Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:46][CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: NCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)NCCN3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL) was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, 4-(2-aminoethyl) morpholine (15 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (17 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C27H38ClN5O5S [M+] 579.2, found 580.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.99-1.11 (m, 2H, CH2), 1.37-1.85 (m, 8H, 4×CH2), 2.05-2.18 (m, 1H, CH), 2.25-2.37 (m, 6H, 3×NCH2), 2.57 (t, J=6.4 Hz, 2H, COCH2), 3.18 (s, 3H, SO2CH3), 3.21 (q, J=5.4 Hz, 2H, CONCH2), 3.47 (t, J=7.5 Hz, 1H, CH), 3.50-3.58 (m, 4H, 2×OCH2), 4.23 (t, J=6.4 Hz, 2H, NCH2), 5.94 (brm, 1, NH), 6.50 (d, J=2.3 Hz, 1H, Ar), 7.22 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.51 (d, Jm=1.7 Hz, 1H, Ar), 7.84 (s, 1H, NH), 8.00 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)acetic acid and t-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.Cl.[NH2:19][CH2:20][CH2:21][SH:22].[OH-].[Na+]>CN(C)C=O.O>[NH2:19][CH2:20][CH2:21][S:22][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3
Reactant: NCCS
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CSCCN)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a suspension of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (0.882 g) in dimethylformamide (40 ml), cysteamine hydrochloride (3.41 g) and caustic soda (2.40 g) in water (20 ml) were added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was combined with water, and extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated and the residue was crystallized from chloroform--n-hexane to obtain 0.714 g of the title compound as pale yellow prisms (mp.: 182°-184° C.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(O)(=O)C.BrBr.Br>O>[CH3:1][C:2]1[C:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CC1CC(=O)NN=C1c1ccc(C#N)cc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)[nH]nc1-c1ccc(C#N)cc1

Procedure:
A 200 g. portion of p-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile [Journal of Medicinal Chemistry 17, 281(1974)] is suspended in 500 ml. of glacial acetic acid with overhead stirring at steam bath temperature, then 56 ml. of liquid bromine is dissolved in an additional 500 ml. of acetic acid and this solution is added to the stirring mixture all at once. After approximately half an hour of heating, a vigorous exothermic reaction occurs with the expulsion of the excess bromine and hydrogen bromide. The reaction mixture is then diluted with 4 liters of distilled water and the resulting solid is filtered and the filter cake is copiously washed with water and is air dried. This material is recrystallized from a large amount of ethyl alcohol to afford the product p-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=3[F:19])[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(C)=O)c1
Reaction time: 0.08 h
Yield: 34 %

Procedure:
N-[1-{[3-(aminomethyl)phenyl]methyl}-7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 46) (70 mg, 0.15 mmol) was dissolved in DCM (0.75 mL) and triethylamine (0.203 mL, 1.45 mmol) was added to the solution. The solution was stirred for 5 min and acetic anhydride (0.013 mL, 0.13 mmol) was added. The reaction was stirred for 1 h, and then concentrated under a stream of nitrogen. The residue was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (26 mg, 34%): LCMS (System A) RT=1.04 min, ES+ve m/z 523/524 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[C:12]([CH3:28])=[N:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[C:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[C:15]=2[CH3:16])=[O:10])[CH2:5]1)[CH3:2]>CCO.O.[Pt](=O)=O>[CH2:29]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[C:12]([CH3:28])=[N:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[CH:18]=3)[C:15]=2[CH3:16])=[O:10])[CH2:5]1)[CH3:30]
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(C#CC(C)C)c3)c2C)C1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(CCC(C)C)c3)c2C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.5 %

Procedure:
A suspension of 0.041 g (0.10 mmol) of (3-diethylamino-pyrrolidin-1-yl)-{3,5-dimethyl-1-[3-(3-methyl-but-1-ynyl)-phenyl]-1H-pyrazol-4-yl}-methanone (Example 361) and 6 mg of platinum(IV) oxide hydrate in 0.2 ml of EtOH was stirred under hydrogen atmosphere 17 h at RT and 1 atm. The suspension was filtered and evaporated to give 0.038 g (93%) of the titled compound as colorless viscous oil. MS: 411.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[Cl:14][CH:15]([Cl:19])[C:16](Cl)=[O:17]>C(OCC)(=O)C>[Cl:14][CH:15]([Cl:19])[C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:17]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccc(F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cn1)C(Cl)Cl
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
To 2-amino-5-fluoropyridine (250 mg) in ethyl acetate (10 mL), dichloroacetyl chloride (279 μL) was added at room temperature, followed by stirring at 60-70° C. for 2.5 hours. The reaction mixture was cooled, and saturated aqueous sodium hydrogencarbonate was added thereto for partitioning the mixture. The resultant organic layer was dried over magnesium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (438 mg) as acrude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[SH:11][CH2:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19].[H-].[Na+]>>[CH3:9][C:4]1[C:3]([CH3:10])=[C:2]([S:11][CH2:12][CH2:13][C:14]2[S:18][CH:17]=[N:16][C:15]=2[CH3:19])[CH:7]=[CH:6][N+:5]=1[O-:8]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: Cc1ncsc1CCS
Agent: [H-]
Agent: [Na+]
Product: Cc1ncsc1CCSc1cc[n+]([O-])c(C)c1C
Yield: 79 %

Procedure:
Following the procedure described in Example Aa), the reaction of 4-chloro-2,3-dimethylpyridine N-oxide with 5-(2-mercaptoethyl)-4-methylthiazole in the presence of sodium hydride gives 2,3-dimethyl-4-[2-(4-methyl-5-thiazolyl)-ethylthio]pyridine N-oxide; m.p.: 135°-137° C (yield: 79%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:24](=[O:25])[NH:12][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=2)[CH3:11])=[CH:22][CH:23]=1)=[O:18]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Product: COC(=O)c1ccc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 2 from 1-(3-trifluoromethoxy-phenyl)-ethyl amine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:11]([NH2:14])=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].CI.[CH2:17](Cl)Cl>CN(C=O)C>[CH3:17][O:3][C:4]1[CH:5]=[C:6]([C:11]([NH2:14])=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1N
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of NaH (washed three times with dry THF to remove oil, 0.145 g, 1.1 eq) in dry DMF (5 mL, CaH2 dried), 420 mg of methyl 3-hydroxy- 6-aminobenzoate (E) was added in 3 mL of DMF immediately followed by MeI (443 mg [0.195 m], 1.2 eq), and stirred at room temperature under argon for 16 hr, at which time TLC indicated the absence of E. 200 mL of CH2Cl2 was added and the mixture was extracted with brine (5×100 ml); the organic solvent was evaporated; the crude product was added to 200 mg of NaOH in 5 mL of water; and the reaction mixture was heated at 70° C. for 2 hr. The reaction mixture was neutralized to pH 7.0 with dilute HCl and extracted with CH2Cl2 (5×25 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to yield crude product, which was applied to silica gel (230-400 mesh and eluted with EtOAc/MeOH, 50:1) to yield product 39, 206 mg (yield 45%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.Cl[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].O>C1(C)C=CC=CC=1>[OH:28][CH:25]([CH2:26][OH:27])[CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1ccnc2ccccc12
Reactant: OCC(O)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(OCC(O)CO)cc2C1=Cc1ccnc2ccccc12
Yield: 70 %

Procedure:
To a solution of 5-hydroxy-3-(quinol-4-ylmethylene)-2-oxindole (2.883 g, 10 mmol) in toluene (100 ml) was added portionwise under nitrogen NaH 80% (0.300 g, 10 mmol). After salification was complete, 3-chloro-1,2-propanediol (1.547 g, 14 mmol) was added and the mixture heated to reflux for 5 h. After cooling, water was added, the organic phase washed and evaporated to dryness. The residue was submitted to flash chromatography, using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1c[nH]c(Sc2ccc(Cl)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2ccc(Cl)c(Cl)c2)c1

Procedure:
Methyl 5-(3,4-dichlorophenylthio)pyrrole-3-carboxylate (1.7 g.) was combined with 20 ml. of methanol and 20 ml. of 1 N sodium hydroxide and refluxed for 3 hours. The methanol was allowed to evaporate, and approximately one volume of water was added to the aqueous residue, which was then extracted twice with ether, cooled in an ice-water bath, acidified with conc. hydrochloric acid, and the product extracted into ethyl acetate. The three ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a gummy solid which was crystallized by trituration with hexane and recovered by filtration (1.34 g., m.p. 156°-159° C.). Recrystallization from chloroform gave purified 5-(3,4-dichlorophenylthio)pyrrole-3-carboxylic acid (850 mg., m.p. 159°-161° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([CH:10]2[NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][S:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CSC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.3 %

Procedure:
To a suspension of L-cysteine methyl ester hydrochloride (1.717 g, 10 mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen was added benzaldehyde (1.02 mL, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). After stirring at room temperature for 3.5 hrs, the resulting mixture was filtered through a pad of silica gel eluting with EtOAc. Evaporation of the filtrate gave the title compound (1.95 g, 88%) as a colorless oil. TLC(EtOAc-hexane; 1:5) Rf=0.22.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([Br:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:12].[Na+]>O>[Br:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([OH:12])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(Br)c1
Temperature: 140 °C

Procedure:
The title compound was made according to the method described in Org. Proc. Res. rev. 2002, 6, 591-595. To 5-iodo-3-bromo-benzoic acid (500 mg, 1.53 mmol), NaOH (250 mg, 6.1 mmol), Cu2O (240 mg, 1.68 mmol) was added water (4.0 mL)). The mixture was heated for 1.5 h at 140° C. in a sealed tube. The cooled mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was acidified (pH˜2) with TFA and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to yield 3-bromo-5-hydroxy-benzoic acid. 1H NMR (400 MHz, DMSO-d6): 10.30 (s, 1H), 7.46 (m, 1H), 7.31 (m, 1H), 7.17 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)O>>[CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C@H:31]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]([OH:40])=[O:29])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1sc(Cc2ccccc2)c(-c2ccc(-c3ccc(O)cc3)cc2)c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: Cc1sc(Cc2ccccc2)c(-c2ccc(-c3ccc(O[C@H](Cc4ccccc4)C(=O)O)cc3)cc2)c1C

Procedure:
The title compound was prepared from 4′-(2-benzyl-4,5-dimethyl-thiophen-3-yl)-biphenyl-4-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 29, and was obtained as an off-white solid, mp 142-144° C.; MS m/e 517 (M−H)+;
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:12]1[C:13]2[C:9](=[C:8]([O:7][CH3:6])[CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH:3]1[O:5][CH2:4]1
Reactant: COc1cccc2[nH]ccc12
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1ccn2CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (0.64 ml, 7.5 mmole) was added to a stirred solution of 4-methoxyindole (1.0 g, 6.8 mmole) and sodium hydride (0.3 g, 7.8 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for two hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a yellow colored oil (1.5 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a light oil (1.27 g, 92% yield).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:9])[CH:3]=1.N>C(O)(=O)C.C(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:9])[CH:3]=1
Reactant: COc1cc(C(=O)c2cccnc2)ccc1OCc1ccccc1
Agent: Br
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2)ccc1O
Reaction time: 3 h

Procedure:
ca) 50 ml of 33 percent hydrobromic acid in acetic acid are added dropwise within 15 minutes at 10° to 20 g of 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml of methylene chloride. After stirring at 20° for 3 hours, the reaction mixture is poured into a mixture of 100 ml of conc. aqueous ammonia and ice. The pH is adjusted to 6 by adding acetic acid. The methylene chloride phase is separated; the aqueous phase is extracted twice more with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone of m.p. 150°-151°.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:12](=[O:13])[N:11]([CH2:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=2[C:8]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:7]1)C.[OH-].[Na+].[OH-].[K+]>>[CH:26]1([C:8]2[C:9]3[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=3[N:11]([CH2:14][C:15]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[C:12](=[O:13])[N:6]([CH2:5][C:4]([OH:32])=[O:3])[N:7]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O

Procedure:
The [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid ethyl ester is reacted with an aqueous base such as NaOH, KOH, and the like, according to known methods, to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl )-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid, which is preferably isolated, according to known methods.
Reaction SMILES: N1C=CN=C1.[F:6][C:7]1[CH:8]=[C:9]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][C:12]=1[OH:13].[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18].O>ClCCl>[Si:21]([O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[F:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(O)c(F)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of imidazole (7.29 g, 107.0 mmol) and 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (15.0 g, 97.3 mmol) in anhydrous dichloromethane (500 mL) was added drop-wise a solution of t-butyldiphenylchlorosilane (28.09 g, 102.0 mmol) in anhydrous dichloromethane (100 mL). The solution was stirred overnight at room temperature. The mixture was poured into water (500 mL) and the organic layer separated and washed with saturated sodium hydrogen carbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to give the title compound which was used without further purification (37.9 g, 96.55 mmol). MS (APCI+, m/z): 393 [M+H]+.
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:31])[CH:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]#[CH:40]>CN(C=O)C>[C:1]([O:5][NH:6][C:7](=[O:31])[CH:8]([NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:40][C:39]#[CH:38])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NOC(C)(C)C)c2ccc(O)cc2)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NOC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 321.6 mg (0.72 mmol) of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide from Example 176 in 3 ml DMF at 0° C. was added 199 mg (1.44 mmol) of K2CO3. The reaction mixture was stirred for 15 min, 94.4 mg (0.79 mmol) of propargyl bromide was added, and reaction mixture was stirred at room temperature overnight. DMF was removed in vacuo. The residue was diluted with ethyl acetate, washed with 1N HCl solution, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel, eluting with hexane/ethyl acetate (5:1, 4:1 then 3:1) to provide 75 mg (17%) of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide as a white solid. Electrospray Mass Spec 485.4 (M+H)+