Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:15][CH:16]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(F)cc2)CC1
Product: Fc1ccc(N2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-fluorophenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18].Cl.[OH-].[Na+]>O.C(O)C>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH:18][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2c(C)cccc2C)nc(-c2ccccn2)n1
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol), 2,6-dimethylaniline (45 μl, 0.365 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (75 ml), which was washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow oil (58 mg, 82%). 1H NMR (CDCl3): 8.81–8.78 (m, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.83–7.77 (m, 1H), 7.36–7.30 (m, 1H), 7.21–7.13 (m, 3H), 6.91 (s, 1H), 5.77 (s, 1H), 2.39 (s, 3H), 2.23 (s, 6H).
Reaction SMILES: [H-].[Na+].C([O:5][C:6]([C:8]1([CH:24](O)[CH3:25])[CH2:12][CH2:11][CH:10]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:9]1)=[O:7])C.C1C(Cl)=CN=C(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)C=1>O1CCCC1>[CH:21]([Si:14]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[O:13][CH:10]1[CH2:11][CH2:12][C:8]([CH:24]=[CH2:25])([C:6]([OH:7])=[O:5])[CH2:9]1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)C1(C(C)O)CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
A cooled (−78° C.) suspension of sodium hydride (1.474 g, 36.868 mmol, 60% dispersed in mineral oil) in anhydrous tetrahydrofuran (60 mL) was treated with a solution of 1-(1-hydroxy-ethyl)-3-triisopropylsilanyloxy-cyclopentanecarboxylic acid ethyl ester (6.61 g, 18.434 mmol). After stirring at −78° C. for 10 min, the reaction mixture was treated with a solution of N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (13.2 g, 33.615 mmol) in anhydrous tetrahydrofuran (20 mL). The cooling bath was removed and the reaction was allowed to stir at room temperature for 24 h. More sodium hydride (1.474 g, 36.868 mmol, 60% dispersed in mineral oil) was added. After stirring at room temperature for 5 h, more sodium hydride (1.474 g, 36.868 mmol, 60% dispersed in mineral oil) was added. After stirring at room temperature for 17.5 h, the reaction was quenched at 0° C. with a saturated solution of ammonium chloride (100 mL). The aqueous layer was extracted with dichloromethane (2×). The aqueous layer was acidified to pH 2 with hydrochloric acid (2 M) and extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 followed by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 4:1 to afford the title compound (876.9 mg, 15%) as a light yellow oil and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 311.2 [M−H], Tr=4.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1.[CH2:40]1[O:43][CH:41]1[CH3:42]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:40][CH:41]([OH:43])[CH3:42])[CH2:26][CH2:27]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Solvent: CO
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(C)O)CC2)c(OC(C)C)c1

Procedure:
The compound was prepared by the treatment of [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (example 10 g) with propylene oxide in methanol for 7 h at 45° C. in a sealed tube. HR-MS (ES, m/z) calculated for C33H38N4O4Cl2[(M+H)+]625.2343, observed 625.2350.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)CCC>[Br:12][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cn1cccc(Br)c1=O
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)Cn1cccc(Br)c1=O
Yield: 62 %

Procedure:
As described for example 112a, (3-bromo-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at reflux for 16 h. The precipitate was filtered and triturated with hot methanol to afford the title compound as an off-white solid (yield: 62%). MS: m/e=244.2/246.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.C[N:25](C)C=O.C1COCC1.Cl>CO>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[CH2:8][NH2:25])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(Oc1ccc(F)cc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CN)Oc1ccc(F)cc1
Temperature: 65 °C

Procedure:
Into a 1 L-single neck round-bottom flask was added 2-(4-fluorophenoxy)-2-methylpropanoic acid (5.10 g, 0.0257 mol), methylene chloride (66.0 mL, 1.03 mol), oxalyl chloride (3.27 mL, 0.0386 mol) and N,N-dimethylformamide (20 μL, 0.0003 mol). The reaction was stirred until bubbling had stopped. Volatiles were removed and crude product then dissolved in DCM and 15 mL of 7N ammonia in MeOH was added. Volatiles were removed and crude product then dissolved in DCM and 15 mL of 7N ammonia in MeOH was added. Borane-dimethyl sulfide complex (5.7 mL, 0.064 mol) was added to the amide in THF (50 mL, 0.6 mol) at room temperature. The reaction was heated at 65° C. overnight. MeOH was added carefully. 1 N HCl was added and was heated at 65° C. for 2 hours. The reaction was concentrated in vacuo. The solid was dissolved in water and was washed with DCM. The aq. layer was basified with 1 N NaOH. The reaction was extracted with DCM. The reaction was dried with MgSO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:35]4[CH2:34][CH2:33][N:32]([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: CC(C)NC(=O)CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: CC(C)NC(=O)CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-piperazinyl-N-isopropylacetamide as in General Procedure 10 to give the title compound. LCMS: m/z=615.03 (M+H+); retention time=0.58 minutes.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:27])=[CH:3]\[C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10]/[C:11](/[CH3:26])=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)=[O:5].[N+:28]([C:31]1[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=1)[CH:34]=[C:35]([C:42]([CH3:44])=O)[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])([O-:30])=[O:29]>C(O)(C)C>[CH3:27][C:2]1[NH:1][C:42]([CH3:44])=[C:35]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:34]([C:33]2[CH:45]=[CH:46][CH:47]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=2)[C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10]/[C:11](/[CH3:26])=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:17][CH:18]=1)=[O:5]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Reactant: C/C(N)=C/C(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCOC/C(C)=C/c2ccc(Cc3cccnc3)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Yield: 75.9 %

Procedure:
In 1.36 ml of isopropanol were dissolved 340 mg of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl 3-aminocrotonate and 257 mg of isopropyl 2-(3-nitrobenzylidene)acetoacetate, and the resulting solution was subjected to reaction under refulx for 2 hours. The reaction mixture was thereafter stirred with ice-cooling, and the crystals thus precipitated were collected by filtration to obtain 440 mg (yield 75.8%) of 3-[2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl] 5-isopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate having a melting point of 124°-126° C. The physical properties of this product were identical with those of the compound obtained in Example 29.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([CH:22]=[CH:23][NH:24]5)=[CH:20][CH:19]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[CH:3]=2)=[O:43])=[CH:45][CH:46]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4cc[nH]c4c3)n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5cc[nH]c5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(1H-indol-6-yl)-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure 4-tert-butyl-N-{3-[8-(1H-indol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[C:27]#[N:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CCOC(C)=O>[C:27]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH3:26])=[O:24])#[N:28]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
Methyl 7-(4-(tert-Butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate (18.5 g, 45.185 mmol) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (50 mL) was added and the mixture was stirred at ambient temperature for 1.5 hours, and then concentrated under reduced pressure to provide a crude solid. The solid was dissolved in EtOAc (200 ml), and hexanes (600 ml) were added with stirring. White solid was crashed out and was collected by filtration to provide 13.11 g of the desired compound as white solid (81.9%). The mother liquor was concentrated and the residue was dissolved in EtOAc (25 ml). Hexanes (100 ml) were added with stirring and a white solid was crashed out and was collected by filtration to provide an additional 1.14 g of the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][NH2:39]>C1COCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][NH:39][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)CC1CCN(C(=O)CBr)Cc2ccccc21
Reactant: NCCNc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(C(=O)CNCCNc2ccccn2)Cc2ccccc21
Reaction time: 18 h

Procedure:
To a stirring solution of methyl 2-(2-(2-bromoacetyl)-1H,3H,4H,5H-benzo[e]azepin-5-yl)acetate in THF (0.2 M), was added diisopropylethylamine (1.5 eq) and 2-(2-pyridylamino)-1-aminoethane (1.2 eq). The reaction was stirred for 18 hr, followed by concentration by rotary evaporation and the product was purified by flash chromatography (10% MeOH/CH2Cl2). EI-MS m/z 397 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[N:18]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][C:21]=3[CH3:22])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCCC1.C1([Mg]Br)C=CC=CC=1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([C:17]3[N:18]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][C:21]=3[CH3:22])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[OH:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(-c2cccnc2)nc1C(=O)CN1CCN(c2ccc(F)cc2)CC1
Agent: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2cccnc2)nc1C(O)(CN1CCN(c2ccc(F)cc2)CC1)c1ccccc1
Yield: 82.9 %

Procedure:
A mixture of 1.5 g of 2-[4-(4-fluorophenyl)-1-piperazinyl]-1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 20 ml of dry tetrahydrofuran and 10 ml of 1.7M phenyl magnesium bromide in 10 ml of ether was reacted as described in Example 41 giving 2 g of a foam. This foam was purified by chromatography, giving 0.75 g of the desired product as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([CH3:25])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[NH2:18]>>[CH3:16][C:17]([NH:18][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[CH3:25]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(Cl)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 83 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=351.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[CH:31]2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[CH:31]2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2cnc3ccccc32)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-n2cnc3ccccc32)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
5.0 mL trifluoroacetic acid solution containing 34 mg of tert-butyl 2-(benzamido)-4-(1H-benzimidazol-1-yl)benzoate was stirred at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 24 mg of 2-(benzamido)-4-(1H-benzimidazol-1-yl)benzoic acid as white solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]CCC(=O)C)[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7].[CH:39]([C:41]([CH3:43])=[O:42])=C>C1(C)C=CC=CC=1>[F:35][C:33]([F:36])([F:34])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:38])([F:1])[F:37])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:39][C:41](=[O:42])[CH3:43])[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7]
Reactant: C=CC(C)=O
Reactant: CC(=O)CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Solvent: Cc1ccccc1
Product: CC(=O)CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-pentanon-1-yl)piperazine (1.37 g) in toluene (15 mL) was added drop-wise methyl vinyl ketone (0.3 g). After 2.5 h at room temperature the solution was concentrated to afford crude (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-butanon-1-yl)piperazine which was used as such. Rf 0.55 (CH2Cl2/MeOH 95/5).
Reaction SMILES: Cl[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][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:18].[H][H]>[OH-].[K+].[Pd]>[O:15]1[CH2:14][CH2:13][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=[C:3]([OH:18])[CH:4]=2)[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1Cl
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: Oc1cc(N2CCOCC2)c2ccccc2c1

Procedure:
1-Chloro-4-morpholino-2-naphthol (15.0 g;0.057 mol), prepared as described in 2(a) above, was dissolved in 10% aqueous potassium hydroxide (100 ml) and was treated in the presence of palladium on charcoal (1.75 g;5%) at room temperature under 3 atmospheres of hydrogen until a stoichiometric amount of hydrogen was absorbed (approximately 24h). The palladium catalyst was removed by filtration and the filtrate neutralised with glacial acetic acid to afford 4-morpholino-2-naphthol as a white solid (8.5 g;65%), m.pt. 231°-232° C. ##STR19##
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Br:37])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(Br)cc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Yield: 74 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 6-bromo-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow foam (303 mg, 74%). LCMS (Method A) RT=5.02 min, [M+H]+=546/548.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOCC>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:11]1[N:18]([CH2:19][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C(CCCC(=O)O)NCc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A yellow solution of 5-(2,6-dimethoxyphenyl)-5-((quinolin-3-ylmethyl)amino)pentanoic acid (1.074 g; 2.72 mmol; 1.0 equiv.) in anh. DMF (50 ml) was treated successively with HATU (1.294 g; 3.40 mmol; 1.25 equiv.) and with DIPEA (0.59 ml; 3.40 mmol; 1.25 equiv.). The resulting orange solution was stirred at rt, under nitrogen, for 2 h45. Water (100 ml) and Et2O (100 ml) were then added, and the separated aq. layer was further extracted with Et2O (3×100 ml). The mixed organic layers were washed with water (15 ml) and with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded 6-(2,6-dimethoxyphenyl)-1-(quinolin-3-ylmethyl)piperidin-2-one as a beige solid. LC-MS (conditions B): tR=0.68 min.; [M+H]+: 377.36 g/mol.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=O.[C:14]([CH2:16][C:17]([OH:19])=[O:18])#[N:15].C([O-])(=O)C.[NH4+].[OH-].[Na+]>C1C=CC=CC=1.O.C(Cl)(Cl)Cl.C(O)(=O)C>[C:14]([CH:16]([CH:2]([CH3:1])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)[C:17]([OH:19])=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(C)C(C#N)C(=O)O)cc1OC
Yield: 28.6 %

Procedure:
To a solution of 3, 4-dimethoxyacetophenone (5.68 g, 31.53 mmol) and cyanoacetic acid (2.95 g, 34.68 mmol) in benzene were added acetic acid (1.9 ml) and ammonium acetate (150 mg), and the resultant mixture was refluxed with Dean Stark's dehydrating apparatus for 13 hours while adding ammonium acetate (130 mg) every 4 hours. The mixture was mixed with chloroform (200 ml), 2N aqueous sodium hydroxide solution (100 ml) and water (200 ml), stirred well and the aqueous layer was separated. The aqueous layer was acidified with dilute hydrochloric acid, and the resulting precipitate was filtered off. The residue was washed with diethyl ether to give a carboxylic acid, 2-cyano-3-methyl-3-(3, 4-dimethoxyphenyl) propionic acid (2.25 g, 29%).