Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:18][O:19][C:20]([C@H:22]1[N:25]([S:26]([O-:29])(=[O:28])=[O:27])[C:24](=[O:30])[C@H:23]1[NH:31]C(OCC1C=CC=CC=1)=O)=[O:21]>CO.[Pd]>[NH2:31][C@H:23]1[C@@H:22]([C:20]([O:19][CH3:18])=[O:21])[N:25]([S:26]([OH:29])(=[O:27])=[O:28])[C:24]1=[O:30]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: COC(=O)[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
A solution of 186 mg of (cis)-4-(methoxycarbonyl)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt in 2 ml of methanol is hydrogenated over 10% palladium on charcoal (95 mg) for 1.5 hours at 1 atmosphere. The catalyst is filtered off and rinsed with dichloromethane and the filtrate is treated with 97% formic acid and cooled to -50° C. (the presence of a seed crystal at this stage is necessary to induce crystallization). After crystallization commences, the mixture is allowed to stand for about 16 hours at 10° C. The resulting solid is washed with dichloromethane, hexane, and dried in vacuo, yielding 50 mg of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:44]=[CH:45][CH:46]=2)[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[CH:29]=2)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1.CO>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:44]=[CH:45][CH:46]=2)[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH:29]=2)=[O:27])[C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CCOC(=O)CCn1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cn(CCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 3-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]propionate (507 mg) in a mixture of 1,4-dioxane (8 ml) and methanol (2 ml) was added 1N aqueous sodium hydroxide (2 ml), and the mixture was stirred at 25° C. for 5 hours. After evaporation of the organic solvent, the residue was acidified (pH 2) with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with chloroform to give 3-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]propionic acid (375 mg) as an oil.
Reaction SMILES: [CH:1]1([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[OH:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:31]([O:30][C:28]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Oc1ccc(F)cc1C1NCc2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C1c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an-ice cooled solution of (±)-2-(2,3-dihydro-1H-isoindol-1-yl)-4-fluoro-phenol (13 mg, 0.055 mmol, 1.00 eq.) and DIPEA (37 μL, 0.218 mmol, 4.00 eq.) in DCM (2 mL), benzyl chloroformate (8 μL, 0.057 mmol, 1.05 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×2 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-(5-fluoro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH2:36][NH:37][CH2:38][CH2:39][CH2:40][OH:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:37]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OCCCNCc1ccc2ccccc2n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCCO)Cc2ccc3ccccc3n2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-[(quinolin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)[C:14]=3[S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:37].Cl>CN(C)C=O>[CH3:37][N:20]([C:19]1[C:14]2[S:13][CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[C:15]=2[N:16]=[CH:17][N:18]=1)[CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)csc23)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ncnc2c(-c3ccc(S(C)(=O)=O)cc3)csc12)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
54 mg (0.11 mmol) of tert-butyl 4-(7-(4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate obtained in Example 109 was dissolved in 2 ml of N,N-dimethylformamide, and 3.4 mg (0.143 mmol) of NaH was added thereto. After 0.5 hr, 10 μl (0.143 mmol) of iodomethane was dropwise added to the mixture at room temperature, heated to 50° C. and stirred for 3 hr. The resulting mixture was neutralized with 1 N aqueous hydrochloride, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure to obtain 40 mg of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1>[C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:3][CH:4]=2)[N:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(CCc2ccc(NCCNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of N-{4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg) in toluene were added tert-butyl (2-bromoethyl)carbamate (87.5 mg) and N,N-diisopropylethylamine (52 μl), and the mixture was stirred at 80° C. for 24 h. The reaction mixture was allowed to cool to room temperature, water (10 ml) was added, and the organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl {2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]ethyl}carbamate as a pale brown amorphous.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]4[S:22][C:23]([CH:25]=O)=[CH:24][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]4[S:22][C:23]([CH2:25][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:24][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: C1CCNC1
Reactant: CN1CCCN(c2ccc(-n3cnc4cc(C=O)sc4c3=O)cc2)CC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(CN5CCCC5)sc4c3=O)cc2)CC1

Procedure:
3-[4-(4-Methylperhydro-1,4-diazepin-1-yl)phenyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-6-carbaldehyde was reacted with pyrrolidine by method BA. The product with the molecular weight of 423.58 (C23H29N5OS) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][N:33]1CCO[CH2:35][CH2:34]1.CNCC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:34]([N:33]([CH3:32])[C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(C)C(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), N-methylethanamine (4.93 mg, 0.083 mmol), and HATU (31.7 mg, 0.083 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to give (R/S)-N-ethyl-2-hydroxy-N-methyl-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (11 mg, 0.022 mmol, 47.7% yield): LCMS=473.2 [M+H]+; 1H NMR (mixture of rotamers, 400 MHz, methanol-d4) δ ppm 8.16-8.27 (2H, m), 7.48-7.75 (7 H, m), 5.54 (1 H, s), 5.51 (1 H, s), 3.35-3.55 (2 H, m), 2.96 (3 H, s), 2.91 (3 H, s), 1.11 (3 H, t, J=7.15 Hz), 0.92 (3 H, t, J=7.04 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[S:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)([O-])=O.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.ClCCl.[Pd]>[N:14]1([CH2:13][CH2:12][N:11]2[CH2:10][CH2:9][S:8][C:7]3[CH:19]=[CH:20][C:4]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:5][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(CCN1CCCC1)CCS2
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: ClCCl
Product: N=C(Nc1ccc2c(c1)N(CCN1CCCC1)CCS2)c1cccs1
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a stirred solution of 6-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (649 mg, 2.212 mmol) in ethanol (5 mL) was added palladium, 10 wt. % on activated carbon (235 mg, 0.221 mmol) as a suspension in ethanol (5 mL). The resulting suspension was stirred under an atmosphere of hydrogen (balloon pressure) for 3 hours (yellow color disappears). The balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (1.262 g, 4.42 mmol) was added to the mixture. The resulting mixture was stirred under argon overnight at room temperature. The mixture was then diluted with dichloromethane and filtered through Celite. The filtrate was then diluted with saturated sodium carbonate and extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 25 (438 mg, 53.1%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.38 (brs, 2H), 6.19 (s, 1H), 6.08 (d, J=1H), 3.63-3.58 (m, 2H), 3.40-3.33 (m, 2H), 3.01-2.97 (m, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.49-2.42 (m, 4H), 1.70-1.61 (m, 4H); ESI-MS (m/z, %): 373 (MH+, 62), 276 (100); HRMS calculated for C19H25N4S2 (MH+), calculated: 373.1515, observed: 373.1512; HPLC purity: 97% by area.
Reaction SMILES: N[C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2.[OH-:14].[Na+]>>[OH:14][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2
Reactant: [OH-]
Reactant: Cc1nccc2[nH]c(=O)c(N)cc12
Agent: [Na+]
Product: Cc1nccc2[nH]c(=O)c(O)cc12
Reaction time: 8 h

Procedure:
This compound was prepared by heating 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one following in part the procedure described in Example E-4 without purification of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one by reacting said unpurified 3-amino compound with aqueous sodium hydroxide solution or by similarly reacting said purified 3-amino compound with aqueous sodium hydroxide solution. These procedures are described as follows. Following the procedure described in Example E-4 using 27 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, 60 ml of concentrated sulfuric acid, 200 ml of water and 9.1 g of sodium nitrite and after concentrating the reaction mixture to dryness on a rotary evaporator, the residue containing the corresponding said 3-amino compound was treated with 75 ml of 35% sodium hydroxide solution and 100 ml of water and the resulting aqueous mixture was heated on a steam bath for 30 hours and then acidified with acetic acid. The acidified mixture was allowed to stand at room temperature overnight and the resulting product that separated was collected, washed with water and air-dried. It was then recrystallized from 400 ml of boiling dimethylformamide, filtering off the insoluble material, concentrating the filtrate to a volume of about 200 ml and then allowing it to stand at room temperature for 3 hours. The yellow crystalline solid was collected, washed with methanol and dried at 100° C. to yield 7.6 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one, m.p. >320° C. The same compound was also prepared by heating a mixture containing 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one with 25 ml of 10% aqueous sodium hydroxide solution on a steam bath for 7 hours and then cooled to room temperature. The reaction mixture was acidified with acetic acid and the resulting white crystalline precipitate was collected, washed with water and dried at 95° C. to yield 1.2 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one, m.p. >320° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6])[CH3:2].S(Cl)(Cl)=O.CN(C)C=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1(O)CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)C1=CCOCC1
Temperature: 100 °C
Yield: 98.6 %

Procedure:
Step B To a solution of 2-(4-hydroxy-tetrahydro-pyran-4-yl)-2-methyl-propionic acid ethyl ester (19.5 g, 90 mmol) in chloroform (100 mL) was added thionyl chloride (13.3 mL, 180 mmol) and dimethylformamide (0.28 mL). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH solution (10 N) to adjust the “pH” of the mixture to basic. The mixture was then extracted with ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionic acid ethyl ester as a brown oil (17.6 g, 99%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH2:7]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:4].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:46](=O)[CH3:47])[CH:32]=[CH:33][C:34]=1[O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38].[Cl-].[NH4+]>C(COC)OC>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:46]([CH3:47])=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[O:22])[CH:32]=[CH:33][C:34]=1[O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:38])[CH3:39]
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: COCCCOc1cc(C(C)=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: CCOC(=O)C=C(C)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
In a three-necked round bottom flask, sodium hydride 60% (1.04 g, 26.0 mmol) was suspended in dimethoxyethane (15 mL) at 0° C. Ethyl[bis(2,2,2-trifluoroethoxy)phosphinyl]acetate (8.63 g, 26.0 mmol) was added and the mixture was stirred at room temperature for 15 minutes. A solution of 1-{3-(3-methoxypropoxy)-4-[(triisopropylsilyl)oxy]phenyl}ethanone (6.60 g, 17.3 mmol) and dimethoxyethane (20 mL) was added and the mixture was brought to reflux and stirred for 1 hr. The reaction mixture was hydrolyzed with saturated aqueous ammonium chloride (80 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2) to yield 7.5 g (81%) of the desired product as a colorless oil of a mixture of E and Z isomers.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH:10]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:18][C:19]1[C:20]([F:29])=[C:21]2[C:27]([NH2:28])=[CH:26][NH:25][C:22]2=[N:23][CH:24]=1>C1COCC1>[Cl:18][C:19]1[C:20]([F:29])=[C:21]2[C:27]([NH:28][C:15]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:16])=[CH:26][NH:25][C:22]2=[N:23][CH:24]=1
Reactant: Nc1c[nH]c2ncc(Cl)c(F)c12
Reactant: O=C(Cl)C1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]c2ncc(Cl)c(F)c12)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (279 mg, 2.16 mmol) followed by cyclopentanecarbonyl chloride (143 mg, 1.08 mmol) were added dropwise to 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 1.08 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then concentrated to dryness. The residue was triturated in water and then filtered. The solid was washed with ACN and dried under vacuum to provide N-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (186 mg, 61% yield) as a solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])/[C:6](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:7]/[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>O1CCCC1.CO>[Br:32][C:16]1[CH:17]=[C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])[CH:19]=[CH:20][C:15]=1[C:14]([NH:13]/[C:6](=[CH:7]\[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)/[C:5]([OH:34])=[O:4])=[O:33]
Reactant: COC(=O)/C(=C/c1nccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C(=C/c1nccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
A solution of 1N sodium hydroxide (0.16 mL, 0.16 mmol) was added to a solution of (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(thiazol-2-yl)propenoic acid methyl ester (Example 153; 39.3 mg, 0.076 mmol) in tetrahydrofuran/methanol (2:1; 0.25 mL). After the solution had been allowed to stir at room temperature for 16 h, a second portion of 1N sodium hydroxide solution (0.05 mL) was added and the reaction was allowed to proceed for another 24 h at ambient temperature. The solvent was evaporated using a rotary evaporator then high vacuum. The de-esterification had not gone to completion, so the residue was re-dissolved in tetrahydrofuran/methanol (2:1; 0.25 mL) and treated with a solution of 1N sodium hydroxide (0.16 mL, 0.16 mmol). The reaction mixture was stirred for 16 h and after the solvents were removed in vacuo, the residue was purified by HPLC to give (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(thiazol-2-yl)propenoic acid (14.8 mg, 39%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=417.2 (M+H)+