Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:42]([NH2:44])=[O:43])[CH2:40][CH2:41]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
Combine 1-[2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (6 mmol) and THF (20 mL). Cool using an ice bath. Add a 1M THF solution of tetrabutylammonium fluoride (7 mL) in dropwise fashion. After 30 minutes, concentrate in vacuo to obtain a residue. Add dichloromethane (50 mL) to the residue. Extract with water (3×15 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:39])[C@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[C:27]([OH:26])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was coupled to (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.97 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 585.87; m/z found, 583/585 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.36 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.74-7.70 (m, 2H), 7.34 (d, J=8.2, 1H), 7.21 (d, J=1.9, 1H), 7.15 (d, J=8.4, 1H), 6.97 (dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0, 1H), 4.98 (q, J=5.7, 1H), 3.32-3.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:11]1[C:2]([Cl:1])=[CH:3][C:4]([O:13][CH3:14])=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cc(I)c(Cl)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Yield: 84 %

Procedure:
A mixture of Methyl 4-chloro-5-iodo-2-methoxybenzoate (1.8 g, 5.51 mmol), (2,5-dichlorophenyl)boronic acid (2.1 g, 11.03 mmol), Pd(PPh3)4 (403 mg, 0.55 mmol), Na2CO3 (1.75 g, 16.54 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at reflux under argon for 16 h. The mixture was filtered and filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (1.6 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cc(-c2cc(-c3cncc(Cl)c3)no2)cc(F)c1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 47 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.92 (dd, J=8.6, 6.6 Hz, 2H), 8.39 (t, J=2.0 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.04 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 311 (M+H)+, 313 (M+H)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([Br:9])[CH:3]=1.[CH3:10][C:11](=[CH2:19])[C:12]([O:14][CH2:15][CH:16]([OH:18])[CH3:17])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][C:11](=[CH2:10])[C:12]([O:14][CH2:15][CH:16]([O:18][C:7]1[CH:6]=[CH:5][C:4]([Br:9])=[CH:3][CH:2]=1)[CH3:17])=[O:13]
Reactant: C=C(C)C(=O)OCC(C)O
Reactant: Oc1ccc(O)c(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC(C)Oc1ccc(Br)cc1

Procedure:
Following the same preparation procedure of Example 2, the reaction was carried out with 4-hydroxy bromophenol (4 g), 2-hydroxypropyl 2-methylacrylate (3.33 g), triphenyl phosphine (6.06 g) and DIAD (4.69 g) in 50 ml of THF to give after chromatography purification pure 2-(4-bromophenoxy)propyl 2-methylacrylate as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH3:36])[CH3:35])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH3:35])[CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (90 mg) is dissolved in ethanol (2 ml), and thereto is added a 2N-aqueous sodium hydroxide solution (207 μl), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:4) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (29 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (23 μl) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid ethyl ester sodium salt (30 mg). MS (m/z): 623 [M−Na]−
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:12]2([C:15]#[N:16])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: N#CC1CCOCC1
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N#CC1(c2nccnc2Cl)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36 mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100% EtOAc/Hexane) were conducted to isolate product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2].S([O-])([O-])(=O)=[O:18].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[C:7](=[O:18])[CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)Nc1cc(F)c(F)c2c1CCCC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(F)c(F)c2c1C(=O)CCC2
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in (6) above (810 mg) in 30 ml of acetone was added 3 ml of 15% aqueous solution of magnesium sulfate. 1.17 gm of potassium permanganate was slowly added to the mixture while stirring. After 1 hour, the reaction product was extracted with chloroform, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 806 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[IH:11]>>[I:11][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: I
Product: Ic1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (673 mg, 4.41 mmol) and 7 mL of 57% hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 5 mL of water and brought to pH=8 with aqueous ammonia solution. The suspension was cooled down to 0° C. and the solid was filtered off, washed with cold water and dried to give the product to yield 970 mg of the product as a white powder. The product contains about 10% of the starting material.
Reaction SMILES: [C:1]1([C:7]2[C:20]3[CH2:19][CH2:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=3[N:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]1([C:7]2[C:20]3[CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=3[N:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2c3c(nc4c2CCc2ccccc2-4)-c2ccccc2CC3)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 (1.55 g, 4.31 mmol) was dissolved in 100 mL dioxane and 2,3-dichloro-5,6-dicyanobenzoquinone was added (6.88 g, 30.3 mmol). The mixture was refluxed under argon for 2 days. The reaction mixture was then cooled to room temperature, poured in 300 mL saturated aqueous sodium carbonate solution and stirred at 65° C. for 30 min. The mixture was then cooled to room temperature, the precipitation was filtered and washed with water and methylene chloride. Yield: 1.1 g (72%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:20][S:21]([O:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1COc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Reaction time: 0.5 h

Procedure:
To a solution of 0.410 g (2.467 mM) of (R)-2-hydroxymethyl-1,4-benzodioxane and 0.52 ml (3.70 mM) of triethylamine in 30 ml of diethyl ether was added 0.21 ml (2.71 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was passed through a short silica gel column (hexane-ethyl acetate=3/1 to 2/1) to provide crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1.C(OC(C)C)(C)C>O1CCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:10][CH2:9]1
Reactant: C=C1CC(=O)O1
Reactant: CC1CCC(N)CC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCC(C)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
29 g of diketene were added over 20 minutes to a stirred mixture of 39 g of 4-methylcyclohexylamine in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 3 hours. Isopropyl ether was added thereto and the precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 46 g of N-(4-methylcyclohexyl)-acetylacetamide melting at 111° C. A mixture of 46 g of the latter product, 37 g of methyl orthoformate, 1.5 g of p-toluene sulfonic acid and 100 ml of methanol was stirred for 2 hours at 20° C. and after standing for 16 hours, 3 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residue was added to toluene. The stirred mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope and was then cooled and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 methylene chloride-acetone mixture gave 24 g of N-(4'-methylcyclohexyl)-3-methoxy-crotonamide melting at 125° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(F)cc1Oc1ccc(N)nc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1cnc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of EXAMPLE 318B (1.6 g) in N,N-dimethylformamide (50 mL) was cooled to 0° C., followed by the addition of N-bromosuccinimide (1.195 g) in N,N-dimethylformamide (10 mL) solution. The reaction mixture was stirred at 0° C. for 1 hour, and quenched with ice-cold saturated NaHCO3 aqueous solution. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified using flash column purification with 30-40% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[C:27]5[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:26]=5[O:25][CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4c(OC)cccc4OC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,6-dimethoxy-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2,6-dimethoxybenzoyl chloride (178 mg, 0.87 mmol). The title compound was obtained as light brown powder (180 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[C:16]=3[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:26][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[O:13][C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[C:16]=3[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=2)[C:2]=1[Br:1])[CH3:39]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Method B, Step 5 of Example 1, the title compound was prepared from 1-bromo-6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-ol (1.5 g, 3.66 mmol), cesium carbonate (2.4 g, 7.34 mmol), ethyl bromoacetate (0.48 mL, 4.3 mmol) in acetone (35 mL). The title compound was obtained as an off-white solid (1.6 g), mp 93-95° C. Mass spectrum (+APCl, [M+H]+) m/z 495. 1HNMR (300 MHz, DMSO-d6): δ8.34 (s, 1H), 8.24 (d, 1H, J=9.0 Hz), 8.12 (d, 1H, J=9.1 Hz), 8.06-8.02 (m, 1H), 7.69 (d, 1H, J=7.1 Hz), 7.61 (d, 1H, J=7.7 Hz), 7.48 (d, 1H, J=9.1 Hz), 7.37-7.26 (m, 2H), 5.1 (s, 2H), 4.18 (q, 2H, J=7.1 Hz), 3.01 (t, 2H, J=7.3 Hz), 1.76-1.64 (m, 2H), 1.43-1.26 (m, 4H), 1.22 (t, 3H, J=7.1 Hz), and 0.85-0.79 ppm (m, 3H). Elemental Analysis for C27H27BrO4.1.0H2O: Calculated: C, 63.16; H, 5.69; N, 0.00. Found: C, 62.90; H, 5.19; N, 0.15.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=O)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][CH3:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 171, [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid, di-methylamine, iPr2NEt, and HATU are reacted to afford the product. LC-MS: 390 (M++1). 1H NMR (CDCl3): δ 3.05 (s, 6H), 3.1–3.2 (m, 4H), 3.6–3.8 (m, 4H), 4.05–4.15 (d, 2H), 4.9–5.0 (s, H), 5.8 (m, 1H), 6.1–6.2 (s, 1H), 7.1–7.2 (m, 1H), 7.6 (m, 1H), 7.7–7.8 (m, 1H).
Reaction SMILES: [Cl-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](C(OCC)=O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2.CS(C)=O>O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2ccc(Br)cc2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1Cc2ccc(Br)cc2C1
Temperature: 160 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Lithium chloride (66 mg, 1.55 mmol) was added to a solution of diethyl 5-bromo-1H-indene-2,2(3H)-dicarboxylate (200 mg, 0.58 mmol), DMSO (2 mL), and H2O (0.2 mL). The mixture was stirred overnight at 160° C. After cooled to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×20 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound (120 mg, 76%). 1HNMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.31 (d, 1H), 7.18 (d, 1H), 4.10 (q, 2H), 3.39-3.34 (m, 1H), 3.17-3.01 (m, 4H), 1.19 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)=[O:8])[CH3:2]>Br>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(OC)cc1
Agent: Br
Product: CCOC(=O)CCC(=O)c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 4-(4-methoxy-phenyl)-4-oxo-butyric acid ethyl ester (4.5 g, 19.0 mmol) was added 48% HBr (50 mL). After overnight stirring at 120° C., the reaction was concentrated and ethanol was added several times and concentrated to obtain 4.18 g product (94%); MS m/z 223 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:19])[O:11][C:10](=[O:12])[NH:9][C@H:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([CH2:26][O:27][C@@H:28]([CH3:32])[C:29](Cl)=[O:30])=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O>O1CCCC1>[C:20]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:25]=[CH:24][C:23]([CH2:26][O:27][C@@H:28]([CH3:32])[C:29]([N:9]2[C@@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]([CH3:19])([CH3:6])[O:11][C:10]2=[O:12])=[O:30])=[CH:22][CH:21]=1
Reactant: C[C@H](OCc1ccc(-c2ccccc2)cc1)C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](OCc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC(C)(C)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A butyllithium solution (9.7 M in hexanes, 7.64 mL, 74 mmol) was added drop-wise to a solution of C3 (13.5 g, 70.6 mmol) in tetrahydrofuran (800 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., A solution of C6 (21.3 g, 78 mmol) in tetrahydrofuran (50 mL) was then added slowly, and the reaction was stirred at −78° C. for 30 minutes and then at 25° C. for about 3 hours. The reaction mixture was then poured into phosphate buffer (pH 7) and extracted with ethyl acetate (2×). The organic extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a minimal volume. The resultant residue was then precipitated by addition of 1 liter of hexanes. The solid white product was collected by filtration, and the filtrate was concentrated. The resultant residue was purified by silica gel chromatography (gradient: 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate), to provide C7 as a white solid. Yield: 22.8 g, 75 LCMS m/z 430.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 0.85 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.57 (3H, s), 4.36 (2H, apparent s, actual AB quartet, J=12.3 Hz), 5.21 (1H, s), 5.21 (1H, q, J=6.6 Hz), 7.23 (2H, m), 7.38 (8H, m), 7.61 (4H, m).