Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@H:2]([CH2:10][OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>O>[O:11]1[CH2:10][C@@H:2]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[O:12][C:13]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)[C@H](Br)CO
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C1(C(=O)OCC)OC[C@@H](C(=O)OC(C)(C)C)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
6.90 g of tert-butyl (2R)-2-bromo-3-hydroxypropionate and 5.3 g of diethyl ketomalonate were mixed, and after the heat-generated reaction solution returned to room temperature, 15 ml of hexane and 6.4 g of potassium carbonate were sequentially added, followed by stirring at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl ether. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 8.0 g (yield: 83%) of the above identified compound as a colorless oily substance.
Reaction SMILES: C[O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[CH3:22][O:21][C:15]1[CH:14]=[C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)c(OC)c1
Reaction time: 3 h
Yield: 69.8 %

Procedure:
As described in Example 99, (E,E)-5-(3,4-dimethoxyphenyl)-2,4-decadienoic acid methyl ester (4.9 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 3 hours the reaction was worked up in the usual manner and the crude acid was crystallized from ether-hexane to provide 3.27 g of (E,E)-5-(3,4-dimethoxyphenyl)-2,4-decadienoic acid, mp 98°-99.5° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]2[NH:26][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=3[N:25]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: N=C(N)COCCc1cccc(Cl)c1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 79.2). Light brown solid. MS: m/e=334.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11](N)[CH:12]=[CH:13][C:14]=2[F:15])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.N([O-])=O.[Na+].[OH-].[Na+].N.[BrH:24]>O.[Cu]Br.O1CCOCC1>[Br:24][C:11]1[CH:12]=[CH:13][C:14]([F:15])=[C:9]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=2)[CH:10]=1
Reactant: Nc1ccc(F)c(-c2ncc(F)cc2F)c1
Reactant: Br
Agent: [Cu]Br
Agent: N
Agent: O=N[O-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cnc(-c2cc(Br)ccc2F)c(F)c1
Temperature: -10 °C

Procedure:
To the 3-(3,5-difluoropyridin-2-yl)-4-fluorophenylamine prepared above was added 1,4-dioxane (5 ml) and 48% aqueous hydrogen bromide (15 ml). The solution was cooled to −10° C. and a solution of sodium nitrite (0.252 g) in water (1 ml) was added dropwise with stirring at such a rate as to maintain an internal temperature below −5° C. The mixture was then stirred for a further 1 h at <0° C. before a solution of copper(I) bromide (1.283 g) in 48% aqueous hydrogen bromide (5 ml) was added slowly with stirring to maintain a reaction temperature below 10° C. This mixture was then stirred at 10° C. for 1 h, ambient temperature a further 1 h and then heated at 35° C. for 30 min. The reaction mixture was then cooled in an ice-water bath and 4N aqueous sodium hydroxide (41 ml) was added slowly with stirring, followed by 30% aqueous ammonia (15 ml). The resulting mixture was extracted with ethyl acetate. The organic extract was evaporated and the residue subjected to chromatography on silica gel, eluting with 10% diethyl ether in isohexane, to afford 2-(5-bromo-2-fluorophenyl)-3,5-difluoropyridine (0.48 g) as a colourless solid: m/z (ES+) 288, 290 (MH+).
Reaction SMILES: [OH-].[Li+].[CH:3]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]([O:15]CC)=[O:14])[N:7]=1)([CH3:5])[CH3:4].Cl>O.CO>[CH:3]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]([OH:15])=[O:14])[N:7]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)Cn1nc(C(C)C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)C)nn1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Lithium hydroxide (342 mg, 8.15 mmol) in water (4 mL) was added to ethyl (3-isopropyl-5-methyl-1H-pyrazol-1-yl)acetate (Preparation 166, 571 mg, 2.72 mmol) in methanol (4 mL) and the mixture was stirred at room temperature for 30 minutes. Aqueous hydrochloric acid (2 M) was added to acidify the mixture then the solution was extracted with EtOAc (10 mL). The organic phase was dried over magnesium sulphate and evaporated in vacuo to afford the title compound as a cream solid in 66% yield, 328 mg. m/z 183 [M+H]+.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1COCC1.CC(C1C=C(C(C)C)C(C2C(OC)=CC(Cl)=C(OC)C=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.[Pd+2]>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: COc1cc(Cl)c(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 500 mg, 1.35 mmol) in toluene (5 mL), was added aniline (0.13 mL, 1.48 mmol) and chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalyst, 107 mg, 0.135 mmol), and the reaction was deoxygenated by purging with nitrogen for 10 minutes. Sodium tert-butoxide (194 mg, 2.02 mmol) in THF (2 mL) was added, and the reaction was again purged with nitrogen for 5 minutes. The reaction flask was sealed, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (100 mL) and the layers were separated. The organic layer was washed with water (2×25 mL) followed by saturated brine solution (25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified on a silica gel column (30% EtOAc/petroleum ether) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(phenylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calc'd. for C26H25ClN6 [M+H]+ 457. found 457.
Reaction SMILES: [NH2:1][C:2]1([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:41][CH3:42])[CH2:4][CH2:3]1.[O:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:2]3([NH:1][CH:46]4[CH2:47][CH2:48][O:43][CH2:44][CH2:45]4)[CH2:3][CH2:4]3)=[C:8]([O:41][CH3:42])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C1CCOCC1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(NC2CCOCC2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
The product of Example 2 (200 mg) was mixed with tetrahydro-4H-pyran-4-one (45 mg), NaHB(OAc)3 (96 mg) and HOAc (42 mg) in DCM (5 ml). The reaction mixture was stirred at 30° C. overnight. Saturated NaHCO3 (20 ml) was added to the reaction and the solution was further extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified by preparative TLC plate to give the titled compound. Mass: (M+1), 659
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: Brc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A 5 L, 3-necked round bottomed flask equipped with an overhead stirrer, dropping funnel, N2(g) inlet was charged with AlCl3 (432.5 g, 3.24 mol). The solids were cooled to 0° C. with an ice-H2O bath. DMF (71 ml) was added dropwise over a period of 35 min and the temperature was kept under 32° C. during the addition. The reaction mixture was heated to 50° C. and treated with 3-Nitrobenzoyl chloride (63.2 g, 0.34 mol). The reaction that ensued was exothermic and caused the internal reaction temperature to rise to 65° C. The reaction was stirred for 50 min then bromobenzene (33.5 ml, 0.32 mol) was added. The reaction was heated at 90° C. for 3 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 1:1) indicated completion of reaction. The reaction was cooled and ice-H2O (3 L) was added dropwise over a period of 1.5 h. The reaction was allowed to stir overnight. The solids were filtered, washed with H2O (1 L), saturated NaHCO3(aq) (1 L), another portion of H2O (500 mL) and Hexanes (500 mL). The product was dried in the vacuum oven at 40° C., 28 inHg for 30 hours to yield (4-Bromo-phenyl)-(3-nitro-phenyl)-methanone in 88% (85.34 g, 0.28 mol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>CC(N(C)C)=O>[N+:19]([C:14]1[CH:13]=[C:12]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:21])=[O:20]
Reactant: OCc1ccncc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(OCc2ccncc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
4-Hydroxymethylpyridine (50 mmoles, 5.45 g, 1 equivalent, commercially available from Aldrich) was added in a drop wise fashion to a stirred suspension of 60% sodium hydride (in oil) (55 mmoles, 2.2 g, 1.1 equivalent) in anhydrous DMA (100 ml) at room temperature, over a period of 5 minutes. Upon completion of addition the resulting green reaction mixture was stirred at room temperature for 20 minutes. 4-chloro-2-nitroaniline (50 mmoles, 8.62 g, 1 equivalent) was added to the stirred green reaction mixture over the course of 10 minutes. The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature, poured into ice-water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined ethyl acetate solutions were washed with water (2×100 ml) and saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica flash column chromatography using 20% ethyl acetate-hexane to give 1.576 g of 2-nitro-4-(pyridin-4-ylmethoxy)aniline. (Yield 13%). 1H-NMR (400 MHz, DMSO-d6) 8.60 (d, 2H), 7.91 (d, 1H), 7.52 (br s, 2H), 7.43 (d, 2H), 6.50 (d, 1H), 6.34 (d, 1H), 5.31 (s, 2H). (MS (EI): 246 (MH+).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:41][OH:42]>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:41][OH:42])=[O:27])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1C=Cc2ccccc2-c2ccccc21
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C=C1C=Cc2ccccc2-c2ccccc21)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
6-(2-(5H-dibenzocyclohepten-5-ylidene)acetamido)hexanoic acid (361 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (143 mg, 38%) as a yellow solid.
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>COCCOC>[CH3:20][C:4]1([CH:1]([CH3:3])[CH3:2])[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C(C)C)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Temperature: 30 °C

Procedure:
A stirred suspension of 2-isopropyl-5-methoxy-6,7-dichloro-1-indanone (7.3 g., 0.025 mole) and sodium hydride (810 mg., 0.028 mole) in anhydrous 1,2-dimethoxyethane (250 ml.) is heated in an inert atmosphere at 80°-85° C. for one hour, cooled to 30° C. and treated with methyl iodide (6 ml.). The reaction mixture is heated to 80° C., then the solvent is distilled at reduced pressure and the residue poured into ice water. The 2-methyl-2-isopropyl-5-methoxy-6,7-dichloro-1-indanone which separates (7.0 g.) melts at 143° C. after recrystallization from ethanol-water.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH:15]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:16]=[CH2:17])=[CH:13][C:12]([CH3:27])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[NH:10]2)(=[O:3])[CH3:2].S([O-])([O-])=[O:30].[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([CH:15]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:16]2[O:30][CH2:17]2)=[CH:13][C:12]([CH3:27])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[NH:10]2)(=[O:3])[CH3:2]
Reactant: C=CC(CO[Si](C)(C)C(C)(C)C)c1cc(C)c2[nH]c(=O)ccc2c1OC(C)=O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1c(C(CO[Si](C)(C)C(C)(C)C)C2CO2)cc(C)c2[nH]c(=O)ccc12

Procedure:
5-Acetoxy-6-[1-(tert-butyldimethylsilyloxy)methyl-2propenyl]-8-methylcarbostyril (6.00 g, 15.0 mmol) was dissolved in chloroform (100 ml), to which m-perbenzoic acid (13.0 g, 52.7 mmol) was added. The mixture was stirred for hours. Saturated aqueous sodium sulfite solution was added to the reaction mixture, followed by stirring for 90 minutes. The organic phase was washed with saturated NaCl solution, dried over sodium sulfate and condensed under reduced pressure. The resultant residue was recrystallized from chloroform--n-hexane. As a result, 6.10 g of the title compound (mixtures of diastereomers, 3:1) was obtained as colorless powdery crystals (97.8%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[N:19][N:20]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:21]=2)=[CH:13][C:12]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[N:19][N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:21]=2)=[CH:13][C:12]([C:35]2[CH:36]=[C:37]([Cl:43])[C:38]([OH:42])=[C:39]([Cl:41])[CH:40]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cnn(C2CCNCC2)c1)C1CC1
Yield: 71 %

Procedure:
Following general procedure A-2, tert-butyl 4-(4-((3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (36 mg, 0.058 mmol) was reacted with TFA (2 mL) to afford the desired product (21.5 mg, 41%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.48 (br s, 1H), 8.22 (d, J=9.2 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.69 (s, 1H), 7.39 (br s, 2H), 4.68-4.58 (m, 1H), 3.57 (dt, J=13.2, 3.8 Hz, 2H), 3.27-3.17 (m, 2H), 2.88 (br s, 1H), 2.36-2.25 (m, 4H), 1.41-1.10 (m, 4H). ESI MS m/z 522 [C27H25Cl2N5O2+H]+; HPLC>99% (AUC), tR=9.75 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from 2-Methoxy-5-pyridine boronic acid and (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 366.4
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])OC(C)(C)C)=[C:4]([F:17])[C:3]=1[C:18](=[O:41])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[C:25]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:78]1[CH2:82][CH2:81][CH2:80][C@H:79]1C(O)=O>Cl.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]([C@@H:79]2[CH2:80][CH2:81][CH2:82][O:78]2)=[O:14])=[C:4]([F:17])[C:3]=1[C:18](=[O:41])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[C:25]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12)c1c(Cl)ccc(CNC(=O)[C@@H]2CCCO2)c1F
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of tert-butyl 4-chloro-2-fluoro-3-((4-((3-(trifluoromethyl)phenyl)amino)quinazolin-8-yl)carbamoyl)benzylcarbamate (Intermediate-16, 80 mg, 0.135 mmol) in HCl in MeOH (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (1 mL). The solution was treated with DIPEA (87 mg, 0.675 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (119 mg, 0.27 mmol) followed by (S)-(−)-tetrahydro-2-furoic acid (24 mg, 0.203 mmol) at rt. The reaction mixture was stirred for 2 h before it was diluted with EtOAc and was washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.67 (s, 1H), 10.14 (s, 1H), 8.79 (d, 1H), 8.71 (s, 1H), 8.47 (br t, 1H), 8.37 (m, 2H), 8.25 (d, 1H), 7.73-7.65 (m, 2H), 7.50 (d, 1H), 7.39 (m, 2H), 4.33 (m, 3H), 3.94 (m, 1H), 3.80 (m, 1H), 2.14 (m, 1H), 1.84 (m, 3H); MS (m/z): 588.34 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Yield: 78.8 %

Procedure:
A solution of 4-hydroxy-2-methylbenzoic acid (550 mg, 3.60 mmol), benzyl chloride (458 mg, 3.60 mmol) and N,N-diisopropylethylamine (465 mg, 3.6 mmol) was stirred at 70° C. for 22 h. A solution of saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford phenylmethyl 4-hydroxy-2-methylbenzoate (687 mg, 79%). 1H NMR (400 MHz, DMSO): 10.21-10.18 (br. s, 1H), 7.84-7.77 (d, 1H), 7.48-7.31 (m, 5H), 6.71-6.64 (br. s, 2H), 5.26 (s, 2H), 2.47 (s, 3H). MS (EI) for C15H14O3: 243 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][S:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:13][C:3]1[S:4][CH:5]=[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:2]=1[CH3:1]
Reactant: Cc1cscc1C1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C2CCCCC2)csc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To an icebath-chilled solution of 3-methyl-4-cyclohexylthiophene (10 g, 55.55 mmol) in DMF (60 mL) was added solid N-bromosuccinimide (9.89 g, 55.55 mmol). After addition, the mixture was allowed to warm to room temperature and was stirred for about 1 hr at which point HPLC analysis indicated the reaction was complete. The product mixture was poured into 200 mL of cold water and the aqueous phase was extracted with ether (3×125 mL). The combined ether extracts were washed with water (3×250 mL) and brine (1×200 mL), then passed through a cone of DRIERITE. Solvent was removed by rotary evaporation to afford the crude product 2-bromo-3-methyl-4-cyclohexylthiophene (13.6 g, 94%) as a light amber oil which was judged to be of greater than 95% purity product. 1H NMR (CDCl3) δ 6.88 (s, 1, ArH), 2.53 (m, 1, cyclohexylmethine) 2.19 (s, 3,ArCH3), 1.9 and 1.35 ppm (m, 10, cyclohexyls).13C NMR 147.81, 135.93, 118.32, 109.44 (thiophene carbons), 39.27, 33.55, 26.86, 26.24 and 13.73 (aliphatic carbons). 2D NMR confirmed that the bromine was bonded to the carbon adjacent to the 3-methyl substituent.