Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[H-].[Na+].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.C(N1C2C(=CC=CC=2)C(=O)C=C1C1SC=CC=1)C>>[CH:20]1([C:23]([NH:6][C:5]2[CH:7]=[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:24])[CH2:22][CH2:21]1
Reactant: CCCCOc1cc(N)c(C(C)=O)cc1OC
Reactant: O=C(Cl)C1CC1
Agent: CCn1c(-c2cccs2)cc(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCCCOc1cc(NC(=O)C2CC2)c(C(C)=O)cc1OC
Yield: 87.4 %

Procedure:
2-Acetyl-5-n-butoxy-4-methoxyaniline (320 mg), 60% sodium hydride (81 mg) and cyclopropylcarbonyl chloride (296 mg) were reacted in the same manner as in the preparation of compound 97 to obtain N-cyclopropylcarbonyl-2-acetyl-5-n-butoxy-4-methoxyaniline (360 mg). This compound (250 mg) and potassium t-butoxide (460 mg) were reacted with each other in the same manner as in the preparation of compound 95 to obtain 7-n-butoxy-2-cyclopropyl-6-methoxy-4(1H)-quinolone (compound 115, 90 mg).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([Cl:20])=[O:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: O=S(Cl)Cl
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Temperature: 50 °C

Procedure:
Trans-4-(trans-4-ethylcyclohexyl)cyclohexanecarboxylic acid (2.4 g, 0.01 mol) and thionyl chloride (10 ml) were introduced into a flask and warmed to 50° C. to obtain a uniform reaction liquid in 3 hours, followed by distilling off excess thionyl chloride under reduced pressure to obtain as a remaining oily substance, trans-4-(trans-4-ethylcyclohexyl)cyclohexanecarboxylic acid chloride. This acid chloride was added to a solution obtained by dissolving 2,4-difluorophenol (1.3 g, 0.01 mol) in pyridine (10 ml), followed by adding dry toluene (100 ml), sufficiently shaking the mixture, allowing it to stand over night, pouring the reaction liquid into water, washing with 6N hydrochloric acid, then with 2N NaOH aqueous solution, washing with water till the aqueous layer became neutral, drying the toluene layer with anhydrous sodium sulfate, drying, distilling off toluene under reduced pressure and recrystallizing the remaining oily substance from ethanol to obtain the objective trans-4-(trans-4-ethylcyclohexyl)cyclohexanecarboxylic acid-2,4-difluorophenyl ester. Yield 2.1 g (60%). It had a C-N point (phase transition point) of 76.3°-76.7° C. and a N-I point of 151.7° C. C, N and I are defined as in Table 1.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].CON(C)[C:9]([C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:15]2[CH:14]=[C:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=1)=[O:10]>O1CCCC1.[NH4+].[Cl-]>[C:9]([C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:15]2[CH:14]=[C:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=1)(=[O:10])[CH2:1][CH2:2][CH3:3]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)N(C)OC)n2n1
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12

Procedure:
Propylmagnesium chloride (1.00 mL) was cooled to 0° C. then charged with 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methoxy-methyl-amide (252 mg, 0.682 mmol) in tetrahydrofuran (4.00 mL). After 24 h the reaction was diluted with tetrahydrofuran and neutralized with NH4Cl. The organic was dried over magnesium sulfate and concentrated leaving a solid. The crude was recrystallized (ethyl acetate) to afford the final product 1-(5-butyryl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)-3-ethyl-urea. MS (APCI+): m/z 353.4 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1)(=[O:9])[CH3:8].[N:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[F:33])=[N+:21]=[N-:22]>C(O)(C)(C)C>[NH2:19][C:18]1[N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=2[F:33])[N:21]=[N:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Reactant: CC(=O)Nc1ccc(CC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Yield: 29.2 %

Procedure:
To a stirred and ice-cooled solution of potassium tert-butoxide (0.432 g, 3.6566 mmol) in tert-butanol (15 ml), commercial 4-acetamidophenylacetonitrile (0.5096 g, 2.9252 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (0.500 g, 2.4377 mmol) are added under a nitrogen atmosphere and the reaction mixture is allowed to attain spontaneously room temperature (1 h) and finally refluxed for 6 h. The resulting reaction mixture is concentrated, added water, and extracted with ethylacetate (3×100 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a dark brown gummy material (0.900 g, 97% mass balance). The crude residue is purified by column chromatography over silica gel (230-400 mesh), eluting with 50% ethylacetate in petroleum ether, to obtain the title compound as a light yellow solid (0.270 g, 30% yield). M.p. 114.8-116.2° C. LC-ESI-HRMS of [M+H]+ shows 380.1125 Da. Calc. 380.113447 Da, dev. −2.5 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:20]=[O:21])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>[Zn]>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:20]([OH:21])[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Product: CCOC(=O)C(F)(F)C(O)C(CC1CCCCC1)NC(=O)OCc1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield from N-benzyloxycarbonyl-3-cyclohexylalaninal, ethyl bromodifluoroacetate and zinc by the procedure described in Example 1.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[N:18]2[C:19]3[C:24]([NH:25][C:26](=[O:27])[C:17]2=[N:16][N:15]=1)=[CH:23][C:22]([C:28]([N:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29])=[C:21]([CH3:39])[CH:20]=3)C1C=CC=CC=1>[Pd].C(O)C>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][N:30]1[C:28]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[CH3:39])[N:18]1[C:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[OH:8])=[N:15][N:16]=[C:17]1[C:26](=[O:27])[NH:25]2)=[O:29]
Reactant: Cc1cc2c(cc1C(=O)N1Cc3ccccc3C1)[nH]c(=O)c1nnc([C@@H]3CCC[C@@H]3OCc3ccccc3)n12
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(cc1C(=O)N1Cc3ccccc3C1)[nH]c(=O)c1nnc([C@@H]3CCC[C@@H]3O)n12
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a mixture of 0.355 g of 1-[cis-2-(benzyloxy)cyclopentyl]-7-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 50.0 mL of ethanol was added 142 mg of 10% palladium on carbon (50% wet), followed by stirring overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=97/3 to 90/10) to give a powder from 2-propanol, thereby obtaining 114 mg of 7-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-1-[cis-2-hydroxycyclopentyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][C:7]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[N:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN1C(=O)CCC1.CO>[F:17][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:25]3[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[CH:31][N:32]=3)=[CH:14][C:9]=2[S:8][C:7]1=[O:16]
Reactant: O=c1sc2cc(O)ccc2n1CC1CC1(F)F
Reactant: N#Cc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: N#Cc1cccnc1Oc1ccc2c(c1)sc(=O)n2CC1CC1(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-[(2,2-difluorocyclopropyl)methyl]-6-hydroxy-1,3-benzothiazol-2(3H)-one (18-2) (0.033 g, 0.13 mmol) in anhydrous NMP (1 mL) was added cesium carbonate (0.084 g, 0.26 mmol) and 2-fluoronicotinonitrile (0.024 g, 0.19 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol and NMP, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-[(3-{[2,2-difluorocyclopropyl]methyl}-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)oxy]pyridine-3-carbonitrile (18-3) as an off-white solid. HRMS (M+H)+: observed=360.0623, calculated=360.0613.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1>C(Cl)CCl>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1cc(N)sn1
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)sn1
Yield: 44 %

Procedure:
4-Hydroxy-2-methyl-N-(3-methyl-5-isothiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 5-amino-3-methyl-isothiazole. Yield: 44% of theory; m.p. 268° C (decomp.; from ethylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH2:19][C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cc1c(SC)c2cc(F)ccc2n1Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CSc1c(CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Preparation 6, but using ethyl 1-(p-chlorobenzyl)-5-fluoro-3 -methylthioindole-2-acetate from Example 3 as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 154°-155° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[N:37]([CH3:38])[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>O.C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[N:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Cn1c(C(=O)CBr)nc2ccccc21
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(=O)n(CC(=O)c3nc4ccccc4n3C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 24 h
Yield: 19.4 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-bromo-1-(1-methyl-1H-benzoimidazol-2-yl)ethanone (1.0 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at 50° C. for 24 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.28 g, 19%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11]O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.P(Br)(Br)[Br:21]>C1(C)C=CC=CC=1>[Br:21][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[C:8]=1[CH3:13]
Reactant: BrP(Br)Br
Reactant: Cc1c(CO)sc2c(N3CCOCC3)nc(Cl)nc12
Solvent: Cc1ccccc1
Product: Cc1c(CBr)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirring suspension (2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in toluene at 40° C. was added PBr3 and the reaction mixture stirred at 100° C. overnight. DCM/saturated aqueous NaHCO3 extraction of the cooled mixture gave 6-Bromomethyl-2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([CH2:18][C:19]1[NH:31][C:22]2=[CH:23][N:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=[C:21]2[CH:20]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15]C)([CH3:7])[CH3:6].B(Br)(Br)Br.CO>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]([OH:15])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:17])([CH2:18][C:19]2[NH:31][C:22]3=[CH:23][N:24]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:26]=[C:21]3[CH:20]=2)[C:2]([F:32])([F:1])[F:33])[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cc(S(C)(=O)=O)ncc2[nH]1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CC(O)(Cc1cc2cc(S(C)(=O)=O)ncc2[nH]1)C(F)(F)F)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol (179 mg, 0.37 mmol) was dissolved in 10 mL of dichloromethane. 3.7 mL of a 1 M solution of boron tribromide (3.7 mmol) in dichloromethane were added. The resulting solution was stirred at normal room temperature overnight. After dropwise addition of MeOH (1 mL) at 0° C., the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate (NaHCO3) solution. The organic phase was separated and the aqueous layer was extracted with four 10 mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed. Flash chromatography of the residue yielded 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-3-(5-methanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1-dimethylbutyl]phenol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(F)c2)n1
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2cccc(F)c2)n1
Yield: 116.8 %

Procedure:
Operations are carried out as for Example 7, starting from 1.32 g of 1-(3-fluoro phenyl) isoquinoline 3-carboxylic acid, 0.57 g of triethylamine, 0.62 g of ethyl chloroformate, and 0.47 g of diethylamine in 50 ml of chloroform. 1.86 g of N,N-diethyl 1-(3-fluoro phenyl) isoquinoline 3-carboxamide, melting at 92° C., are obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][C:24]1=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([NH:10][C:9]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[CH:25][C:24]1=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Reactant: COc1ccc(N)cc1OC1CCCC1
Solvent: c1ccccc1
Product: COc1ccc(NC2=CC(=O)N(Cc3ccccc3)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
0.50 g (2.41 mmole) of 3-cyclopentyloxy-4-methoxyaniline produced in Example 1(2) and 0.49 g (2.41 mmole) of 1-benzyl-2,4-dioxopiperidine were dissolved in 20 ml of benzene and the mixture was stirred at room temperature for 20 hours. After the reaction, the precipitated crystal was collected by filtration and washed with benzene, then was dried in vacuo to obtain the title compound 0.76 g (yield 80.6%) as a light pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:6]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 13.7 %

Procedure:
To a solution of 1.0 g 2-aminobenzoic acid and 1.39 g of 4-amino-1-benzylpiperidine in 10 mL of methylene chloride was added 1.18 g of HOBT followed by 2.10 g of EDC. After stirring at rt for 6 hours, the reaction mixture was diluted with methylene chloride. The organic phase was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure followed by flash chromatography eluting with 9% EtOAc in hexane, 50% EtOAc in hexane and 10% MeOH in EtOAc afforded 309 mg of the title compound as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C.CN(C)C=O>ClCCl>[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CC1NCCc2ccccc21
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1c2ccccc2CCN1c1ccnc(Cl)n1
Yield: 28.9 %

Procedure:
A mixture solution of 2,4-dichloropyrimidine(3.0 g, 20 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline(3.3 g, 22 mmol), triethylamine(3.4 ml, 24.4 mmol) and N,N-dimethyl formamide(20 ml) was stirred for 5 hours, diluted with dichloromethane, washed with water several times. The dichloromethane layer was separated, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting residue was crystallized by silica gel column chromatography to give 1.5 g of the titled compound. (Yield: 28.9%)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:16])[C:13]([CH3:15])=O>>[CH2:18]([O:17][C:12](=[O:16])[C@H:13]([CH3:15])[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2ccccc2c1

Procedure:
Following General Procedure AA above and using 2-aminonaphthalene (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](CCOC)=[C:17]([O:20][CH:21]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C(F)=C(NC2C3C(=C[C:52]([OH:68])=[C:53]([O:56][CH:57]4CN(C(OC(C)(C)C)=O)C4)C=3)N=CN=2)C=CC=1F>>[NH:23]1[CH2:24][CH:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:68][CH2:52][CH2:53][O:56][CH3:57])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[C:3]=2[F:36])[CH2:22]1
Reactant: COCCc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2O)C1
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Yield: 100 %

Procedure:
The procedure of step 2) of Example 115 was repeated except for using the compound obtained in step 1) instead of tert-butyl 3-(4-(3-chloro-2,4-difluorophenylamino)-7-hydroxyquinazolin-6-yloxy)azetidin-1-carboxylate to obtain the title compound (37 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6](Br)[CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:9]=1)=[O:17]
Reactant: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
To 3-bromo-5-(2-oxopyrrolidin-1-yl)benzoic acid methyl ester (D9) (70 mg, 0.235 mmol) in DME (2 ml) was added Na2CO3 (290 μl, 2M, 0.588 mmol), benzeneboronic acid (29 mg, 0.235 mmol) and Pd(OAc)2 (3 mg, 0.013 mmol). The mixture was stirred at 85° C. for 2 days. The reaction mixture was cooled down, filtrated through celite and evaporated in vacuo. The product was purified by column chromatography (PE:EtOAc=3:1) which yielded D10 (23 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][O:10][C:9]2[CH:8]=[C:7]3[NH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]3=[CH:5][C:4]=2[NH:3]1.[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OCC)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:15]([C:13]3[NH:12][C:7]4=[CH:8][C:9]5[O:10][CH2:11][C:2](=[O:1])[NH:3][C:4]=5[CH:5]=[C:6]4[CH:14]=3)=[O:17])[CH2:28][CH2:29]2)=[CH:30][CH:31]=1
Reactant: O=C1COc2cc3[nH]c(C(=O)O)cc3cc2N1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C1COc2cc3[nH]c(C(=O)N4CCC(Cc5ccc(F)cc5)CC4)cc3cc2N1

Procedure:
The title compound is prepared from 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylic acid and 4-(4-fluorobenzyl)piperidine according to the method described in Example 1/c. Mp.: 219-226° C. (diethyl ether).