Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:29]([N:33]=[C:34]=[O:35])([CH2:31][CH3:32])[CH3:30]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:34]([NH:33][CH:29]([CH2:31][CH3:32])[CH3:30])=[O:35])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CCC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 75.7 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (150 mg, 0.42 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 475 mg, 1.26 mmol), molecular sieves and sec-butyl isocyanate (49 μL, 0.42 mmol). The resultant mixture was shaken at ambient temperature for 16 b, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (24 mL), then evaporated to afford the desired product as a colourless gum (135 mg, 77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:20]=[C:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](I)[CH3:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:41][CH3:42])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:20]=[C:21]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(NS(C)(=O)=O)c(OCc3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CC)S(C)(=O)=O)c(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ethyl 5-(benzyloxy)-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (0.2 g, 0.41 mmol, 1 eq) was dissolved in DMF and cooled to 0° C. Potassium carbonate (0.171 g, 1.6 mmol, 3 eq) was then added and the reaction mixture stirred for 15 minutes. Ethyl iodide (0.037 ml, 0.45 mmol, 1.1 eq) was added slowly dropwise and the resulting mixture was stirred at room temperature for 4 h. The solution was concentrated completely and diluted with water and the product was extracted with dichloromethane twice. The combined organic extracts were washed with water and concentrated yielding the desired product. Yield: 0.16 g (76 N. 1HNMR (400 MHz, DMSO-d6): δ 1.07-1.10 (t, J=7.16 Hz, 3H), 1.21-1.24 (t, 3H), 3.04 (s, 3H), 3.64 (m, 2H), 4.19-4.24 (q, J=7.04 Hz, 2H), 5.38 (s, 2H), 7.28 (t, J=8.8 Hz, 2H), 7.42-7.54 (m, 3H), 7.57-7.65 (m, 3H), 7.77-7.95 (m, 2H), 9.02 (s, 1H). LCMS: (ES+) m/z=512.0 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:52]1[CH2:55][CH:54]([OH:56])[CH2:53]1>CN(C=O)C>[CH:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([N:52]4[CH2:55][CH:54]([OH:56])[CH2:53]4)=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc2nc(C3CCCCC3)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2nc(C3CCCCC3)oc2c1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-cyclohexyl-benzooxazole-6-carboxylic acid (0.47 g, 1.9 mmol) and HBTU (0.94 g, 2.5 mmol) in DMF (10 mL) was added DIPEA (1.4 mL, 7.6 mmol). The resulting mixture was stirred at room temperature for 10 min, and then the hydrochloride salt of azetidin-3-ol (0.452 g, 4.7 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, and then purified by reverse phase liquid chromatography. Fractions containing product were lyophilized to yield (2-cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone. MS m/z (M+H+) 301.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[F:8][C:6]1[CH:5]=[C:4]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10]/[C:11](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:32]\[OH:33])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2cc(F)cc(F)c2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2cc(F)cc(F)c2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(3,5-difluorophenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=447.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>O1CCCC1>[C:1]([O:5][C:6](=[O:10])[C@@H:7]([NH:8][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: C[C@H](NCCCS(=O)(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a solution of L-Alanine tert-butylester (1.53 g, 10.5 mmol) in tetrahydrofuran (20 mL) was added 1,3-propanesultone (1.16 g, 9.6 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in water (80 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (80 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (1.37 g, 54%). 1H NMR (D2O, 500 MHz) δ ppm 3.88 (m, 1H), 3.09 (m, 2H), 2.86 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.39 (d, 3H, J=7.3 Hz), 1.35 (s, 9H). 13C (D2O, 125 MHz) δ ppm 169.13, 86.12, 56.24, 47.94, 44.71, 27.11, 21.52, 14.17. [α]D=−1.1° (c=0.0027 in water), ES-MS 266 (M−1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH3:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:10]1[CH2:9][C:8]([CH3:24])([CH3:23])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11]1)[CH3:22]
Reactant: CCc1ccccc1C1CC(C)(C)c2cc(C(=O)OC)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccccc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a stirred mixture solution of 2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (0.6 g, 1.78 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.5 g, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=310.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH2:8]1.[OH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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]>[OH:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:34]=[CH:33][CH:32]=[C:4]([CH2:5][O:6][C@H:7]3[CH2:11][CH2:10][N:9]([C:12]([CH3:30])([CH3:31])[CH2:13][CH2:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]#[N:17])[CH2:8]3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(Br)c2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(-c3cccc(O)c3)c2)C1
Yield: 25 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (16 mg, 19 μmol) was added to a solution of the product of example 55 (205 mg, 0.38 mmol), 3-hydroxyphenylboronic acid (106 mg, 0.77 mmol) and sodium carbonate (81 mg, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL) and the mixture was heated under reflux for 16 hours. The cooled reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol, 98:2 to 96:4, to afford the title compound in 25% yield, 51 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:24][C:25](=[O:27])[CH3:26])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:24][C:25](=[O:27])[CH3:26])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: [H][H]
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCOC1CCCCO1)COc1cccc(C(F)(F)F)c1

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-(3-trifluoromethylphenoxy)-2-pentyne (40.18 g.; 0.104 mole) is dissolved in ethyl acetate (200 ml.). 5% Palladium on carbon (5 g.) is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 45 lbs./in2 and 25°. When 0.208 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil, yield 40.60 g.; pmr (CDCl3)δ2.13 (3H, s CH3COO), 4.10 (2H, d CH2O), 5.20 (1H, m CHOCO), 7.22 (4H, m Aryl H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:29][C@H:30]1[CH2:32][O:31]1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:29][C@@H:30]([OH:31])[CH3:32])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: C[C@H]1CO1
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@H](C)O)C1
Temperature: 120 °C
Yield: 26.5 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (2.5 g, 6.3 mmol) in ethanol (130 mL) was treated with (S)-(−)-methyloxirane (1.1 mL, 16 mmol) and heated in the microwave at 120° C. for 25 min. The reaction mixture was concentrated to give a residue that was purified by flash column chromatography using methanol in dichloromethane (0%-10%; methanol contained 0.5% triethylamine) and by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.76 g, 26%). The product was isolated as a single diastereomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 7.34 (br s, 2H), 6.23 (q, J=7.0 Hz, 1H), 4.35 (br s, 1H), 4.14-3.99 (m, 1H), 3.98-3.87 (m, 2H), 3.64 (s, 3H), 3.60-3.52 (m, 1H), 3.13-2.99 (m, 2H), 2.55 (s, 3H), 2.28 (d, J=5.9 Hz, 2H), 1.75-1.69 (m, 3H), 1.00 (d, J=6.2 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[CH2:15][NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNCC(=O)OC(C)(C)C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a mixture of 2,2-dimethoxyethylamine (15 g, 143 mmol), anhydrous potassium carbonate (20 g, 145 mmol) and DMF (140 mL) was added tert-butyl bromoacetate (11.5 mL, 71.2 mmol). After stirring at room temperature for 2 hours, another portion of tert-butyl bromoacetate (11.5 mL, 71.2 mmol) was added to the mixture, which was stirred overnight at room temperature. To the reaction mixture was added ice-water (140 mL). The mixture was extracted with EtOAc. The organic layer was washed with sat. NaCl, dried over Na2SO4, filtered and evaporated. The residue was subjected to distillation under reduced pressure to give the title compound as a colorless oil (6.61 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:4]=[C:3]2[C:8](=[CH:18][CH:17]=1)[C:9]([C:13]1[CH:12]=[CH:11][C:10]3[C:15](=[CH:2][C:3]4[C:8]([CH:9]=3)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:14]=1)=[CH:10][CH:15]=[CH:2]2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc2c(-c3ccc4cc5ccccc5cc4c3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
9,10-Dibromoanthracene (23.63 g, 70.3 mmol), 300 mL of THF and a catalytic amount of dichlorobis(triphenylphosphine)palladium (II) were all placed under nitrogen in a round bottomed flask. The Grignard reagent prepared above was then added via a double-end needle transfer while still warm. After the addition, the reaction mixture was allowed to reflux overnight. After cooling to room temperature, the precipitated solid was collected by vacuum filtration and washed with ether, THF, and water. The collected solid was placed into a beaker and HCl (6M) was added followed by ethanol. This mixture is stirred for 60 minutes and the solid is again collected by vacuum filtration. The product was washed until the washings are neutral. After drying, the solid is refluxed gently in CH2Cl2 for 60 minutes. The pure product was filtered and dried to give 85.2 g solid (82% yield) (AA8790-34). 1H NMR (CDCl3) δ(ppm): 3.97 (s, 6H), 7.29 (dd, J1=8.9 Hz, J2=2.4 Hz, 2H), 7.40 (d, J=6.9 Hz 2H), 7.41 (d, J=6.9 Hz, 2H), 7.53 (d, J=2.2 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.64 (d, J=6.8 Hz, 2H), 7.65 (d, J=6.8 Hz, 2H), 7.94 (d, J=9 Hz, 2H), 7.97 (s, 2H), 8.10 (d, J=8.4 Hz, 2H);. FD-MS: m/z 490 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:20]([F:21])([F:23])[F:22])[CH:4]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(F)c(C(F)(F)F)c4)ncnc23)c1F
Yield: 8.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4-fluoro-3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-17, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 178 mg, 0.62 mmol), oxalyl chloride (118 mg, 0.93 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) in CH2Cl2 (5 mL) to afford 16 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 10.15 (s, 1H), 8.82-8.79 (d, J=8.1 Hz, 1H), 8.69 (s, 1H), 8.33-8.30 (m, 3H), 8.16 (br t, 1H), 7.75-7.69 (t, J=8.4 Hz, 1H), 7.62-7.55 (d, J=10.2 Hz, 1H), 7.42-7.34 (m, 2H), 4.32-4.30 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.28 (M+H)+.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[OH:9][C@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@:12]([C@@H:26]2[CH2:30][S:29][C:28](=[O:31])[N:27]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([O:24][CH3:25])[CH2:11]1.O[C@H]1C[C@@H](CCCC=C)O[C@]([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)(OC)C1.[CH3:70][C:71]([CH3:76])=[CH:72][C:73](O)=[O:74].C/C(/CCC=C)=C/C(O)=O>>[CH3:70][C:71]([CH3:76])=[CH:72][C:73]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][C@@:12]([O:24][CH3:25])([C@@H:26]2[CH2:30][S:29][C:28](=[O:31])[N:27]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:11]1)=[O:74]
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@@H](O)C[C@@H](CCc3ccccc3)O2)cc1
Agent: C=CCC/C(C)=C\C(=O)O
Agent: C=CCCC[C@@H]1C[C@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: O=S(=O)([O-])C(F)(F)F
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H](OC(=O)C=C(C)C)C[C@@H](CCc3ccccc3)O2)cc1

Procedure:
Triflate formation using the method shown in Example 22, with the modification that (R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, followed by triflate displacement using the method shown in Example 23, with the modification that 3-methyl-2-butenoic acid is substituted for (Z)-3-methylhepta-2,6-dienoic acid, affords the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([S:1][C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][N:28]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(S)cc1OC
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2nccnc2Cl)cc1OC
Yield: 33.3 %

Procedure:
To a solution of 6.45 g of methyl 4-mercapto-5-nitro-o-anisate in N,N-dimethylformamide (100 ml) were added 4.4 g of potassium carbonate and 4.75 g of 2,3-dichloropyrazine. Then the mixture was allowed to react at 80° C. for 2 hours. After adding ethyl acetate, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.14 g of the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19](=[O:35])[C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19](=[O:35])[C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br

Procedure:
2-(2-Bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)acetic acid is prepared from tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=[C:12]([C:13]4[C:14]([CH3:27])=[N:15][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=5)[C:17]=4[CH3:18])[C:7]3=[CH:6][C:5]=2[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[CH:40][CH:39]=2)[CH2:3][CH2:2]1.[OH-].[Li+]>CO.O>[CH:1]1([C:4]2[N:9]=[C:8]3[NH:10][CH:11]=[C:12]([C:13]4[C:14]([CH3:27])=[N:15][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=5)[C:17]=4[CH3:18])[C:7]3=[CH:6][C:5]=2[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:45][CH2:46][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:48][CH2:49]3)=[CH:40][CH:39]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c(C4CC4)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2nc(C3CC3)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 16.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(6-cyclopropyl-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (111 mg, 0.14 mmol) was hydrolyzed by lithium hydroxide (17.6 mg, 0.42 mmol), in methanol/water (3/2 ml) to afford 14 mg of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.7 (b, 1H), 7.52 (s, 1H), 7.40-7.37 (m, 2H), 7.107-7.099 (d, 1H), 7.002-6.9 (m, 3H), 6.9-6.8 (m, 1H), 5.26 (s, 2H), 3.62-3.59 (t, 3H), 3.209-3.117 (t, 3H), 2.22 (s, 1H), 3.12 (s, 3H), 1.496 (s, 9H), 1.16-1.15 (m, 2H), 0.91-0.87 (m, 2H). MS: m/z=621.3 (M+1).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([NH:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:7]1=[O:30])([OH:4])=[O:3].[OH-].[Na+].Cl>C(O)C>[ClH:1].[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([NH:23][CH2:24][C:25]([OH:27])=[O:26])[C:7]1=[O:30])([OH:4])=[O:3]
Reactant: CCOC(=O)CNC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
410 mg of the compound obtained in Example 25 was dissolved in a mixture consisting of 3.5 ml of a 1N aqueous solution of sodium hydroxide and 5 ml of ethanol, and the resulting solution was stirred for 30 minutes. Then, the solution was adjusted to pH 1-2 with concentrated hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in ethanol and the insoluble matter was filtered off. After the filtrate was concentrated, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 330 mg of the desired compound.