Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](=[O:25])[C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[O:25]=[C:13]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)[CH2:12][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Reaction time: 1.5 h

Procedure:
The ester (26) (222 mg, 0.64 mmol) was hydrolysed using Method C, except that MeOH (1 mL), THF (1 mL) and 1 M NaOH (1 mL) were used, and the reaction was stirred for 1.5 hours. After work-up, the crude product was triturated with DCM/heptane (×3) to provide the title compound. Yield: 134 mg; LC tr 1.39 min; HPLC Purity: 92%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[C:5](/[NH:11][C:12](=[O:14])[CH3:13])=[C:6](/[N:8]([CH3:10])C)\[CH3:7])[CH3:2].[CH:16]1(N)C[CH2:17]1>C(O)(=O)C.O>[CH2:1]([O:3][C:4](=[O:15])/[C:5](/[NH:11][C:12](=[O:14])[CH3:13])=[C:6](/[NH:8][CH:10]1[CH2:17][CH2:16]1)\[CH3:7])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)/C(NC(C)=O)=C(\C)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(NC(C)=O)=C(\C)NC1CC1

Procedure:
(Z)-2-Acetylamino-3-dimethylamino-but-2-enoic acid ethyl ester (4.3 g, 20 mmol) and cyclopropylamine (1.14 g, 20 mmol) were stirred at room temperature in acetic acid (40 ml) for 2 hrs. The reaction mixture was diluted slowly with 30 ml of water and evaporated under vacuum at 35° C. Water (30 ml) was added to the residue and evaporated again at 35° C. The same procedure was repeated twice with toluene (30 ml each) to obtain the desired crude product as a dark brown oil [MS: m/e=227.4 (M+H+)], which could be used without any further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([OH:24])=O)[O:19][N:18]=2)=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:52][O:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56]>CN(C=O)C.O>[CH3:52][O:53][C:54](=[O:60])[CH:55]([NH:56][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:24])[CH:57]([CH3:59])[CH3:58]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)Nc1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxylic acid (1 g) was dissolved in DMF (20 ml). N,N′-Dicyclohexyl carbodiimide (906 mg) and 1-Hydroxy benzotriazole (396 mg) were added and the reaction mixture was stirred at RT for 15 minutes. L-Valine methyl ester hydrochloride (640 mg) was dissolved in DMF (5 ml), neutralized with TEA (0.53 ml) and added into the above reaction mixture, which was then stirred at RT for 16 h. DMF was removed under reduced pressure to get a pale brown solid which was taken in water and extracted with EtOAc. Organic layer was dried over Na2SO4 and concentrated to get a pale yellow solid which was purified by silica gel column chromatography in 2:8 EtOAc:CHCl3 to get off white solid which was crystallized from DCM/Pet ether to yield 1.1 gm (82%) white solid. 1HNMR (DMSO-d6, 300 MHz): δ 9.33 (s, 1H), 9.18 (d, 1H), 8.62 (s, 1H), 8.13 (m, 1H), 7.85 (d, 2H), 7.67 (s, 1H), 7.59 (d, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 7.02 (m, 1H), 4.29 (m, 2H), 3.66 (s, 3H), 2.2 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 455 (M+1).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([N:16]=[CH:17][C:18]=3[C:19](=[O:21])[CH3:20])[CH:15]=2)=[CH:6][CH:5]=1.Br.ClCCl>CC(O)=O>[Br:1][CH2:20][C:19]([C:18]1[CH:17]=[N:16][N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]=12)=[O:21]
Reactant: BrBr
Reactant: CC(=O)c1cnn2cc(-c3ccc(F)cc3)ccc12
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CBr)c1cnn2cc(-c3ccc(F)cc3)ccc12
Yield: 85.4 %

Procedure:
Bromine (57.9 μL, 1.13 mmol) was added to a solution of 1-[6-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-yl]ethanone (8, 197 mg, 0.775 mmol) in AcOH (1 mL) and hydrobromic acid (88 μL, 0.775 mmol). The reaction was heated to 50° C. for 2 hours after which an aqueous solution of 10% Na2S2SO3 (5 mL) and dichloromethane (10 mL) were added to the reaction. The organic was collected and washed with a saturated solution of sodium bicarbonate (10 mL), dried over sodium sulfate and concentrated. The reaction was purified by column chromatography (10% acetone in hexanes) to yield 2-bromo-1-[6-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-yl]ethanone (9, 220.4 mg, 0.662 mmol, 85% yield). MS APCI: [M+H]+ m/z 334.2.
Reaction SMILES: C1(C([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:56]/[O:57][CH3:58])/[C:27]([NH:29][CH:30]3[C:37](=[O:38])[N:36]4[CH:31]3[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][S:49][C:50]3[N:54]([CH3:55])[N:53]=[N:52][N:51]=3)=[C:35]4[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:56]/[O:57][CH3:58])/[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][S:49][C:50]2[N:54]([CH3:55])[N:53]=[N:52][N:51]=2)=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(/C=C/CSc3nnnn3C)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(/C=C/CSc3nnnn3C)SCC12)c1csc(N)n1

Procedure:
329 mg of the compound of Step A and 9.6 ml of a 33% aqueous solution of formic acid were mixed together and heated for 25 minutes at +65° C., then cooled, diluted with water, filtered, and concentrated to dryness by distilling under reduced pressure. The residue was triturated in water and the insoluble matter formed was eliminated by filtering, and after concentrating to dryness, 142 mg of 7-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyimino-acetamido]-3-[3-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)thio-propen-(E)-yl]-8-oxo-4-thia-1-azabicyclo [4,2,0]oct-2-en-2-carboxylic acid with a specific rotation of [α]D20 =-99° (c=0.8% DMSO) were obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([O:14]C)=[O:13])=[CH:5][CH:4]=1.Cl>C1COCC1.O>[F:16][C:2]([F:1])([F:17])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reaction time: 14 h
Yield: 76.9 %

Procedure:
To a stirring solution of 26B (22 mg, 0.09 mmol) in THF (1 mL) at ambient temperature was added LiOH monohydrate (11 mg, 0.26 mmol) as a slurry in H2O (0.500 mL). The reaction was left to stir for 14 h, acidified to pH 4 via 1N HCl(aq), and then extracted with EtOAc (3×10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give 16 mg 26C (79% yield). m/z (ES+) M+1=232.0; HPLC tR=1.86 min. 1H NMR (500 MHz, MeOH-d4) δ 8.56 (d, J=2.1 Hz, 1H), 7.78-7.65 (m, 2H), 2.62-2.47 (m, 1H), 1.97 (ddd, J=9.0, 4.7, 4.6 Hz, 1H), 1.63 (ddd, J=9.4, 5.0, 4.8 Hz, 1H), 1.49-1.39 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH:33]=1)[CH:31]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:31][C:30]2[CH:33]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[C:34]([F:36])([F:35])[F:37])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(Cl)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-chloro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 523.9.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[F:40]C1C=CC=C(OC)C=1B(O)O>CCCCCCC.CCOC(C)=O>[F:40][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([O:38][CH3:39])[C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cccc(F)c1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to Example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-fluoro-6-methoxyphenylboronic acid (CAS RN 78495-63-3) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (65%). MS (ESI): m/z=233.109 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9](I)[C:8](=[O:13])[NH:7][C:6]1=[O:14].[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[OH-].[K+].O>CC(C)=O>[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[C:9]1[C:8](=[O:13])[NH:7][C:6](=[O:14])[N:5]([CH2:4][C:3]2[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[C:10]=1[CH3:11]
Reactant: Cc1c(I)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: COc1cccc(B(O)O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)[nH]c2=O)c1F
Temperature: 15 °C
Yield: 83.3 %

Procedure:
To a reactor was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (20.0 kg), 2-fluoro-3-methoxyphenylboronic acid (8.7 kg), and acetone (60 L). The mixture was agitated and cooled to 15° C. and a potassium hydroxide/water solution (10.8 kg/64 L) was charged. The reactor contents were degassed for 30 min, then tri-t-butylphosphonium tetrafluoroborate (142 g) was added to the reactor and the contents mixed at 45° C. for 20 min. Palladium (II) acetate (52 g) was charged to the reactor and the contents were mixed at 55° C. The reaction mixture was stirred until the reaction was complete. Acetic acid (5.6 kg) was charged to the reactor over 1 hr, then the mixture was stirred at 55° C. for 30 min. The reactor contents were cooled to 25° C. over 2 hr. The solid was collected by centrifugation and the cake washed with water (40 L) followed by methanol (80 L). The solid was dried in a vacuum oven at 50° C. until the loss-on-drying was less than 1% to provide 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (16.6 kg, 83% molar yield) as an off-white solid. LCMS (ESI) m/z 427.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH:10]([CH3:29])C1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[NH:8]1[CH2:13][CH:12]([N:11]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:40][CH2:39][CH2:38][C:33]4[CH:34]=[C:35]([F:37])[CH:36]=[C:31]([F:30])[CH:32]=4)[N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH3:29])[CH2:14]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cc(F)cc(F)c1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1)C1CNC1

Procedure:
Intermediate 114 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 425. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.74 (s, 1H), 8.38 (d, 2H), 7.97 (d, 1H), 7.71 (m, 2H), 7.90 (d, 2H), 6.74 (s, 1H), 4.58 (m, 5H), 4.07 (m, 4H), 3.25 (q, 2H), 3.07 (t, 2H), 1.39 (t, 3H).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:23][CH2:24][C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:11][C:12]1[C:21]2[N:22]=[C:1]([CH2:2][CH2:3][CH3:4])[N:23]([CH2:24][C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH:26]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 20.2 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0.19 mmol), trimethyl orthobutyrate (2.1 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and heated at 110° C. for 18 hours. The volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica gel (250 g, eluting with 20% to 40% ethyl acetate in hexane) to provide 0.806 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>>[OH:32][CH2:31][CH:30]([CH2:33][OH:34])[NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: NC(CO)CO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(CO)CO)cn2)CC1
Yield: 78 %

Procedure:
By the same procedure as described in the example 2, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-amino-1,3-propandiol. Then, the product was recrystallized with ethyl acetate and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][NH2:15]>C(Cl)Cl>[NH2:12][CH2:13][CH2:14][NH:15][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: NCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of benzylchloroformate (1.3 mL, 9 mmol) in DCM (25 mL) was added over 1.5 h to a solution of 1,2-diaminoethane (6 mL, 90 mmol) in DCM (95 mL) cooled at 0° C. The solution was stirred for 2 h at 0° C., then the solution was washed with brine (40 mL).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:4]=2[O:5]1
Reactant: COC(=O)CBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)OCO2
Yield: 57 %

Procedure:
The mixture of sesamol (13.8 g, 100 mmol, methyl bromoacetate (15.3 g, 100 mmol) and potassium carbonate in acetone (200 ml) was refluxed for 24 h with stirring. Acetone was removed under reduced pressure. The residue was dissolved in water (200 ml) and was extracted with ether (2×100 ml). the combined organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to give methyl 2-[3,4-(methylenedioxy)phenoxy]acetate as an oil (12 g, 57% yield). The aqueous phase was neutralized to pH 2-3 with concentrated HCl and the precipitated solid was filtered to get 2-[3,4-(methylenedioxy)phenoxy]acetic acid as a solid (6 g, 31% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)c(F)c2c1=O
Yield: 37 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 106 mg of 5-fluoroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 108 mg of the target compound.
Reaction SMILES: C[CH2:2][O-:3].[Na+].C(OCC)=O.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[OH:17]/[C:16](/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[C:18](/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)\[CH:2]=[O:3]
Reactant: CC[O-]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Product: O=C/C(=C(\O)c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a cooled solution of NaOEt (763 mg, 11.21 mmol) in EtOH (100 ml) was added ethyl formate (0.91 ml, 11.21 mmol) dropwise. The resulting mixture is allowed to stand for 3 hours at 0 to 5° C., and then deoxybenzoin (2 g, 10.19 mmol) was added. The mixture was stirred for 2 hours at 0 to 5° C. and then placed in the refrigerator for 4 days. After the mixture was stirred overnight at room temperature, it was poured into ice-water, and acidified, and extracted with CH2Cl2. The organic layer was washed with brine, and dried over MgSO4 anhydride, and concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate in hexane) to give the title compound as a light yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.I[CH3:14]>O1CCCC1>[CH3:14][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCc2ccccc21
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
NaH (12 g, 60%, 300.00 mmol) was added in several batches, to a solution of 1,2,3,4-tetrahydroquinoline (26.6 g, 199.70 mmol) in tetrahydrofuran (150 mL) at 0-5° C. The resulting solution was maintained at 0-5° C. for 30 minutes, then iodomethane (50 g, 352.11 mmol) was added dropwise (at 0-5° C.). The resulting solution was then stirred at room temperature overnight. The mixture was filtered, and the filtrate was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 19 g (61%) of 1-methyl-1,2,3,4-tetrahydroquinoline as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1)(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: CC(C)=C1C(=O)N(c2ccc(N)cc2)C(=O)/C1=C(\C)c1cc(C)oc1C
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)Nc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(C)oc3C)C2=O)cc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution obtained by dissolving 105 mg of N-(4-aminophenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 1 in 2 ml of chloroform, 5 ml of pyridine was added, followed by dropwise addition of 0.84 ml of methacryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 4 hours with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to the removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-methacryloylaminophenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethyliden]-3-isopropylidenesuccinimide in yield of 40.0%.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O)O.C([Zn]CC)C.[C:14]1([C:20]#[C:21][Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(#N)C1C=CC=CC=1.CCCCCCCCCCCCC>C1COCC1>[C:1]1([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccccc1O
Reactant: [Li]C#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: CC[Zn]CC
Solvent: C1CCOC1
Solvent: N#Cc1ccccc1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of catechol (0.440 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with diethylzinc (4 ml; 4.00 mmol; 1.0 M in THF) and the resulting solution was allowed to warm to room temperature for 20 min. Solvent was removed in vacuo, then phenylethynyllithium (4.0 ml; 4.00 mmol; 1.0 M THF) was added at room temperature and the resulting mixture was stirred for 30 min. This solution was then added to a room temperature mixture of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol). The reaction mixture was then heated to 65° C. and stirred for 6 days; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.08 mmol (54% yield) of diphenylacetylene and 0.41 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH:28]1C(O)=C[CH:31]=[C:30]([CH3:35])[CH:29]=1>[Cl-].[Cl-].[Zn+2]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[O:4][C:1]1[CH:28]=[CH:29][C:30]([CH3:35])=[CH:31][CH:2]=1)(=[O:10])[CH3:9]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 37.2 %

Procedure:
According to scheme XIV, the coupling of penta-O-acetyl-D-galactopyranose (36 g, 92 mmoles) with p-cresol (30 g, 280 mmoles) is carried out by fusion in the presence of anhydrous ZnCl2 (1.8 g) at 160° C. for 30 minutes, according Helferich technique. After cooling, a chromatography on a column of 60H silica (solvent:hexane-ethyl acetate: 90/10-v/v) is directly performed on the mixture and gives 15 g, yield=40% of 4-methylphenyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside, which crystallises in ethanol. Its analytical characteristics are identical as the one described before.