Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][C@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][N:10](CC=C)[C@@H:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(#N)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(Cl)Cl.C(#N)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:6][O:7][C@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][NH:10][C@@H:9]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN1C[C@@H](C)O[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN[C@H](c2ccccc2)[C@@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Yield: 27.8 %

Procedure:
A similar reaction was carried out using 55 mg (0.12 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methyl morpholine (from Example 23, Step A) and 111 mg (0.12 mmol) of tris(triphenylphosphine)rhodium chloride in 12 mL of 4:1 v/v acetonitrile/water. Flash chromatography on 4 g of silica gel using 50:1 v/v methylene chloride/acetonitrile as the eluant afforded 14 mg (28%) of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-6-(R)-methyl morpholine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(F)c(C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)c(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
Concentrated H2SO4 (17.5 mL) was slowly added to methyl 4-fluoro-3-methylbenzoate (12.8 g, 76 mmol) and the mixture was cooled to 0° C. A solution of fuming HNO3 (69.5%, 11.6 mL) in concentrated H2SO4 (17.5 mL) was then added drop-wise over 10 min. The mixture was stirred for 80 min while slowly warming up to room temperature (reaction completion monitored by TLC). The mixture was slowly poured into ice, the aqueous layer was extracted with CH2Cl2 (3×200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography to afford methyl 4-fluoro-3-methyl-5-nitrobenzoate (I-35a) as a white solid. MS calculated for C9H9FNO4 (M+H+) 214.04. found 214.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[C:25]([O:28][CH2:29][CH2:30]Br)(=[O:27])[CH3:26].CN(C)C=O>O>[C:25]([O:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: CC(=O)OCCBr
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A mixture of 6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (5.0 g, 15.8 mmol), 2-bromoethyl acetate (3.2 g, 19 mmol) and N,N-dimethylformamide (20 ml) was stirred at 50° C. for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous-magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and filtered to give 2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethyl acetate (5.0 g, yield 79%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a solution of 3-bromo-5-nitro-phenol (770 g, 3.53 mol) in acetone (10 L) was added pulverized K2CO3 (2.45 kg, 17.75 mol) in one portion at rt followed by addition of benzyl bromide (632 mL, 5.32 mol) over a period of 30 min. The resulting reaction mixture was stirred for 15 min then heated at reflux for 3 h. After reaction completion (by TLC), the reaction mixture was filtered through celite and the acetone distilled off. The crude residue thus obtained was purified over silica gel (60-120 M) using EtOAc:hexane (5:95) to obtain the desired product (551 g, 51%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:11]([CH2:24][C:25]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26]2)[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[F:23][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[CH2:24][C:25]1([C:29]#[N:30])[CH2:26][CH2:27][CH2:28]1
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2CC2(C#N)CCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(O)cc2CC2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.6 %

Procedure:
To a solution of 1-((4-((tert-butyl(dimethyl)silyl)oxy)-2′-fluoro-5′-methoxybiphenyl-2-yl)methyl)cyclobutanecarbonitrile (116 mg) in THF (5 mL) was added a solution (1 M, 0.54 mL) of tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (76 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:19]3[CH:18]=[C:17]([Br:20])[CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][C:10]([Br:21])=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][Br:36])=[CH:26][CH:27]=3)[C:8]3[CH:9]=[C:10]([Br:21])[CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C2(c3ccccc3)c3cc(Br)ccc3-c3ccc(Br)cc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(C2(c3ccccc3)c3cc(Br)ccc3-c3ccc(Br)cc32)cc1
Yield: 89.8 %

Procedure:
Into a flask, 9-phenyl-9-(4-methylphenyl)-2,7-dibromofluorene (0.90 g, 1.84 mmol), NBS (0.33 g, 1.84 mmol), BPO (0.044 g, 0.184 mmol) and CCl4 (10 ml) were added and reacted under reflux for 2 hr. Then, the reaction system was cooled and filtered. After removing the filtrate, a gray solid of 9-phenyl-9-(4-bromomethylphenyl)-2,7-dibromofluorene (0.94 g) was obtained as a pure intermediate product (yield, 90%). 1HNMR (300 MHz, CDCl3): δ 7.51-7.48 (m, 6H), 7.26-7.00 (M, 9H), 4.46 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[N:40][N:41]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[N:40][N:41]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2nnco2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2nnco2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate (0.049 g) in ethyl acetate (1 mL) and methanol (1 mL), 10% palladium-carbon (25 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.034 g of tert-butyl 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:12]>>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CBr)cc1
Product: NC(=O)c1ccc(CBr)cc1
Yield: 65 %

Procedure:
A solution of 4-(bromomethyl)benzonitrile (500 mg, 2.55 mmol) in 90% sulphuric acid (8 ml) was heated at 100° C. for 1 h. The solution was carefully poured onto ice water (50 ml) and a precipitate formed. The solid was filtered, washed with water and diethyl ether and dried in vacuo to afford the title compound as a white solid (353 mg, 65%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][C:15](=O)[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A suspension of 7-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (2.314 g., 8.00 mmol) in 30 ml anhydrous THF was brought to reflux, and borane-dimethyl sulfide complex (2.4 mL, 10 M solution) was added dropwise via syringe. The solution was refluxed for two hours, at which time the solution was cooled to room temperature and ethanolic HCl (10 mL., 2 N solution) was added dropwise. The resulting solution was refluxed for 3 hours and allowed to cool to room temperature. The reaction mixture was poured into 100 mL water, the resulting solution made basic with potassium carbonate and extracted three times with 50 mL Et2O. The organic fractions were washed with 100 mL brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (20 to 50% EtOAc in hexanes) to give 1.75 g of 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (79.5%) as a yellow solid. MS: 276 (M+H)+.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[C:25]([N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)(=[S:27])[NH2:26]>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:26]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:27][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3sc(N4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.61 g, 1.5 mmol; Preparation #A.2) and tert-butyl 4-carbamothioylpiperazine-1-carboxylate (Beta Pharma Inc, 0.341 g, 1.39 mmol) in EtOH (3 mL) was heated to reflux overnight. After cooling to ambient temperature, the crude mixture was partitioned between DCM and 1N aqueous HCl. The aqueous layer was basified with saturated aqueous Na2CO3 and extracted with DCM. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using DCM/MeOH (linear gradient, 100:0 to 90:10) to give the title compound (0.061 g, 10%): LC/MS (Table 1, Method a) Rt=2.31 min; MS m/z: 442.8 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]([O:23]C)=[O:22])=[C:19]([O:25][CH3:26])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.CO.O.[OH-].[Li+].Cl>O.CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:25][CH3:26])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COC(=O)c1c(OC)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1C(=O)O)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 30 °C
Reaction time: 10 h
Yield: 66.9 %

Procedure:
Methyl (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate (0.070 g, 0.20 mmol) was added with methanol (3.0 mL), dimethyl sulfoxide (1.0 mL), and water (0.50 mL), and then added with lithium hydroxide monohydrate (0.025 g, 0.60 mmol), and the mixture was stirred at 30° C. for 10 hours. The reaction mixture was made acidic with 3 N hydrochloric acid, and the solid formed was collected by filtration. The solid was suspended in chloroform/methanol (95:5), then collected by filtration and dried to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.045 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][NH:10][CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1CNCC(=O)N1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1

Procedure:
To a solution of ethyl [1-(4-fluorobenzyl)-6-oxo-piperazin-2-yl]acetate (3.7 g, 12.5 mmol) in dichloromethane (100 mL) was added benzyl chloroformate (2.2 mL, 15.1 mmol) and triethylamine (3.5 mL, 25.1 mmol), stirred over night. The reaction mixture was diluted with dichloromethane, washed with 1N HCl, water and brine, dried over sodium sulfate, filtered and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 7H), 7.01 (t, J=8.6 Hz, 2H), 5.12-5.22 (m, 3H), 4.40-4.56 (m, 1H), 3.90-4.24 (m, 5H), 3.72-3.86 (m, 1H), 3.04-3.18 (m, 1H), 2.49-2.62 (m, 2H), 1.12-1.28 (m, 3H). ES MS (M+1)=429.24.
Reaction SMILES: [C:1]1([C:7]2[CH:38]=[CH:37][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][C@H:21]([NH:32][S:33](=[O:36])(=[O:35])[NH2:34])[C:22]([O:24]CC5C=CC=CC=5)=O)=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl>CO.C1COCC1>[C:1]1([C:7]2[CH:38]=[CH:37][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][C@@H:21]5[NH:32][S:33](=[O:35])(=[O:36])[NH:34][C:22]5=[O:24])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NS(=O)(=O)N[C@H]1Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of Compound 45b (130 mg, 0.24 mmol) in MeOH (3 mL) and THF (3 mL) at 0° C. was added a solution of NaOMe (1.0 M in MeOH, 0.11 mL, 0.48 mmol) and the reaction mixture was stirred for 0.5 h. The reaction mixture was added dropwise to 1 N HCl (5 mL) at 0° C. The solution was extracted with DCM (3×) then the combined extracts dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 20% MeOH/DCM to give Compound 45c (51 mg, 46% yield) as a yellow solid. LCMS=1.80 min using analytical method (B), 442.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=1.8 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.86-7.81 (m, 1H), 7.79-7.73 (m, 2H), 7.57-7.48 (m, 2H), 7.44-7.37 (m, 1H), 4.92 (s, 2H), 4.63 (dd, J=7.9, 4.6 Hz, 1H), 3.44-3.19 (m, 2H). LC/MS=1.80 min using analytical method (B), 442.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12](=O)([O-])[O-].[K+].[K+].ICI>CN(C)C=O>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]2[O:10][CH2:12][O:11][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)cc(O)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Product: O=Cc1cc(Br)cc2c1OCO2
Temperature: 85 °C
Yield: 79.4 %

Procedure:
Dimethylformamide, 750 mL, was purged with dry nitrogen gas and 5-bromo-2,3-dihydroxy-benzaldehyde (83 g, 382 mmol) was added. To the solution was added potassium carbonate (158 g, 1,14 mol) followed by diiodomethane (306 g, 1,14 mol). The mixture was warmed to 85° C. for 2.5 hours, and evaporated in vacuo to an oil. The mixture was partitioned between ethyl acetate and water and filtered through celite. The phases were separated, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a small volume causing a solid to precipitate. The solid was filtered, washed with 50:50 hexane/ethyl acetate, and set aside. Three more crops of solid were subsequently isolated in this manner from the filtrate. The solids were combined and dried in vacuo giving a beige solid, 69.45 g, 79.4% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[C:21]([Cl:27])[C:3]=1[C:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[C:9]=2[CH:8]=[CH:7]1)=[O:5].P(Br)(Br)[Br:29]>ClCCl>[Br:29][CH2:25][C:23]1[CH:24]=[C:2]([Cl:1])[C:3]([C:4]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[C:9]=3[CH:8]=[CH:7]2)=[O:5])=[C:21]([Cl:27])[CH:22]=1
Reactant: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CO)cc1Cl)C1CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CBr)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-{1-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide (0.37 mmol) in dichloromethane was cooled to 0° C. and was treated dropwise with phosphorous tribromide (0.74 mmol). The reaction mixture was then stirred at room temperature for about 2 hours, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to get N-{1-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropane carboxamide as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[S:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[S:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1csc(-c2cccs2)n1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: c1csc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)cs2)c1
Yield: 82 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with 4-chloromethyl-2-(2-thienyl)thiazole to obtain 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)thiazole. The yield was 82%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 108-109° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](N[C@@H]1CCN(C2SC(C([O-])=O)=CN=2)C[C@@H]1F)=[O:10].OCC(CO)([NH3+])CO.O=S(Cl)[Cl:37]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([Cl:37])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)[O-])s3)C[C@@H]2F)c(Cl)c1Cl
Agent: [NH3+]C(CO)(CO)CO
Product: Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl

Procedure:
A solution of 10.4 g (54 mmol) of 3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 1) in 100 ml SOCl2 was heated at reflux for 30 min. Solvent was removed to afford product. NMR (CDCl3): 2.3 (s, 1H), 8.8 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][CH:32]=[CH:31]4)[CH:25]=[C:24]([O:37][CH2:38][CH3:39])[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][CH:32]=[CH:31]4)[CH:25]=[C:24]([O:37][CH2:38][CH3:39])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4[nH]ccc4c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3[nH]ccc3c2)c1
Yield: 85.1 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-ethoxy-5-(1H-indol-5-yl)-phenoxy]-hexyl}-phenoxy]-butyric acid ethyl ester (24 mg, 0.04 mmol) and 1.0 N aqueous sodium hydroxide (0.4 mL) to afford 4-[2-(2-carboxy-ethyl)-3-{6-[3-ethoxy-5-(1H-indol-5-yl)-phenoxy]-hexyl}-phenoxy]-butyric acid (20 mg, 91%) as a light brown solid: ES(+)-HRMS m/e calcd for C35H41NO7 (M+Na)+ 610.2775, found 610.2773.