Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:16])[CH:11]2[O:14][CH3:15])=[C:7]([CH2:17][CH2:18]O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C1C(=O)N([Br:51])C(=O)C1>>[Br:51][CH2:18][CH2:17][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH3:16])[CH:11]2[O:14][CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1c2cc(C(C)(C)C)cc(CCO)c2CC1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1c2cc(C(C)(C)C)cc(CCBr)c2CC1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 27.58 g (105 mmol) of 2-(6-tert-butyl-1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)ethanol and 27.58 g (105 mmol) PPh3 in 450 ml of THF 18.72 g (105 mmol) of NBS was added at vigorous stirring for 5 min at 0° C. This mixture was stirred for 2 h at room temperature and then evaporated to dryness. A solution of the residue in 500 ml of hexanes was filtered through glass frit (G3), and the precipitate was additionally washed by 3×300 ml hexanes. The combined organic extract was evaporated to dryness. The product was isolated from the residue using flash chromatography on Silica Gel 60 (40-63 um, d 80 mm, 1250 mm; eluent: hexanes/ether=20/1, vol.). Yield 25.48 g (74%) of ca. 1 to 2 mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[C:20]3[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@@H:34]1OC(=N)C(Cl)(Cl)Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>ClCCl>[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:34]1[O:28][C:27]1[C:20]2[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:12][CH:13]=3)=[CH:23][S:22][C:21]=2[CH:24]=[CH:25][CH:26]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)c1ccc(CCc2csc3cccc(O)c23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccc(C(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 3-[2-(4-benzyloxycarbonylphenyl)ethyl]-4-hydroxybenzo[b]thiophene (35 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (53 mg) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.006 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-benzyloxycarbonylphenyl)ethyl]benzo[b]thiophene (38 mg). This material was dissolved in dichloromethane (1 mL). To the solution were added dimethyl sulfide (0.15 mL) and boron trifluoride-diethyl ether complex (0.067 mL), and the mixture was stirred at 35° C. for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C1COCCN1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)cc(N2CCOCC2)c1
Reaction time: 24 h

Procedure:
A solution of 1-bromo-3-chloro-5-fluorobenzene (5.05 g, 24.11 mmol), morpholine (3.15 mL, 36.2 mmol), potassium carbonate (6.66 g, 48.2 mmol), and DMF (45 mL) was stirred at 60° C. for 48 h, then at 110° C. for 24 h. The reaction mixture was concd, and the resulting residue was partitioned between EtOAc and water. The organic phase was dried over magnesium sulfate and concd, affording a crude material that was purified by column chromatography (silica; 0-10% EtOAc in hexanes) to yield 4-(3-bromo-5-chlorophenyl)morpholine as a white amorphous solid. Mass Spectrum (ESI) m/e=276.0 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2)(=[O:3])[CH3:2]
Reactant: COc1ccc2cc(N)cc(C)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc2cc(NC(C)=O)cc(C)c2n1

Procedure:
A solution of acetic anhydride (0.55 cm3) in dichloromethane (20 cm3) was added dropwise to a stirred solution of 6-amino-2-methoxy-8-methylquinoline (1.0 g) in dichloromethane (30 cm3) at room temperature. After 1 hour the solution was diluted with dichloromethane (50 cm3), washed with saturated sodium carbonate solution (10 cm3), and dried (MgSO4). Evaporation of the solution in vacuo afforded a solid which was recrystallised from dichloromethane/hexane to give 6-acetamido-2-methoxy-8-methylquinoline, m.p. 193°-196° (1.143 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([O:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc(CO)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C=O)o1

Procedure:
Prepared by reacting 5-(hydroxymethyl)-2-furan-carboxaldehyde with methanesulfonic acid chloride in the presence of triethylamine in methylene chloride at ambient temperature. The crude product is further reacted without any more purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[C:16]([Br:28])=[CH:17][C:18]2[C:23](=[O:24])[O:22][C:21]([CH3:26])(C)[O:20][C:19]=2[CH:27]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([O:14][C:15]1[C:16]([Br:28])=[CH:17][C:18]([C:23]([O:22][CH3:1])=[O:24])=[C:19]([O:20][CH2:21][CH3:26])[CH:27]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OC(=O)c2cc(Br)c(OCc3ccccc3)cc2O1
Agent: [K+]
Solvent: CO
Product: CCOc1cc(OCc2ccccc2)c(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Potassium carbonate (7.57 g) was added to a mixture of 7-(benzyloxy)-6-bromo-2,2-dimethyl-4H-1,3-benzodioxin-4-one (9.95 g) and methanol (50 mL), and the resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and then, the solvent was distilled off under reduced pressure. Iodoethane (3.29 mL) was added to a DMF (50 mL) suspension of the obtained residue and potassium carbonate (7.57 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (9.80 g).
Reaction SMILES: O[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:5](=[O:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[C:3]1[CH3:15].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][C:3]1[CH:2]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:5](=[O:6])[C:4]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cccc(C2=C(C)C(O)(c3cccc(OC)c3)C2=O)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C2=C(C)C(c3cccc(OC)c3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A CH2Cl2 solution (15 mL) of 4-hydroxy-3-methyl-2,4-bis[3-(methyloxy)phenyl]-2-cyclobuten-1-one (246) (0.464 g, 1.50 mmol, 1 equiv) was cooled to ca. 0° C. Triethylsilane (3.02 mL, 1.0 M, 1.5 equiv) was added followed by TFA. After 5 min, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After an additional 2 h, the reaction was quenched with 50% saturated aqueous NaHCO3. The organic portion was separated and pooled with those extracted using EtOAc (3×20 mL). The organic portions were dried (Na2SO4), filtered, and concentrated. Radial chromatography (SiO2, 2 mm plate, 80:20; hexanes/EtOAc) afforded the title compound as a yellow oil (0.374 g, 85%). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.30 (m, 4H), 6.96-6.80 (m, 4H), 4.69 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 2.49 (s, 3H). TLC (80:20; hexanes/EtOAc): Rf=0.46.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:37][CH2:38][CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])[CH:12]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:46]([O:45][P:40]([CH2:39][CH2:38][CH2:37][O:36][C:13]1[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=[C:11]([NH2:10])[CH:12]=1)(=[O:41])[O:42][CH2:43][CH3:44])[CH3:47]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCP(=O)(OCC)OCC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCP(=O)(OCC)OCC)c1
Yield: 92 %

Procedure:
A mixture of 2.47 g of [3-[3-(diethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]carbamic acid phenylmethyl ester and 0.4 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from ether-hexane to give 1.83 g (92% yield, mp 63°-65°) of [3-[3-amino-5-(octadecyloxy)phenoxy]propyl]phosphonic acid diethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][CH:42]1[C:48]([CH3:50])([CH3:49])[CH:47]=[CH:46][CH2:45][N:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[C:48]([CH3:50])([CH3:49])[CH:47]=[CH:46][CH2:45][N:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)C=CCN(c2ccccc2)C(=O)C1N
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3C(=O)N(c4ccccc4)CC=CC3(C)C)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S,Z)-4,4-dimethyl-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (10 mg, 0.018 mmol) and Intermediate 33 (4.1 mg, 0.018 mmol) to give a white solid (4.0 mg, 27% yield). Anal. Calcd. for C45H54N4O6S m/z 778.4. found: 779.4 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.00-8.08 (m, 1H), 7.31 (t, J=7.70 Hz, 2H), 7.27-7.09 (m, 11H), 6.98 (d, J=7.70 Hz, 2H), 5.77 (ddd, J=11.41, 8.11, 3.57 Hz, 1H), 5.63-5.49 (m, 2H), 5.38 (d, J=9.35 Hz, 1H), 5.04-4.97 (m, 1H), 4.96-4.90 (m, 1H), 3.75 (dd, J=17.60, 8.25 Hz, 1H), 3.59 (s, 3H), 3.03-2.88 (m, 2H), 2.84-2.65 (m, 5H), 2.62-2.53 (m, 1H), 2.34 (d, J=13.75 Hz, 1H), 2.16-2.01 (m, 1H), 1.96 (d, J=10.45 Hz, 1H), 1.89-1.79 (m, 2H), 1.76-1.47 (m, 6H), 1.41-1.30 (m, 1H), 0.89-0.80 (s, 3H), 0.54-0.46 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:29][CH2:30]1
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2nc(N3CCN(CCCCn4cnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl) piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.9 g compound (I-17) with a yield of 59.6%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: CC[O-].[Na+].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[OH:16])([CH3:7])[CH3:6].Cl.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21]([N:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH2:39][CH2:40][CH2:41]3)[N:36]([C:43](=[O:46])[CH2:44][Cl:45])[CH2:35][CH2:34]2)[N:20]=1>C(O)C>[ClH:45].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21]([N:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH2:39][CH2:40][CH2:41]3)[N:36]([C:43](=[O:46])[CH2:44][O:16][C:9]3[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=3[CH:5]([CH3:7])[CH3:6])[CH2:35][CH2:34]2)[N:20]=1
Reactant: COc1cc2nc(N3CCN(C(=O)CCl)[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Reactant: COc1cccc(C(C)C)c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc2nc(N3CCN(C(=O)COc4c(OC)cccc4C(C)C)[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Reaction time: 0.5 h
Yield: 21 %

Procedure:
10 ml of a freshly prepared 0.095M EtONa solution was added to a stirred solution of 0.16 g of 2-isopropyl-6-methoxyphenol in 5 ml of ethanol and stirring was continued for 0.5 hours at room temperature. The resulting solution was added dropwise in 15 minutes into a stirred solution 0.2 g of the above intermediate 4B in 50 ml of ethanol under nitrogen atmosphere. The mixture was stirred for 5 hours at room temperature and was then refluxed for 20 hours. The residue obtained after solvent evaporation was converted into the hydrochloride salt and crystallized from i-propanol to give 0.64 g (21%) of the title compound; m.p. 208-209° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[CH2:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)=[O:24]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:17][CH2:18][CH2:19][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH3:22])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: CC(=O)Nc1ccc(CCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized according to Example 84B from 4-[(2,2-dimethylpropyl)(2-propen-1-yl)amino]-2-(trifluoromethyl)benzonitrile (Example 49A) and 4-bromoacetanilide: MS (APCI) m/z 432 (M+1).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)=[CH:13][C:12]=3[OH:30])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Li+].C1COCC1.Cl>O>[C:1]12([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)=[CH:13][C:12]=3[OH:30])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc(C34CC5CC(CC(C5)C3)C4)c(O)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/c2ccc(C34CC5CC(CC(C5)C3)C4)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
258 mg (0.5 mmol) of ethyl (E)-4-[[2-[4-(1-adamantyl)-3-hydroxyphenyl]ethenyl]]benzoate, 105 mg (2.5 mmol) of lithium hydroxide and 10 ml of THF were introduced into a round-bottomed flask. The reaction medium was stirred at room temperature for 12 hours, poured into water, neutralized with hydrochloric acid and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from a mixture of dichloromethane and hexane, filtered and dried. 95 mg (51%) of the expected acid, having a melting point of 334°-5° C., were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][N:26]1[CH:30]=[N:29][N:28]=[CH:27]1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][N:26]2[CH:30]=[N:29][N:28]=[CH:27]2)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: Nn1cnnc1
Product: COc1ccc(C(=O)Nn2cnnc2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-triflouromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 4-amino-1,2,4-triazole in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[C:27]=2[F:30])[NH:22]1>>[F:30][C:27]1[C:26]([F:31])=[CH:25][CH:24]=[C:23]2[C:28]=1[CH2:29][CH:21]([CH3:20])[N:22]2[C:10](=[O:12])[CH2:9][C:5]1[NH:6][C:7](=[O:8])[C:2]([F:1])=[C:3]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:4]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: CC1Cc2c(ccc(F)c2F)N1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2F)N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 57.1 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 140 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 93 mg of (−)-2-methyl-4,5-difluoro-2,3-dihydro-1H-indole (reference example 2a). After silica column purification: eluent 98/02 dichloromethane/methanol, 117 mg of 2-[2-((+)-4,5-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-5-fluoro-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[N+]([C:20]([CH2:47][CH2:48][CH2:49][CH3:50])=[CH:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][C:23]=1[C:35]([N:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)=[O:36])([O-])=O>>[C:29]([O:28][C:26]([C:25]1[CH:33]=[CH:34][C:22]([C:21]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:20]=2[CH2:47][CH2:48][CH2:49][CH3:50])=[C:23]([C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[CH:24]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccc(OC)cc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(OC)cc1
Yield: 45 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-methoxyphenyl)hydrazono)acetate (24 mg, 0.108 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (50 mg, 0.108 mmol) were converted to the title compound (31 mg, 45%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.08 (dd, J=8, 2 Hz, 1H), 8.03-8.02 (m, 1H), 7.42-6.81 (m, 9H), 5.02-4.98 (m, 1H), 4.46-4.38 (m, 1H), 4.32-4.26 (m, 2H), 4.15-3.98 (m, 1H), 3.86 (s, 1.5H), 3.85 (s, 1.5H), 3.54-3.33 (m, 1H), 2.81-2.45 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.22 (t, J=8 Hz, 1.5H), 1.30-0.95 (m, 4H), 0.61-0.57 (m, 3H); MS(ESI+) m/z 638.3 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][CH:8]([Cl:22])[C:9]([O:11][N:12]=[C:13]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14](O)=[O:15])=[O:10]>C(Cl)Cl>[Cl:7][CH:8]([Cl:22])[C:9]([O:11][N:12]=[C:13]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:14]([Cl:2])=[O:15])=[O:10]
Reactant: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cccs1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1

Procedure:
Phosphorus pentachloride (27.2 g.) was added portionwise during ca. 20 minutes to a stirred and cooled (ice-bath) suspension of 2-dichloroacetoxyimino-2-(thien-2-yl)acetic acid (syn-isomer) (37.0 g.) in methylene chloride (370 ml.). The mixture was stirred at 0° for a further 30 minutes during which time all the solid dissolved. After removal of the solvent under reduced pressure, benzene was evaporated from the residue at 20°, and the process repeated to give 2-dichloroacetoxyimino-2-(thien-2-yl)acetyl chloride (syn-isomer) as an oil that was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][C:25]1[NH:29][N:28]=[C:27]([CH2:30][N:31]2[C:35](=[O:36])[CH2:34][S:33][C:32]2=[O:37])[N:26]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:34]4/[C:35](=[O:36])[N:31]([CH2:30][C:27]5[N:26]=[C:25]([CH3:24])[NH:29][N:28]=5)[C:32](=[O:37])[S:33]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: Cc1nc(CN2C(=O)CSC2=O)n[nH]1
Product: Cc1nc(CN2C(=O)S/C(=C\c3ccc4c(c3)nnn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)n[nH]1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 86) following General Procedure F.