

Procedure:
To a mixture of 100 mg of 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one (0.251 mmol, 1 eq) in 1 mL of N,N-dimethylethane-1,2-diamine in a sealed tube, one drop of HCl was added. The solution was heated at 140° C., O/N. The mixture was then diluted with EtOAc, washed with an excess of NaHCO3 (aq, sat), dried on MgSO4, filtered and concentrated. The crude was purified on silica gel chromatography (MeOH:NH4OH (95:5)/EtOAc, 0 to 15%). The product was then washed with ether to give a white solid. (37 mg, 32%) m/e+=410 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.51 (d, 1H, D, J=6.6 Hz), 7.72 (d, 2H, D, J=8.6 Hz), 7.61 (d, 1H, D, J=9.2 Hz), 7.45 (d, 2H, D, J=8.4 Hz), 7.24 (t, 1H, D, J=8.8 Hz), 6.85 (t, 1H, D, J=6.4 Hz), 5.06 (s, 2H), 4.89 (m, 1H), 4.67 (s, 1H), 3.56 (s, 2H), 2.99 (m, 2H), 2.42 (m, 2H), 2.15 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.C(#N)C.[Br:22]N1C(=O)CCC1=O>>[Br:22][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)=[CH:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: CC#N
Product: C[C@@]1(c2ccc3c(Br)c(O)ccc3c2)COC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 5.05 g, 20.8 mmol) was suspended in acetonitrile (50 mL, 1000 mmol) in a capped 200 mL round-bottom flask equipped with a magnetic stir bar. The mixture was cooled to 0° C. and N-bromosuccinimide (3.88 g, 21.8 mmol) was added. The reaction mixture was stirred for 1 hour. HPLC analysis indicated that the reaction was complete. The mixture was filtered. The residue was rinsed with acetonitrile, air dried under vacuum and collected (5.54 g). The crude product required no purification (82% yield).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]([O:15]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCCC1.C>[O:1]=[C:2]1[N:6]([C:12]([Cl:11])=[O:15])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)n1c(=O)[nH]c2ccccc21
Yield: 257 %

Procedure:
To a 1 L, 3-neck round bottom flask fitted with a thermometer, condenser, and an addition funnel was placed 2-hydroxybenzimidazole (36.9 g, 275 mmol), 275 mg of activated charcoal, and 750 mL of dry tetrahydrofuran. The bis(trichloromethyl)carbonate (36.3 g, 122 mmol), dissolved in 100 mL of tetrahydrofuran, was added dropwise at room temperature. The addition funnel was replaced with a gas outlet tube that was dipped into an aqueous concentrated ammonium hydroxide trap. The mixture was heated at reflux for about 18 hours. The solids which formed were filtered and the filtrate was evaporated under reduced pressure to give 61.64 g of a white solid which was used in subsequent reactions without further purification. Yield: >100%.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[Cl:29][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClC(Cl)Cl
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step B is dissolved in chloroform and cooled to 0° C. under nitrogen. Thionyl chloride (molar equivalent) is added slowly via syringe. The reaction is stirred for 30 min, and extracted with sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@H:18]1[CH2:23][C@@H:22]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:21](=[O:35])[C@@H:20]([CH3:36])[CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](O)[CH2:38][OH:39].B(F)(F)F.CCOCC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@@H:18]1[CH2:19][C@H:20]([CH3:36])[C:21]2([O:39][CH2:38][CH2:37][O:35]2)[C@H:22]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OCc2ccccc2)C1=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OCc2ccccc2)C12OCCO2
Temperature: 100 °C
Yield: 100 %

Procedure:
(+/−)-Benzyl ((1R,3S,5R)-5-(3-((benzoxycarbonyl)amino) pyridin-4-yl)-3-methyl-2-oxocyclohexyl)carbamate (1.0 equiv.) was dissolved in dry THF (0.20 M) under nitrogen and ETHYLENE GLYCOL (8.0 equiv.) was added followed by BF3.OEt2 (1.4 equiv.). The solution was microwave vial and heated at 100° C. for 60 mins. The solution was diluted with EtOAc and washed with sat. sodium bicarbonate, water, brine, dried over sodium sulfate and concentrated. The crude material was purified by ISCO chromatography to afford (+/−)-benzyl ((6R,8R,10S)-8-(3-((benzoxycarbonyl)amino)pyridin-4-yl)-10-methyl-1,4-dioxaspiro[4.5]decan-6-yl)carbamate in 100% yield. LC/MS (m/z)=532.2 (MH+), Rt=0.81 min.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].O1CCOCC1.Cl[CH2:18][C:19](=[O:21])[CH3:20]>O>[C:1]1([S:7]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)CS(=O)(=O)c1ccccc1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Sodium benzenesulfinate (50 g, 304.6 mmol) was dissolved in water (200 ml). A dioxane solution (200 ml) of chloroacetone (29.6 g, 319.9 mmol) was added and the solution was stirred and heated to 50° C. for 22 hours then cooled to approximately 25° C. The solution was extracted with methylene chloride (2X, 250 ml), the methylene chloride layers were combined and washed with saturated aqueous sodium bicarbonate solution (1X, 250 ml) and water (1X, 250 ml) then the aqueous wash solutions were combined and extracted with methylene chloride (2X, 100 ml). All of the methylene chloride layers were combined and washed with saturated aqueous sodium chloride solution (1X, 150 ml), dried over sodium sulfate, filtered and concentrated in vacuo to a solid. The solid was dissolved in diethyl ether (800 ml) with gentle heating and then the solution was stirred and allowed to cool to room temperature. The solution was slowly cooled to 0° C. with stirring, causing the product to crystallize. The resulting crystals were collected by filtration, washed with cold diethyl ether, and dried in vacuo at 35° C. for 4 hours to yield 36.43 g of (phenylsulfonyl)acetone. The filtrate was concentrated to approximately one-eighth of its volume in vacuo and was gradually cooled below room temperature to induce crystallization, then stirred overnight at room temperature. The resulting crystals were collected by filtration, washed with cold diethyl ether, and dried in vacuo at 35° C. for 8 hours to yield an additional 14 g of the (phenylsulfonyl)acetone: n.m.r. (90 MHz, CDCl3): δ 2.39 (s, 3), 4.17 (s, 2), 7.55-7.95 (m, 5); m.p. 56°-58° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 4-fluorobenzenesulfonyl chloride (564 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(4-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (937 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:20])=[C:5]2[CH2:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][C:6]=12.Br>C(O)(=O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:20])=[C:5]2[CH2:9][NH:8][CH2:7][C:6]=12
Reactant: Cc1ccc(S(=O)(=O)N2Cc3c(Cl)sc(Cl)c3C2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Clc1sc(Cl)c2c1CNC2
Temperature: 90 °C
Yield: 122.4 %

Procedure:
A mixture of 6.98 g (0.02 mol) of 1,3-dichloro-5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole and 50 ml of a 33% solution of hydrobromic acid in acetic acid, placed in a sealed tube, is heated at 90° C. in a water bath for 90 min. The reaction mixture is then cooled, and the precipitate formed is filtered off, washed twice with diethyl ether and dried. There are obtained 4.75 g of compound in the hydrobromide form (Melting point >270° C.). Treatment of this salt with sodium carbonate in water produces 3.35 g of base. Melting point: 80.5°-82.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][O:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:13]=1
Reactant: ClCCCCBr
Reactant: Cc1cc(O)cc(-c2ccc(F)cc2)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(OCCCCCl)cc(-c2ccc(F)cc2)n1
Yield: 40.1 %

Procedure:
A mixture of 2.5 g of 2-(4-fluorophenyl)-4-hydroxy-6-methylpyridine, 3.16 g of 1-bromo-4-chlorobutane, 1.7 g of silver carbonate, and 100 ml of toluene was refluxed for 40 hours. This reaction mixture was filtered to remove insolubles and the filtrate was concentrated. The residue was purified with silica gel column chromatography to provide 1.45 g of the title compound as white crystals.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23]([C:25]1[N:26]([CH2:34][C:35]([O:37]CC)=[O:36])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:7]>CO>[Cl:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23]([C:25]1[N:26]([CH2:34][C:35]([OH:37])=[O:36])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:7]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3n2CC(=O)O)s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
Methanol (60 ml) and a 2M aqueous sodium hydroxide solution (7.0 ml) were added to ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate (4.0 g), and the mixture was stirred at 50° C. for 30 minutes and at room temperature for 4 hours. Methanol was evaporated, and water and ethyl acetate were added. The aqueous layer was taken out, and citric acid was added to adjust the solution to pH 3. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 2.6 g of 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[CH3:27][N:28]([CH3:44])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41](O)=[O:42])=[CH:35]2.CCN=C=NCCCN(C)C>CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[N:5]([C:41]([C:36]2[NH:37][C:38]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:44])[CH3:27])=[CH:40][CH:39]=3)=[O:42])[CH2:4]1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NCCO)cc13)C(CCl)CN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NCCO)ccc43)cc2c1
Reaction time: 4 h
Yield: 20.7 %

Procedure:
(Scheme C). A mixture of compound 121 (46 mg, 0.11 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (37 mg, 0.13 mmol) and EDCI (83 mg, 0.44 mmol) in DMA (3 mL) was stirred under a N2 atmosphere for 4 h. The mixture was then partitioned between CH2Cl2 and cold (0° C.) 5% aqueous KHCO3. The aqueous portion was extracted with cold CH2Cl2 (×4) and the combined extracts were washed with H2O (×2), brine (×2), dried and evaporated. The residue was dissolved in CH2Cl2/MeOH and the solvents were evaporated under reduced pressure until precipitation began. The precipitate was filtered off and washed with MeOH to give 35 (14 mg, 21%): mp 205-210° C.; 1H NMR [(CD3)2SO] δ 11.73 (s, 1H), 9.30 (s, 1H), 8.85 (d, J=1.6 Hz, 1H), 8.43 (d, J=8.9 Hz, 0.1H), 8.03 (dd, J=8.9, 1.6 Hz, 1H), 7.92 (t, J=5.4 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.9, 2.4 Hz, 1H), 4.97 (t, J=10.3, Hz, 1H), 4.74 (dd, J=10.9, 2.3 Hz, 1H), 4.68-4.61 (m, 2H), 4.19-4.09 (m, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.43-3.35 (m, 21H), 2.88 (q, J=5.8 Hz, 21H), 2.66 (t J=5.8 Hz, 2H), 224 (s, 6H). HRMS (FAB) calcd. for C28H3035ClN5O7S (MH+) m/z 616.1633, found 616.1630.