Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][C:30]=1[O:37][CH3:38])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1.C1COCC1>[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]([OH:34])[C:16]([CH3:20])([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]([OH:19])=[O:18])=[CH:31][C:30]=1[O:37][CH3:38])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A stirred solution of LDA in cyclohexane (1.5 M) was cooled to −20° C., to which a solution of 2-phenoxypropionic acid (10 g, 60.2 mmol) in THF (80.3 mL) was slowly added, keeping the temperature below −10° C. The resulting dianion solution was stirred for 15 min, then a solution of 4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) in THF (80.3 mL) was added over 1 h, maintaining temperature below −10° C. Fifteen minutes after completion of aldehyde addition, the reaction mixture was poured onto ice water (200 mL), and extracted using 1:2 Et2O:hexane (500 mL). The aqueous layer was isolated, extracted again with 1:2 Et2O:hexane (240 mL), then acidified with concentrated HCl until pH=3. The product acid was extracted into EtOAc (2×165 mL), which was dried over Na2SO4 and concentrated to an orange paste (16.5 g crude, 67%): MS (EI) 426.2 (M+NH4)+, 407.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[NH:5][C:4](=[O:21])[CH:3]=1.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:11]2[C:9](=[O:10])[CH2:8][C:6]1[NH:5][C:4](=[O:21])[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[CH:28]=2)[N:7]=1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc(=O)[nH]c(CC(=O)N3CCc4c(F)cccc43)n2)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
120 mg of 6-chloro-2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one, 96 mg of 2-methylpyridine-4-boronic acid pinacol ester, 45 mg of tetrakis(triphenylphosphine)palladium(0), 2.5 ml of 1,4-dioxane and 0.52 ml of an aqueous 1.5 M cesium carbonate solution are successively placed in a 5 ml microwave tube. The resulting suspension is stirred under microwave irradiation at a temperature of 100° C. for 2×1 hour. After cooling to ambient temperature, the reaction mixture is diluted with 6 ml of ethyl acetate and then filtered through Clarcel®. The solid is washed with 3 ml of ethyl acetate, and then the filtrate is treated with 12 ml of water and stirred at ambient temperature for 1.5 hours. After settling out, the organic phase is separated and the aqueous phase is extracted with 3×10 ml of ethyl acetate. The organic extracts are combined, washed with 10 ml of saturated brine, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, by making a solid deposit and eluting with a 95/5 v/v dichloromethane/methanol mixture at a flow rate of 25 ml/min. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is taken up twice in diethyl ether, triturated, and then concentrated to dryness under reduced pressure. 46 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylpyridin-4-yl)-3H-pyrimidin-4-one are thus obtained in the form of a white crystalline powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][CH2:13][CH:14]=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:16](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:17]([C:19](O)=[O:20])[CH3:18].O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([CH:19]=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC=O
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C=O)NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Similar to comparative example 4, CTC-Phe-H was synthesized by the solid phase reaction method using CTC as a solid phase carrier. Then, to dichloromethane (2 ml) were added CTC-Phe-H (110 mg (0.145 mmol)), Fmoc-Gly-OH (120 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)), respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml) and dichloromethane (3×2 ml), respectively. Subsequently, to the solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-H. This CTC-Phe-Gly-H was dissolved in dichloromethane (2 ml), and Fmoc-Ala-OH.H2O (130 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)) were added, respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml), and dichloromethane (3×2 ml), respectively. Subsequently, to the solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-Ala-H.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51]CC5C=CC(Cl)=C(Cl)C=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.CCN(CC)CC>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)CO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (1.0 g) was dissolved in EtOAc (4.0 mL), MeOH (12.0 mL), NEt3 (0.236 g), followed by catalytic amount of 10% palladium on activated carbon (wet) was added. After degassing, hydrogen was introduced through a balloon; the reaction mixture was stirred at room temperature for 1.0 hour. The reaction mixture was then filtered through celite, the celite cake was washed three times with ethyl acetate, and the filtrates combined. The solvent was then removed in vacuo, dried under vacuum to get 0.81 g of title compound. LCMS (m/z): 695.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:30][C@H:31]([C:35]([O:37][CH3:38])=[O:36])[C@@H:32]([CH3:34])[OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOCC>[CH2:3]([O:33][C@H:32]([CH3:34])[C@@H:31]([C:35]([O:37][CH3:38])=[O:36])[NH:30][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A 250-mL, round-bottomed flask, under an atmosphere of N2, was charged with sodium hydride (60% oil dispersion, 772 mg, 19.3 mmol). The sodium hydride was washed with 3 portions of hexanes to remove the oil and then 8 mL of anhydrous DMF was added followed by benzyl bromide (3.38 mL, 28.4 mmol). The solution was cooled to 0° C. and then a solution of methyl N-trityl-L-threoninate (4.83 g, 12.9 mmol) dissolved in 12 mL of DMF was added dropwise via cannula over 5 minutes. After stirring for 2 hours, the reaction mixture was treated with saturated aqueous Na2CO3 solution and 200 mL of Et2O and the layers were separated. The organic portion was washed successively with H2O (5×100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 4.61 g of methyl O-benzyl-N-trityl-L-threoninate as a colorless syrup.
Reaction SMILES: Cl.[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH2:7]([CH:9]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][N:11](CC(CC)CCCC)[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:8]>>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH:11][CH2:10][CH:9]([CH2:7][CH3:8])[CH2:28][CH2:29][CH2:30][CH3:31])[CH3:19]
Reactant: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Agent: Cl
Agent: [Al+3]
Agent: [O-2]
Product: CCCCC(CC)CNCC(CC)CCCC

Procedure:
Using a mixture of 1,155 g of tri-(2-ethylhexyl)-amine and 1,155 g of xylene (850 l/hr), 505.4 kg of 9.85 percent strength hydrochloric acid containing sodium chloride (250 ml/hr) were extracted in counter-current at 50° C. in the course of 1,913 hours. The extract was subjected to hydrochloride cleavage in the cleavage column at 148°-152° C.; it gave a total of 46.9 kg of hydrogen chloride, of which about one-third was obtained as concentrated hydrochloric acid, alongside hydrogen chloride gas. Since the cleavage takes place virtually quantitatively, an extraction rate of 94.2% can be calculated from the stated amount of HCl. To regenerate the amine, 100 ml per hour of the bottom product from the cleavage column were constantly passed over the adsorption column filled with aluminum oxide. After completion of the example, 1.036 g out of the 1,155 g of tri-(2-ethylhexyl)-amine employed were recovered unchanged; this corresponds to a loss of 119 g or 10.3% relative to amine employed. In addition, di-(2-ethyl-hexyl)-amine in an amount corresponding to 40 g of tertiary amine preparable therefrom could be isolated from the regeneration process. If this is taken into account, the amine loss is reduced to 6.8%. Relative to hydrogen chloride produced, the amine loss is calculated to be 0.17%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:57](O)=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][C@H:55]([C:57]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 94 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-alanine. Yield 94%. [α]D =+16.3° (c=1.12, dichloromethane). m.p. 103-105°.
Reaction SMILES: [C:1]1([C:7]2([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1(C2C=CC=CC=2)CCC2(CCNCC2)CC1>>[C:1]1([C:7]2([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(N3CCCC3)CCC3(CC2)OCCO3)cc1
Agent: CN(C)C1(c2ccccc2)CCC2(CCNCC2)CC1
Product: O=C1CCC(c2ccccc2)(N2CCCC2)CC1
Yield: 80 %

Procedure:
The reaction was performed starting from 1-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidine in an analogous manner to stage 2 amine (A1). Yield: 80%
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:6][CH2:7]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCCCC[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)O[C@H]1CC[C@H](CCCCCC(=O)O)CC1
Reaction time: 5 h

Procedure:
trans-6-(4-Hydroxycyclohexyl)hexanoic acid (5 g) is dissolved in acetic anhydride (25 ml), and p-toluenesulfonic acid (10 mg) is added to the solution. The mixture is stirred at 60° to 70° C. for an hour. The excess acetic anhydride is distilled off under reduced pressure and, after addition of water, the mixture is stirred at room temperature for 24 hours and then at 50° to 60° C. for further 5 hours and poured into ice-water. The resulting crystalline precipitate is recrystallized from ethanol-water to give 4.93 g (82%) of trans-6-(4-acetoxycyclohexyl)hexanoic acid as colorless needles, m.p. 82°-86° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:14]C([N-]C(C)C)C.CI.CN1C(=O)N(C)CCC1>C1COCC1.O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:14])[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCOC(=O)C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Under N2 atmosphere, a solution of ethyl phenylacetate (800.0 g, 4.87 mol) in anhydrous THF (6.4 L) was cooled to −40° C. and a solution of LDA (2.0 M in heptane/THP, ethylbenzene, 2.43 L, 4.86 mol) was added dropwise over 30 min. The reaction mixture was stirred for 1 h, and methyl iodide (968 g, 6.82 mol) was added dropwise over 20 min, followed by the addition of DMPU (320 mL). After 1 h, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water (6.4 L) and extracted with ethyl acetate (3×1.6 L). The combined organic layers were washed with saturated aqueous NH4Cl solution (1.6 L), 1 N HCl (1.6 L), saturated aqueous NaHCO3 solution (1.6 L), and saturated aqueous NaCl solution (1.6 L). The solution was dried over MgSO4 and concentrated in vacuo. The residue was distilled in high vacuo to give 202 (620.0 g, 72%) as a colorless oil. Bp 55-60° C./0.2 Torr (lit. (Shiner, V. J. et al. J. Am. Chem. Soc. 1961, 83, 593-598) bp 59-60° C./0.3 Torr). 1H NMR (CDCl3): δ 7.36-7.18 (m, 5H), 4.11 (m, 2H), 3.69 (q, 1H, J=7.1), 1.49 (d, 3H, J=7.1), 1.19 (t, 3H, J=7.1). 13C NMR (CDCl3): δ 174.44, 140.73, 128.57, 127.48, 127.04, 60.66, 45.59, 18.66, 14.16.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37]Br>>[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37][N:25]([S:26]([CH3:29])(=[O:28])=[O:27])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][OH:7])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN(Cc1c(Cl)cccc1Cl)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2,6-dichlorobenzyl bromide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2oc(=O)[nH]c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1ccc2oc(=O)n(C)c2c1
Yield: 74.2 %

Procedure:
5-Acetylbenzo[d]oxazol-2(3H)-one (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol), and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 5-acetyl-3-methylbenzo[d]oxazol-2(3H)-one (0.4 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 3.48 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=C)=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[O:34]1CCOCC1>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:34])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:15])=[CH:7]2
Reactant: C=Cc1nc([C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)cc2cccc(Cl)c12
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347) (10.6 g, 23.3 mmol, 1.0 eq) in 1,4-dioxane (200 mL) and water (100 mL), OsO4 (50 mg) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, NaIO4 (15 g, 69.9 mmol, 3.0 eq) was added, and then the mixture was stirred at RT for 16 h. The mixture reaction was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-20% ethyl acetate-petro ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3-fluorophenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.16 g, 92%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:17][O:16][C:4]1[CH:3]=[C:2]([CH:18]=[CH2:19])[N:7]=[N:6][C:5]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
In toluene (2 mL) was dissolved 123 mg (0.490 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 246 mg (0.776 mmol) of tributyl(vinyl) tin, and then, 119 mg (0.103 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours. The reaction mixture was allowed to stand for cooling, ethyl acetate (5 mL), water (3 mL) and sodium fluoride were added to the mixture, and the resulting mixture was stirred for 30 minutes and allowed to stand at room temperature overnight. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated and washed with brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=1:2) to obtain 105 mg (0.434 mmol, Yield: 88.6%) of 4-methoxy-3-(2-methylphenoxy)-6-vinylpyridazine.