Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[Cl:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][NH:24][CH2:23]1>CS(C)=O>[Cl:20][CH2:21][CH:22]1[CH2:23][N:24]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:25][CH2:26][O:27]1
Reactant: ClCC1CNCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21

Procedure:
A solution of 0.54 g of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.60 g of 2-chloromethylmorpholine in 20 ml of dimethyl sulfoxide is stirred at 120° C. for 8 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added water followed by extracting with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate and then the solvent is distilled off. Further, the obtained crystals are recrystallized from chloroform-methanol to give 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 212°-215° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][CH2:36][C:37]([O:39][CH2:40]C)=[O:38].O>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCBr
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
To a solution of compound 1 (1.0 g, 2.25 mmol) in dry DMF (10 mL) was added NaH (60%, 92 mg, 2.3 mmol) at 0° C. and the mixture was stirred for 10 min, ethyl 3-bromopropanoate (410 mg, 2.25 mmol) was added and stirred at rt for 5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=5/1) to give compound 38 (400 mg, 34%) as a white solid.
Reaction SMILES: [ClH:1].C1C=C[C:5]2N(O)N=[N:8][C:6]=2C=1.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=C[C:24]([N:27]2[CH2:32]CC3(CCNCC3)C[CH2:28]2)=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:5][CH2:6][N:8]=[C:26]=[N:21][CH2:22][CH2:23][CH2:24][N:27]([CH3:28])[CH3:32].[ClH:1]
Reactant: On1nnc2ccccc21
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN=C=NCCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (503 mg, 2.62 mmol), HOBT (177 mg, 1.311 mmol) and DIPEA (0.6 ml) were added to a solution of the product just obtained in step 5 (400 mg, 1.3114 mmol) in methylene chloride (10 ml). The reaction mixture was stirred at 25° C. for 30 min and then cooled to 0° C. and 3-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane (364 mg, 1.57 mmol) was added. The reaction mixture was stirred at 25° C. for 12 h, subsequently diluted with methylene chloride and washed with sat. NH4Cl solution and with NaHCO3 solution. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:22][CH:23]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]3[CH:13]=[CH:12][N:11]4[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][N:9]=[C:10]4[CH:15]=3)=[CH:17][CH:18]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(Cc2ccc(-c3ccn4c(-c5ccccc5)cnc4c3)cc2)CC1
Product: OCc1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(3-phenylimidazo[1,2-a]pyridin-7-yl)benzaldehyde (2-5, 75 mg, 0.25 mmol, 1 equiv), 4-(methylsulfonyl)piperazine (49 mg, 0.30 mmol, 1.2 equiv), sodium triacetoxyborohydride (64 mg, 0.30 mmol, 1.2 equiv), acetic acid (14 μL, 0.25 mmol, 1.0 equiv), and 4-angstrom molecular sieves (50 mg) in 1,2-dichloroethane (5 mL) was stirred at 23° C. for 18h. The reaction mixture was filtered, and the filtrate concentrated. The residue was purified by reverse-phase liquid chromotography (H2O/CH3CN gradient w/0.1% TFA) to provide [4-(3-phenylimidazo[1,2-a]pyridin-7-yl)phenyl]methanol (2-6) and 7-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)-3-phenylimidazo[1,2-a]pyridine (2-7).
Reaction SMILES: C([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[N:19]=[C:20]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:52][CH:53]=[CH:54][C:49]=2N=N1.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>O>[CH2:49]([C:7]1[CH:6]=[CH:5][CH:38]=[CH:37][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[N:19]=[C:20]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[O:34])=[CH:35][CH:36]=3)[C:21]3[N:22]([CH:24]=[CH:25][N:26]=3)[CH:23]=2)[CH:13]=1)=[O:10])[CH2:54][CH2:53][CH3:52]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc(C(=O)O)cc4)n3)c2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: CCCCc1ccccc1C(=O)Nc1cccc(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoic acid (21) (0.16 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (0.16 mmol), and N′N-diisopropylethylamine (0.48 mmol) is stirred at room temperature for 20 min. Morpholine (0.48 mmol) is added and the mixture is stirred at room temperature or 16 hrs. Water (10 mL) is added and the mixture extracted with ethyl acetate (2×70 mL), the extracts are washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is triturated with diethyl ether to give 4-tert-B\butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]imidazo[1,2-a]pyrazin-6-yl}-phenyl)benzamide (22) as a cream solid.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](Cl)=[O:13].CCN(CC)CC>C1COCC1>[CH3:7][O:6][C:4]([C:3]1[N:1]=[CH:2][O:13][C:12]=1[C:11]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:9]([Cl:8])[CH:10]=1)=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(Cl)c(Cl)c1
Yield: 64 %

Procedure:
A solution of methyl isocyanoacetate (5.0 g, 50.0 mmol), 3,4-dichlorobenzoyl chloride (10.6 g, 50.0 mmol), and Et3N (20.9 mL, 150 mmol) was stirred in THF (20 mL) for 48 h at rt. The solution was concentrated, diluted with EtOAc, washed with water, dried (MgSO4), and concentrated to afford a solid. The solid was washed with hexanes and collected by filtration to provide 8.7 g (64%) of the desired product. HPLC: RT=9.68 min. MS (ESI+): mass calcd. for C11H7Cl2NO3, 270.98; m/z found, 272/274 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.29 (d, J=2.1, 1H), 8.03 (dd, J=8.5, 2.1, 1H), 7.94 (s, 1H), 7.56 (d, J=8.5, 1H), 3.98 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N#N>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([NH2:11])=[N:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(-c2ccc3c(N)n[nH]c3c2)cc1

Procedure:
A commercial “Miniblock” reactor was charged with trityl-resin bearing 6-bromo-1H-indazol-3-amine (95 mg, 0.066 mmol); 4-methoxyphenylboronic acid (0.3 mmol); Pd2dba3 (5 mg). Subsequently the reactor was sealed and the reaction mixture was put under inert atmosphere (N2 or Ar).
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][CH:3]=2)=[CH:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 65 °C

Procedure:
To a stirred solution of sodium (2.51 g, 105 mmol, 7 eq) in absolute methanol (50 mL) was added the indole (15.0 mmol) and N-t-butoxycarbonyl-4-piperidone (8.96 g, 45.0 mmol 3.0 eq). The resulting reaction solution was heated at reflux (65° C.) under nitrogen for 3-24 hours, depending on the indole used. The resulting reaction solution was evaporated under reduced pressure, and the residue was partitioned between a saturated solution of sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was removed, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue was purified either by trituration in diethyl ether or by column chromatography to afford the desired 3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole.
Reaction SMILES: [OH:1][CH:2]([CH2:9][C:10]([O:12][CH2:13][C:14]#[CH:15])=[O:11])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)(=O)C.C(N(CC)CC)C>O>[CH3:16][S:17]([O:1][CH:2]([CH2:9][C:10]([O:12][CH2:13][C:14]#[CH:15])=[O:11])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCOC(=O)CC(O)C(=O)OCC#C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOC(=O)CC(OS(C)(=O)=O)C(=O)OCC#C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
6.10 g (0.029 mol) of the obtained di(2-propynyl) 2-hydroxysuccinate and 3.32 g (0.029 mol) of methanesulfonyl chloride were added to 40 g of ethyl acetate, and 2.93 g (0.029 mol) of triethylamine was dropwise added thereto within a range of from 5° C. to 15° C., taking 15 minutes. This was reacted at room temperature for 1 hour, the disappearance of the starting materials was confirmed through gas chromatography, and 20 ml of water was added for liquid-liquid separation. The organic layer was concentrated under reduced pressure. The residue was purified through column chromatography (Wakogel C-200, elution with hexane/ethyl acetate=2/1) to give 4.50 g (yield 54%) of the intended di(2-propynyl) 2-(methanesulfonyloxy)succinate.
Reaction SMILES: C1C(C=O)=CC=C(C=O)C=1.C(O)(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:26]1[CH:30]=[CH:29][O:28][CH:27]1[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[CH2:39]([N:43]1[C:47](=[O:48])[CH2:46][NH:45][C:44]1=[O:49])[CH2:40][CH2:41][CH3:42]>C1C=CC=CC=1.O>[CH2:39]([N:43]1[C:47](=[O:48])[C:46](=[CH:35][C:34]2[CH:37]=[CH:38][C:31]([CH:27]3[O:28][CH:29]=[CH:30][O:26]3)=[CH:32][CH:33]=2)[NH:45][C:44]1=[O:49])[CH2:40][CH2:41][CH3:42]
Reactant: O=Cc1ccc(C2OC=CO2)cc1
Reactant: CCCCN1C(=O)CNC1=O
Agent: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(C=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCN1C(=O)NC(=Cc2ccc(C3OC=CO3)cc2)C1=O

Procedure:
Terephthaldialdehyde (67 g; 0.5 mole), ethanediol (31 g, 0.5 mole) and p-toluenesulphonic acid (0.5 g) in benzene (400 ml.) were boiled under reflux for 2 hours, with the removal of the water formed via a Dean and Stark separator. After cooling, the mixture was washed with dilute sodium bicarbonate solution (100 ml, 2% W/V), then saturated sodium chloride solution (2×100 ml.) and dried over magnesium sulphate. After filtration, the benzene solution was evaporated in vacuo to give a straw-coloured oil containing ca 70% of the desired aldehyde, viz: 4-(1,3-dioxol-2-yl)benzaldehyde, which was reacted with 3-n-butylhydantoin as in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([N:11]1[CH2:12][CH2:13][C@H:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]5[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=5[CH:24]=4)[CH:16]=3)=[C:4]([CH3:14])[CH:5]=2)[CH2:10]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCNC5)cc4C)c3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(C(C)=O)C5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 94.4 %

Procedure:
The crude methyl 2-((S)-6-((2′,6′-dimethyl-4′-((S)-pyrrolidin-3-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8a (45 mg, 0.09 mmol) were dissolved in 3 mL of dichloromethane, followed by addition of acetic anhydride (13 mg, 0.11 mmol) and triethylamine (18 mg, 0.18 mmol). The reaction solution was stirred for 2 hours. The resulting solution was mixed with 20 mL of dichloromethane. The organic phase was washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound methyl 2-((S)-6-((4′-(((S)-1-acetylpyrrolidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 9a (45 mg, yield 92.5%) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:29][C:30](=[N:36]O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:36]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCOC(=O)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 29 mg (0.22 mmol, 1.1 eq.) of ethyl 2-amino(hydroxyimino)ethanoate were reacted according to the General Method 1. Yield: 24 mg (22% of theory)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+].CCCCCC>CN(C)C=O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)CNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.1 %

Procedure:
Into a solution of isoindoline (1.788 g, 15 mmol) and ethyl bromoacetate (2.756 g, 16.5 mmol) in N,N-dimethylformamide (20 mL), was added Cs2CO3 (5.376 g, 16.5 mmol) under N2. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the resulting mixture was subjected to silica gel chromatography, eluting with 33:66 ethyl acetate:hexane to afford Intermediate 200(a) (1.14 g, 5.56 mmol) as a yellow oil in 37% yield.
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH3:14])[CH:5]=[C:4](OC)[C:3]=1[C:17](=[O:19])C>C(O)C>[CH:17](=[O:19])[C:3]1[CH:2]=[CH:7][C:6]([O:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COc1ccc(C=O)cc1

Procedure:
In 80 ml of ethanol were dissolved 13.76 g of the 2'-hydroxy-4',6'-dimethoxy-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 14 and 7.5 ml of p-anisaldehyde, and the solution was cooled to 0° C. and 120 ml of a saturated ethanol solution of potassium hydroxide was added to the solution. The mixture was stirred for 38 hours. After the reaction, the reaction liquid was diluted with water and neutralized with 6 N hydrochloric acid, and the precipitated crystal was recovered by filtration, washed with water, dried and recrystallized from methanol to obtain 16.20 g (yield=81.4%) of 2'-hydroxy-4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow needle.
Reaction SMILES: Br.[CH:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)([CH3:4])[CH3:3].[NH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23](=[O:25])[CH3:24].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:23]([C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[NH:14][C:11]([C:9]1[N:10]=[C:6]([NH:5][CH:2]([CH3:3])[CH3:4])[S:7][CH:8]=1)=[O:13])(=[O:25])[CH3:24]
Reactant: CC(C)Nc1nc(C(=O)O)cs1
Reactant: COc1ccc(C(C)=O)c(N)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A mixture of compound 69 (4.4 g, 16.5 mmol) and the aniline derivative 66 (2.75 g, 16.5 mmol) in pyridine (140 mL) was cooled to −30° C. (upon cooling, the clear solution became partially a suspension). POCl3 (3.3 mL, 35 mmol) was added slowly over a 5 min period. The mixture was stirred at −30° C. for 1 h, and was then allowed to assume rt. After stirring at rt for 1.5 h the reaction mixture was poured over ice, and the pH was adjusted to about 9-10 using solid and saturated NaHCO3. The crude product was extracted into CH2Cl2 (3×) and the combined organic phases were dried (MgSO4) and evaporated. The crude dark-beige solid was purified by flash column chromatography (hexane/EtOAc 55:45) to give compound 70 (5.6 g, 76%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:21].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1Br
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.7 g), 3-bromo-4-neopentyloxyaniline (2 g), triethylamine (2.3 g) and diethyl cyanophosphate (1.9 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (1.4 g), melting point: 193–194° C.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=1[CH3:22].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][S:6][C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:15]([CH3:22])[CH:16]=1)#[N:21]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1csc(Br)c1-c1ccc(C#N)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of ethyl 3-(5-bromo-4-(4-cyano-2-methylphenyl)thiophen-3-yl)propanoate (35 mg, 0.09 mmol), 4-methoxyphenylboronic acid (16 mg, 0.10 mmol), Na2CO3 (19 mg, 0.18 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in a mixture of dioxane and H2O (5 mL, 4:1) was stirred at 100° C. overnight under nitrogen. The mixture was neutralized to pH=5, and extracted with EtOAc. The organic layer was concentrated, and purified by preparative TLC to give 3-(4-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid (30 mg, yield 86%) as yellow oil.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[O:8]1[CH2:23][CH2:24][O:25][CH:7]1[C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[CH:2][CH:1]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: OCc1ccc(C2OCCO2)cc1
Temperature: 110 °C
Yield: 48 %

Procedure:
A mixture of terephthaldehyde (5.4 g, 40 mmol), para-toluenesulfonic acid—monohydrate (0.4 g, 2 mmol), and ethylene glycol in toluene (80 mL) was heated at 110° C. for 4 hours. The reaction mixture was allowed to cool and was washed with saturated sodium hydrogen carbonate and dried with anhydrous magnesium sulphate. The filtrate was evaporated at reduced pressure to afford a oil. The oil was dissolved in ethanol (200 mL), and then the reaction mixture cooled to 0° C. Sodium borohydride (5.9 g, 160 mmol) was added portionwise, and the resultant reaction mixture allowed to warm to ambient temperature over 16 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate and subsequently extracted twice with ethyl acetate. The combined organic extracts were dried with anhydrous magnesium sulphate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford the title compound as a colourless oil (3.4 g, 48%).