Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[NH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.CCCCCC>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:28]2[C:29]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][CH:4]=1
Reactant: Ic1ccc(-c2nc3ccccc3o2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc2oc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2c1
Temperature: 110 °C
Reaction time: 11 h
Yield: 88.6 %

Procedure:
In a 100 mL three-neck flask were put 1.5 g (4.7 mmol) of 2-(4-iodophenyl)benzoxazole, 0.78 g (4.7 mmol) of 9H-carbazole, and 0.99 g (10 mmol) of sodium tert-butoxide. The atmosphere in the flask was replaced with nitrogen. To this mixture was added 15 mL of toluene. The resulting mixture was degassed under reduced pressure, and then the atmosphere in the flask was replaced with nitrogen. To this mixture were added 0.10 mL of a 10% hexane solution of tri(tert-butyl)phosphine and 0.030 g (0.48 mmol) of bis(dibenzylideneacetone)palladium(0). This mixture was stirred under a nitrogen stream at 110° C. for 11 hours. After that, toluene was added to this mixture, and this suspension was washed with 1M dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in that order. After that, magnesium sulfate was added to the organic layer to dry it. Next, this mixture was suction filtered. The resulting filtrate was suction filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The resulting filtrate was concentrated, followed by purification by silica gel column chromatography. As developing solvents for the column chromatography, a mixed solvent of a 1:1 ratio of toluene to hexane, and then toluene were used. The fraction obtained was concentrated to give a solid. This solid was recrystallized with a mixed solvent of chloroform and methanol to give 1.5 g of a white powdered solid in a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]1.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>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]3)=[O:15])[N:12]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: OC1CCCNC1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Temperature: 25 °C

Procedure:
The 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylic acid (23a) (100 mg, 0.336 mmol) was dissolved in DMF (5 mL), piperidin-3-ol (1.679 mmol) was added and stirred at room temperature. Added DIPEA (1.343 mmol), followed by addition of HATU (1.008 mmol) and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH:CHCl3 as eluent to afford the title compound, (2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone.
Reaction SMILES: N[C:2]1C=C(C2C=CC=CC=2)C=C[C:3]=1C(NC1C=CC(OCCN2CCCC2)=C(OC)C=1)=O.[NH2:33][C:34]1[CH:58]=[C:57]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:56]=[CH:55][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[C:41]([O:53][CH3:54])[CH:40]=1)=[O:37]>>[CH3:54][O:53][C:41]1[CH:40]=[C:39]([N:38]2[C:36](=[O:37])[C:35]3[C:34](=[CH:58][C:57]([O:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)=[CH:56][CH:55]=3)[N:33]=[C:2]2[CH3:3])[CH:44]=[CH:43][C:42]=1[O:45][CH2:46][CH2:47][N:48]1[CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2c(C)nc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
Using 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide [Example C5] in the manner of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide in Example C4, gave the title compound;
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[C:14](=O)[CH3:15])C.[CH3:18][NH2:19]>CO.[O-]S([O-])(=O)=O.[Mg+2].ClCCl>[CH3:18][N:19]1[C:14](=[CH2:15])[C:6]2[C:5](=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:8][CH:7]=2)[C:4]1=[O:3]
Reactant: CCOC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: C=C1c2cccc([N+](=O)[O-])c2C(=O)N1C
Reaction time: 0.25 h

Procedure:
Ethyl-2-acetyl-6-nitrobenzoate (11.12 g) is suspended in a mixture of MeOH (70 mL) and MgSO4. Methylamine (2 molar in THF, 28.13 mL) is added dropwise and the solution is stirred for 15 min at this temperature. Then it is preheated to 70° C. for 18 h. The solvent is eliminated in vacuo, the residue is taken up in dichloromethane (100 mL), washed with sodium chloride solution (10%) dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. For purification it is recrystallised from toluene (250 mL).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:10]([OH:16])(O)[C:11]([F:14])([F:13])[F:12])[O:3]1>C1(C)C=CC=CC=1>[OH:3][C:4]1[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[O:16][C:6](=[O:8])[CH:5]=1
Reactant: CC1(C)OC(=O)C=C(CC(O)(O)C(F)(F)F)O1
Solvent: Cc1ccccc1
Product: O=c1cc(O)cc(C(F)(F)F)o1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2,2-dimethyl-6-(3,3,3-trifluoro-2,2-dihydroxy-propyl)-[1,3]dioxin-4-one (example C.22 step 1) (70 g, 273 mmol) in toluene (500 mL) was placed in a preheated (135° C.) oilbath, needed 10 min to reflux, then was refluxed for 25 min while distilling off about 150 mL of solvent. The hot solution was concentrated in vacuum to about 300 mL, some heptane was added, cooled to 23° C., filtered the precipitate off, washed with little cold toluene and dried in HV to give the title compound a light yellow solid (17.93 g, 36%). MS (ISN) 179.1 [(M−H)−].
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].Cl[C:9]1[N:14]=[N:13][C:12]([O:15][CH2:16][CH2:17][C@@H:18]([N:20]([C:35]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]2)=[O:36])[C:21]2[CH:25]=[C:24]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:23][C:22]=2[C:32]([OH:34])=[O:33])[CH3:19])=[CH:11][CH:10]=1.CC([O-])=[O:46].[Na+]>CC(O)=O.CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]#[C:26][C:24]1[S:23][C:22]([C:32]([OH:34])=[O:33])=[C:21]([N:20]([C@@H:18]([CH3:19])[CH2:17][CH2:16][O:15][C:12]2[N:13]=[N:14][C:9]([OH:46])=[CH:10][CH:11]=2)[C:35]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]2)=[O:36])[CH:25]=1
Reactant: C[C@@H](CCOc1ccc(Cl)nn1)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: C[C@@H](CCOc1ccc(O)nn1)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reaction time: 3 h

Procedure:
A mixture of 3-[[3-(6-chloro-pyridazin-3-yloxy)-1(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid TFA salt (0.56 g, 0.087 mmol) in AcOH (2.0 mL) and NaOAc (0.37 g, 0.434 mmol) was placed in a preheated 100° C. oil bath and stirred for 3 h. The reaction was determined to be complete by LC/MS. After cooling, the reaction was diluted with CH3OH (5 mL). 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(6-hydroxy-pyridazin-3-yloxy)-1-(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (0.07 g, 13%) was isolated by reverse phase HPLC as an off-white solid.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:12])[C:6]=2[CH:11]=1
Reactant: O=C1CCCOc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: OC1CCCOc2ccc(Br)cc21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
104.9 g (0.64 mole) of 2,3-dihydro-1-benzoxepin-5(4H)-one are dissolved at room temperature in 780 ml of glacial acetic acid and then, while stirring vigorously at 10° C., 113.9 g (0.64 mole) of N-bromosuccinimide are introduced in portions so that the temperature does not exceed 18°-20° C. (about 30 min). The reaction is complete after about 4 hours (TLC check) and the mixture is poured into 3 l of vigorously stirred ice-water and then stirred for 30 minutes. The solid produced which is initially oily crystallizes completely after some time. The solid is filtered off with suction and washed with about 5 l of water. It is dried over calcium chloride in vacuo and crystallized in cyclohexane.
Reaction SMILES: [CH2:1]=O.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:7]=3[C:6]=2[CH:5]=1.N>C(O)=O>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[C:8]3[CH2:20][CH2:21][N:22]([CH3:1])[CH2:23][CH2:24][C:7]=3[C:6]=2[CH:5]=1
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CCNCC3)cc1
Reactant: C=O
Agent: N
Solvent: O=CO
Product: CN1CCc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
8.7 ml of a 35% formaldehyde solution are added dropwise to a solution of 9 g of 9-fluoro-6-p-fluorophenyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole in 6.9 g of formic acid. The mixture is heated for 10 minutes to 70°, cooled, poured onto water, made alkaline with concentrated ammonia and extracted with ether. The ether extracts are dried over sodium sulphate and concentrated to give the title compound in hydrochloride form, m.p. 215° (decomp.; from ether/acetone).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:9][N+:10]([O-:12])=[O:11].Cl.[Cl-].[Na+]>C(O)(C)(C)C>[C:18]([N:17]1[CH2:16][CH2:15][CH2:14][S:13][C:8]1=[CH:9][N+:10]([O-:12])=[O:11])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(NCCCSC(Cl)=C[N+](=O)[O-])c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)(C)O
Product: O=C(c1ccccc1)N1CCCSC1=C[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
A solution of 0.10 g of potassium t-butoxide in 3 ml of t-butanol was added drop-by-drop over 5 minutes to a solution of 0.23 g of 15 in 10 ml of t-butanol under nitrogen, at room temperature. After 40 minutes, the mixture was poured into 2% hydrochloric acid saturated with sodium chloride and the resulting mixture was extracted with methylene chloride. The solvent was purified over silica gel to give 24, as a solid, m.p.: 90°-92° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[NH2:5]
Reactant: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
N-Boc-O-benzyl tyrosine methylamide (5.29 g, 13.8 mmol) was taken up in CH2Cl2 (100 ml). To the solution at 0° C. TFA (10 ml) was added dropwise and the solution allowed to warm to ambient temperature. After 4 hours the solvent and TFA were removed under vacuum. Any remaining TFA was quenched with saturated NaHCO3 solution (100 ml). The reaction mixture was extracted using CH2Cl2 (100 ml) and washed with saturated NaHCO3 solution (100 ml) and brine (100 ml). The CH2Cl2 layer was dried over Na2SO4 and the solvent was removed under vacuum to give a white solid, which was recrystallised from ethyl acetate/hexane to yield the title compound as a white crystalline solid (3.35 g, 85.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.ClC1C=CC=C(Cl)N=1.[Na].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:37]([NH:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1)(=[O:39])[CH3:38]>S1(CCCC1)(=O)=O>[C:37]([NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH2:43][CH2:42]1)(=[O:39])[CH3:38]
Reactant: Clc1cccc(Sc2ccccc2)n1
Reactant: CC(=O)Nc1ccncc1
Agent: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCN(c2cccc(Sc3ccccc3)n2)CC1
Temperature: 150 °C
Reaction time: 50 h
Yield: 48.5 %

Procedure:
A mixture of 9.5 g of 2-chloro-6-(phenylthio) pyridine (b.p. 112° to 116° C./0.01 mm Hg, prepared by reaction of 2,6-dichloropyridine with the sodium salt of thiophenol), 7.8 g of potassium carbonate and 7.6 g of 4-acetamidopyridine in 75 ml of sulfolane is heated to 150° C. with stirring for 50 hours, then the sulfolane is concentrated to 1/5th of its volume, the mixture is poured in 100 ml of water and extraction is effected four times with 150 ml of diethyl ether. The organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated to dryness and the residue is crystallised in 40 ml of ethyl acetate. 6.8 g of 4-acetamido-1-(6-phenylthio-2-pyridyl)piperidine are thus obtained; m.p. 110° to 112° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:21]>ClCCl>[OH:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:20]([C:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:21]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)C2(C)CCCN2C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.576 g, 3.45 mmol) and pyridine (0.546 g, 6.9 mmol) in anhydrous dichloromethane (20 mL) was added drop wise a solution of benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate (1.07 g, 3.8 mmol) in anhydrous dichloromethane (5 mL). After the addition, the mixture was stirred at room temperature overnight. Removed the solvents and purified by silica gel chromatography (petroleum ether/ethyl acetate=100:1 to 25:1) to obtain a yellow oil of benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (1 g, yield 66%). 1H-NMR (400 MHz, DMSO-d6): δ 1.53-1.58 (m, 3H), 1.88-1.91 (m, 3H), 1.28 (brs, 1H), 3.53-3.65 (m, 2H), 3.92 (s, 3H), 5.02-5.15 (m, 2H), 6.92-6.96 (m, 1H), 7.16-7.34 (m, 5H), 7.55-7.57 (d, J=7.8 Hz, 1H), 7.88-8.12 (m, 1H), 8.72-8.89 (d, 1H), 10.82 (s, 1H); LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:2]3[C:3](=[CH:21][C:22]([F:26])=[C:23]([F:25])[CH:24]=3)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O

Procedure:
19.2 g of ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-(4-fluoroanilino)-acrylate was dissolved in 95 ml of dimethylformamide, and 8.3 g of potassium carbonate was added thereto. The mixture was heated for 60 minutes at a temperature of from 100° to 110° C. The reaction mixture was returned to room temperature and poured into water. Precipitated crystals were collected by filtration and washed with ethonol. 15.6 g (90%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]2)=[N:4][N:3]=1.[CH3:27][N:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[CH3:26][N:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:32]3[N:28]([CH3:27])[N:29]=[CH:30][CH:31]=3)=[N:3][N:4]=2)[CH2:13][CH2:14]1)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Br)c3ccccc23)CC1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
Charge a reaction tube with tert-butyl 1-(4-bromophthalazin-1-yl)piperidin-4-yl(methyl)carbamate (500 mg, 1 2 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (370 mg, 1.8 mmol), sodium carbonate (252 mg, 2.4 mmol), toluene (3.75 mL), ethanol (1.25 mL), and water (1.25 mL). Degas the reaction mixture with nitrogen for 10 min. Add tetrakis (triphenylphosphine) palladium (137.1 mg, 118.7 μmol). Bubble nitrogen through the reaction mixture for another 10 min. Cap the reaction vial and heat at 90° C. overnight. Cool the reaction and filter through a silica gel pad eluting with 5% MeOH:CH2Cl2. Concentrate the fractions under reduced pressure. Purify the resulting residue using silica gel chromatography (2% 2 N NH3 in MeOH:CH2Cl2) to obtain the final product (345.6 mg, 69%). ES/MS m/z 423.2 (M+1).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[CH3:18]S(C)=O>>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:16][CH2:18]2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A stirred solution of 60% aqueous sodium hydroxide solution (117 mg, 2.92 mmol) in dimethyl sulfoxide (2 ml) was added with trimethyl sulfoxinium iodide (627 mg, 2.79 mmol) under a nitrogen atmosphere. The mixture was stirred for 45 minutes in ice-water bath, added slowly with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) while maintaining the temperature below 10° C. Upon completion of the addition, the mixture was stirred for 5 minutes in the ice-water bath and stirred for another 2 hours at 25° C. in an oil bath. The resulting mixture was added with cold water (20 ml) and extracted with ethyl ether (20 ml×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (479 mg, 85.5%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:17][CH2:24][C:23]([O:22][CH2:21][CH3:20])=[O:25])=[C:11]2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCBr
Reactant: Cc1cc2c(O)ccnc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccnc2c1cc(C)n2Cc1ccccc1

Procedure:
A mixture of 1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol 7 (0.30 g, 1.26 mmol), 2-bromoethylacetate (1.05 g, 6.29 mmol) and K2CO3 (2.0 g) in anhydrous acetone (15 mL) were heated at reflux for 6 h under N2. After cooling, the mixture was filtered through celite and the filtrate was concentrated to yield a syrup. It was then re-dissolved in ethyl acetate and washed with water (10×2 mL), brine and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was chromatographed on a silica gel column eluting with 40% ethylacetate in hexanes afforded the title compound 8 as an amorphous white solid. Yield: 0.25 g, 61%; ESI MS: m/z 325.0 (M+1).
Reaction SMILES: Cl.C(O)C.[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)C(=O)C3C=CC=CC=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:36]>O>[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:36]
Reactant: Cn1c(=O)ccc2cc(OCCCN(Cc3cccnc3)C(=O)c3ccccc3)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1c(=O)ccc2cc(OCCCNCc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 88.8 %

Procedure:
3N-Hydrochloric acid(5 ml) was added to a ethanol solution(5 ml) of N-[3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide(250.1 mg), and stirred for 60 hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, washed with ethyl acetate. A saturated sodium hydrogencarbonate aqueous solution was added to the aqueous layer, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure to give the title compound(168 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:20]([Cl:27])=[CH:21][C:22]([Cl:26])=[C:23]([OH:25])[CH:24]=1>>[Cl:27][C:20]1[CH:21]=[C:22]([Cl:26])[C:23]([OH:25])=[CH:24][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cc(O)c(Cl)cc1Cl
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Oc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(Cl)cc1Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-amino-2,4-dichlorobenzenol (51 mg, 0.289 mmol) similar to Example 117 and isolated as a white solid (24 mg, 31%). 1H NMR (DMSO-d6): 10.80 (s, 1H), 9.90 (s, 1H), 9.39-9.38 (m, 1H), 8.75-8.72 (m, 1H), 8.57-8.53 (m, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.59-7.55 (m, 1H), 7.31 (s, 1H).