Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12]([OH:14])=O)[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH:16]1([CH2:15][C@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[C:12]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1nccs1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2nccs2)C1
Yield: 27.8 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.54 mmol) (Example 7, Step 2c), commercially available 2-amino-thiazole (66 mg, 0.64 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (113 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (80 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-Cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-thiazol-2-yl-propionamide (68 mg, 27.9%), as an off white solid. 1H NMR (DMSO-d6) δ: 12.56 (br. s., 1H), 7.49 (d, J=3.4 Hz, 1H), 7.11-7.31 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.05 (d, J=5.4 Hz, 1H), 4.36 (d, J=19.1 Hz, 1H), 4.05 (d, J=18.6 Hz, 1H), 3.82 (s, 3H), 3.55 (br. s., 2H), 1.47-1.89 (m, 7H), 0.78-1.29 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Br-].[Br-].C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1C(=O)C(c2ccc(Cl)c(Cl)c2)C(c2ccncc2)N1CC1CCCCC1
Agent: CC[N+](CC)(CC)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2ccc(Cl)c(Cl)c2)c(-c2ccncc2)n1CC1CCCCC1

Procedure:
The solution of 1-Cyclohexylmethyl-4-(3,4-dichloro-phenyl)-2-methyl-5-pyridin-4-yl-pyrazolidin-3-one 0.16 g in toluene 20 mL and DMF 2 mL was treated with phenyltriethylammonium tribromide 0.22 g at room temperature, The reaction mixture was refluxed for 4 h. The reaction was quenched with sat. Na2SO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×25 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as light yellow solid 80 mg. MS (ES+): 416 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:17]=[C:16]([NH:18][C:19]([CH3:21])=[O:20])[C:15]([Cl:22])=[CH:14][C:10]=1[C:11](O)=[O:12])(=[O:7])[CH3:6]>>[C:5]([O:8][C:9]1[CH:17]=[C:16]([NH:18][C:19]([CH3:21])=[O:20])[C:15]([Cl:22])=[CH:14][C:10]=1[C:11]([Cl:3])=[O:12])(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)O)cc1Cl
Product: CC(=O)Nc1cc(OC(C)=O)c(C(=O)Cl)cc1Cl

Procedure:
501 g of thionyl chloride and 71.5 g of 2-acetoxy 4-acetamino 5-chlorobenzoic acid were introduced into a two liter balloon flask provided with a reflux condenser. Heating was effected by a water bath under reflux until dissolution of reactants occurred. Some cooling was applied and 71.5 g of 2-acetoxy 4-acetamino 5chlorobenzoic acid was added. Heating was effected as before under reflux for a period of 1 hour, but without causing the acid to dissolve. 63 g of thionyl chloride was added. The acid dissolved immediately, and an acid chloride quickly crystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([NH2:9])[CH:8]=1.Cl[C:18]1[CH:27]=[CH:26][N:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:7]([NH:9][C:18]2[C:19]3[C:24](=[N:23][C:22]([CH3:28])=[CH:21][CH:20]=3)[N:25]=[CH:26][CH:27]=2)[CH:8]=1
Reactant: COc1ccc(Sc2ccccc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 9b (69 mg, 0.30 mmol) was reacted with the product from Example 1d (53 mg, 0.30 mmol) following the procedure from Example 1g giving the title compound as a hydrochloride salt after trituration with solid (119 mg, 96%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3H) 3.83 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.07 (m, 7H) 7.57 (d, J=8.46 Hz, 1H) 7.76 (d, J=8.46 Hz, 1H) 8.85 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.46 Hz, 1H) 11.16 (br s, 1H) 14.43 (brs, 1H); MS (ESI+) m/z 374 (M−Cl)+; (ESI−) m/z 372 (M−HCl)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([N:14]=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2].C([BH3-])#N.[Na+].O>CO>[CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=2)[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(c(C)nn2C)C(N=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1c2c(c(C)nn2C)C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a stirred solution of [(3,5-Bis-trifluoromethyl-benzylidene)-amino]-6-ethyl-1,3-dimethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridine-7-carboxylic acid ethyl ester (0.19 g, 0.04 mmol) obtained in step (v), in 10 mL of methanol was added sodium cyanoborohydride (0.078 g, 0.12 mmol). This reaction mixture was stirring for around 3 hours at room temperature, after which time the methanol was evaporated from the solution to afford a crude residue. Water was added to this residue, and the product was extracted with ethyl acetate (3×10 mL). The organic solvent was dried over sodium sulfate, filtered, and the solvent was evaporated from the filtrate under vacuum to provide the desired amine compound (0.019 g, 95%).
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C(Cl)Cl>[C:2]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 67.3 %

Procedure:
To a solution of (chloromethanetriyl)tribenzene (9.8 g, 35.2 mmol) in DCM (500 ml), ethyl 2-hydroxyacetate (4.33 ml, 45.7 mmol) and Py (3.70 ml, 45.7 mmol) were added at RT. The reaction was heated at 50° C. for 9 hours. HCl 2N was added to the mixture, and the organic phase was separated, dried over Na2SO4 and evaporated under vacuum. The resulting white solid was triturated in Hexane. Ethyl 2-(trityloxy)acetate was obtained (8.2 g, 23.67 mmol, 67.3% yield) and used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][C@H:11]([C:16]([OH:18])=O)[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4].[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:16]([C@@H:11]2[CH2:10][CH2:9][C:8]3[N:7]=[C:6]([C:3]([CH3:5])([CH3:4])[C:2]([F:19])([F:1])[F:20])[CH:15]=[CH:14][C:13]=3[CH2:12]2)=[O:18])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)Nc1ccc(Br)cc1)C2)C(F)(F)F
Temperature: 14 °C

Procedure:
(R)-2-(1,1,1-Trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (30 mg), 4-bromoaniline (17.9 mg), propanephosphonic acid cyclic anhydride (50% wt solution in dichloroethane) (0.093 mL), triethylamine (0.044 mL), and dioxane (2 mL) were combined and heated in a microwave at 14° C. for 20 mins. The solution was evaporated and the residue dissolved in ethyl acetate and extracted with sodium carbonate soln (2×20 ml) and brine (3×20 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give a gum which solidified on standing. Yield 40 mg.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH:8]([CH3:15])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].[Cl:16][C:17]1[C:22]([OH:23])=[CH:21][C:20]([N:24]2[C:29](=[O:30])[N:28]([CH3:31])[C:27](=S)[N:26]([CH3:33])[C:25]2=[O:34])=[C:19]([F:35])[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([F:35])[C:20]([N:24]2[C:25](=[O:34])[N:26]([CH3:33])[CH2:27][N:28]([CH3:31])[C:29]2=[O:30])=[CH:21][C:22]=1[O:23][CH:8]([CH3:15])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: C=CCOC(=O)C(C)Br
Reactant: Cn1c(=S)n(C)c(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(C)Oc1cc(N2C(=O)N(C)CN(C)C2=O)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.37 g (2.65 mmol) of K2CO3 and 0.51 g (2.65 mmol) of rac. allyl 2-bromopropionate were added approximately at 20° C. to a solution of 0.80 g (2.52 mmol) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,5-dimethyl-6-thioxo-[1,3,5]triazinane-2,4-dione in 15 ml of dimethylformamide. After the reaction mixture had been stirred for two hours at approximately 20° C., it was stirred into ice-water. The product was extracted three times with methyl tert-butyl ether. The combined organic phases were dried over magnesium sulfate and then concentrated. The crude product (1.18 g) was purified by column chromatography (mobile phase: cyclohexane/ethyl acetate=15:1). Yield: 0.88 g (81%); 1H NMR (270 MHz, in CDCl3): δ[ppm]=1.7 (d, 3H), 3.8 (s, 6H), 4.6 (m, 2H), 4.7 (q, 1H), 5.2 (d, 1H), 5.3 (d, 1H), 5.9 (m, 1H), 6.9 (d, 1H), 7.3 (d, 1H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[OH-].[Na+].CN1C[CH2:16][C:15](=O)[CH2:14]1.ICCC.Cl>O>[CH2:14]([S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1)[CH2:15][CH3:16]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CN1CCC(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCI
Product: CCCSc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-mercaptopyrimidine-4,6-diol (25 g, 173.61 mmol, 1.00 equiv.), sodium hydroxide (15.8 g, 395.00 mmol, 2.27 equiv.), 1-methylpyrrolidin-3-one (50 mL), and 1-iodopropane (30.6 g, 180.00 mmol, 1.05 equiv.) dissolved in water (60 mL) was stirred at ambient temperature for about 48 hours. The pH value of the solution was adjusted to 2-3 by adding hydrochloric acid. The solids were then collected by filtration to give the product as an off-white solid (35 g; (crude)). 1H NMR (300 MHz, DMSO-d6) δ: 11.78 (b, 1H), 10.30 (b, 1H), 5.13 (s, 1H), 3.07 (t, J=7.2 Hz, 2H), 1.58-1.70 (m, 2H), 0.96 (t, J=7.2 Hz, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[C@H:14]1[CH3:21])=[O:12])=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:8][C@H:9]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[C@H:14]1[CH3:21])=[O:12]
Reactant: C[C@@H]1C(=O)NCCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NCCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Reaction time: 2.5 h

Procedure:
(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2H-1,4-diazepin-2-one from Step E was treated with 4N hydrogen chloride in dioxane, stirred for 2.5 h and evaporated to yield the title compound. LC/MS 344.1 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:32]4[CH:33]=[N:34][CH:35]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:31]=4)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cncc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 5-(methylsulfonyl)-3-pyridineboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-3-isopropyl-4-[3-(5-methanesulfonyl-pyridin-3-yl)-phenyl]-imidazolidin-2-one as a light yellow oil. MS: 499.9 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[C:9]([CH3:23])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.[OH-].[Na+].CO.C(OCC)(=O)C>O>[NH2:27][C:25](=[O:26])[C:24]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:29])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:9]=1[CH3:23])=[O:28]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of 767 mg (1.9 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 10 mL of 1N NaOH and 30 mL of MeOH was heated to maintain reflux for 0.67 hours, cooled to room temperature and stirred 1 hour. Ethyl acetate and water were added and the aqueous layer separated, made acidic to pH 2-3 with 1N HCl and the mixture extracted wtih ethyl acetate two times. The combined ethyl acetate extracts were dried (MgSO4) and concentrated. The remaining solid was washed with a small volume of ethyl acetate to give 593 mg (81% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid, mp, 244°-247° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:22])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[CH:13]=1)[C:5](O)=[O:6].B([O-])[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C(Br)C.Cl>C(Cl)Cl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:22])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]([CH3:20])[CH3:21])[CH:13]=1)[CH2:5][OH:6]
Reactant: CC(C)c1cc(Oc2c(Br)cc(C(=O)O)cc2Br)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [O-]B[O-]
Solvent: CCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1cc(Oc2c(Br)cc(CO)cc2Br)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (Example 1(c) (1.0 g, 3.3 mmol), tetrabutylammonium boronate (2.6 g, 9.9 mmol) and ethylbromide (1.0 ml, 13.2 mmol) in 25 ml of CH2Cl2 and 10 ml of tetrahydrofuran was stirred at room temperature over night. The reaction mixture was treated with 1M HCl and extracted several times with EtOAc. The combined organic phases were washed once with water followed by a saturated solution of NaCl. After drying over MgSO4, filtration and evaporation, the residue was purified by column chromathography (silica gel, 7:3 p-ether/EtOAc). This gave 0.922 g (98%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy) benzyl-alcohol.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:20]=3)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:31](I)[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:31]([O:30][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][C:10]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)[CH3:32]
Reactant: CCI
Reactant: CCS(=O)(=O)c1ccc(O)c(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(S(=O)(=O)CC)cc1-c1cn(C)c(=O)c2ccc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of the title compound of Example 80 (25.0 mg, 0.059 mmol), ethyl iodide (27.7 mg, 0.177 mmol), and K2CO3 (24.5 mg, 0.177 mmol) in acetone (2 mL) was stirred at room temperature for 18 h. After CH2Cl2 extractive work up, purification by preparative TLC (PE:EA=2:1) gave the title compound (15.8 mg, 60%) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.48 (d, J=8.4 Hz, 1H), 7.97 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.61 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.17 (d, J=1.2 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 4.3 (q, J=7.2 Hz, 2H), 3.94 (s, 3H), 3.66 (s, 3H), 3.17 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H). LCMS: 452.1 (M+H)+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[Cl:21][C:22]([Cl:31])([Cl:30])[CH2:23][O:24][C:25](=[O:29])/[CH:26]=[CH:27]/[CH3:28].C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Cl:21][C:22]([Cl:30])([Cl:31])[CH2:23][O:24][C:25](=[O:29])/[CH:26]=[CH:27]/[CH2:28][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/C(=O)OCC(Cl)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(/C=C/CBr)OCC(Cl)(Cl)Cl
Yield: 75 %

Procedure:
The bromination reaction takes place in carbon tetrachloride with N-bromosuccinimide and AIBN as radical former. For this purpose, an equimolar amount of ester (i) and 0.45 mole N-bromosuccinimide are mixed with 300 ml. carbon tetrachloride and a spatula tip of AIBN added thereto. The reaction mixture is heated under reflux for 4 hours, subsequently allowed to cool and the precipitated succinimide (0.41 mole; 92% of theory) is filtered off. After distilling off the solvent in a vacuum, the residue is purified by column chromatography using PE/EE (25:1 v/v) as elution agent. The end product obtained is a yellow oil. The yield of 75% of theory. C6H6O2BrCl3 (296.3752 g./mole).
Reaction SMILES: [C:1]([NH:9][C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:26][CH2:27][N:28]([C:11](=[O:13])[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:14]([CH3:16])[CH3:15])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: CC(C)=C(NC(=O)c1ccccc1)C(=O)O
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: CC(C)=C(NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1

Procedure:
The crude 2-benzamido-3-methylbut-2-enoic acid from Step 1 was coupled with 4-(4-chlorophenyl)piperidine hydrochloride in a similar manner as described for the preparation of Example 75 to provide Example 288, N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobut-2-en-2-yl)benzamide. MS found: 397 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=O)[CH3:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([C:7]1[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=2[C:16]=1[CH3:17])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(O)cccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12

Procedure:
The (2-acetyl-3-hydroxy-phenoxy)-acetic acid tert-butyl ester was dissolved in DMF, and heated to 110-130° C. in the presence of potassium carbonate for 4 hours. The resulting suspension was slowly poured into cold water. The product precipitated out and was collected by filtration. Recrystalyzation in toluene afforded 34.26 g of the desired 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as pale yellow solid (60% overall yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28]O)[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][Br:33])[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2occc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C2=C(c3cn(CCCBr)c4ccccc34)C(=O)NC2=O)c2occc2c1
Reaction time: 0.17 h

Procedure:
Dissolve 3-(5-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.058 g, 0.118 mmol) in 10 mL dichloromethane. Add carbon tetrabromide (0.077 g, 1 equivalent) and triphenyl phosphine (0.061 g, 1 equivalent). Stir for 10 min, add another equivalent of both reagents. Stir 10 min then dilute with dichloromethane and wash with water followed by brine. Dry over magnesium sulfate then filter and concentrate. Purification by column chromatography (2% methanol:dichloromethane) affords the 3-(5-methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl)pyrrole-2,5-dione. 3-(5-Methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl]pyrrole-2,5-dione is dissolved in 1.5 mL 1-methyl-2-pyrrolidinone and add dimethylamine (2M solution in tetrahydrofuran, 0.3 mL, 5 equivalents). Heat to 60° C. for 16 hrs. Extract with ethyl acetate versus water, concentrate organic layer. Redissolve in a minimal amount of methanol and load onto an SCX™ Varian column (pretreated with a 5% acetic acid: methanol solution). Wash with methanol and ethyl acetate to remove impurities, flush with 2M ammonia methanol to recover product. ES(M++H)444.0.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C@H:12]([C:14]([C:16]1([NH2:37])[C:22](=[O:23])[N:21]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:17]1=[O:36])=[O:15])[CH3:13]>>[CH:1]1([CH2:6][C:7]([NH:11][C@H:12]([C:14]([C:16]2([NH2:37])[C:22](=[O:23])[N:21]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17]2=[O:36])=[O:15])[CH3:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.50 (CH2Cl2/EtOAc, 1:1).